研究者データベース

中村 明枝(ナカムラ アキエ)
北海道大学病院 小児・周産・女性科
講師

基本情報

所属

  • 北海道大学病院 小児・周産・女性科

職名

  • 講師

学位

  • 医学博士(北海道大学大学院医学研究科)

J-Global ID

研究分野

  • ライフサイエンス / 代謝、内分泌学

研究活動情報

論文

  • Sayaka Kawashima, Akiko Yuno, Shinichiro Sano, Akie Nakamura, Keisuke Ishiwata, Tomoyuki Kawasaki, Kazuyoshi Hosomichi, Kazuhiko Nakabayashi, Hidenori Akustu, Hirotomo Saitsu, Maki Fukami, Takeshi Usui, Tsutomu Ogata, Masayo Kagami
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2022年07月20日 
    Loss of methylation (LOM) at GNAS-A/B:TSS-differentially methylated regions (DMRs) in the GNAS locus is observed in pseudohypoparathyroidism type 1B (PHP1B). Many PHP1B cases are sporadic, but autosomal dominant-PHP1B has a deletion involving NESP55 expressed from the maternal allele or STX16 located upstream of the GNAS locus on the maternal allele. We report the possible first familial PHP1B cases with retrotransposon insertion in the GNAS locus on the maternal allele. To our knowledge, they are the possible first cases with imprinting disorders caused by retrotransposon insertion. The two sibling cases experienced tetany and/or cramps from school-age and had hypocalcemia and an increased serum intact PTH level together with overweight, round face, and normal intellectual levels. Methylation analysis for DMRs in the GNAS locus showed only LOM of the GNAS-A/B:TSS-DMR. Copy number abnormalities at STX16 and the GNAS locus were not detected by array comparative genomic hybridization. Whole-genome sequencing and Sanger sequencing revealed an approximately 1000-bp SVA retrotransposon insertion upstream of the first exon of A/B on the GNAS locus in these siblings. Whole-genome methylome analysis by Enzymatic Methyl-Seq in the siblings showed normal methylation status in the region surrounding the insertion site and mild LOM of the GNAS-A/B:TSS-DMR. We conducted transcriptome analysis using mRNA from skin fibroblasts and induced pluripotent stem cells (iPSCs) derived from the siblings and detected no aberrant NESP55 transcripts. Quantitative reverse-transcriptase PCR (qRT-PCR) analysis in skin fibroblasts showed increased A/B expression in the patients and no NESP55 expression, even in a control. qRT-PCR analysis in iPSCs showed decreased NESP55 expression with normal methylation status of the GNAS-NESP:TSS-DMR in the patients. The retrotransposon insertion in the siblings likely caused decreased NESP55 expression that could lead to increased A/B expression via LOM of the GNAS-A/B:TSS-DMR, subsequent reduced Gsα expression, and finally, PHP1B development.
  • Tomoko Fuke, Akie Nakamura, Takanobu Inoue, Sayaka Kawashima, Kaori Hara-Isono, Keiko Matsubara, Shinichiro Sano, Kazuki Yamazawa, Maki Fukami, Tsutomu Ogata, Masayo Kagami
    Journal of human genetics 2022年05月24日 
    Silver-Russel syndrome (SRS) is a representative imprinting disorder (ID) characterized by growth failure and diagnosed by clinical features. Recently, international consensus has recommended using the Netchine-Harbison clinical scoring system (NH-CSS) as clinical diagnostic criteria. Loss of methylation of H19/IGF2:intergenic differentially methylated region (H19LOM) and maternal uniparental disomy chromosome 7 (UPD(7)mat) are common etiologies of SRS; however, other IDs, pathogenic variants (PVs) of genes, and pathogenic copy number variants (PCNVs) have been reported in patients meeting NH-CSS. To clarify the frequency and clinical characteristics of each etiology, we conducted (epi)genetic analysis in 173 patients satisfying NH-CSS. H19LOM and UPD(7)mat were identified in 34.1%. PCNVs, other IDs, and PVs were in 15.0%. Patients with all six NH-CSS items were most frequently observed with H19LOM and UPD(7)mat. This study confirmed the suitability of NH-CSS as clinical diagnostic criteria, the (epi)genetic heterogeneity of SRS, and showed the necessity of further discussion regarding the "SRS spectrum".
  • Kaori Hara-Isono, Akie Nakamura, Tomoko Fuke, Takanobu Inoue, Sayaka Kawashima, Keiko Matsubara, Shinichiro Sano, Kazuki Yamazawa, Maki Fukami, Tsutomu Ogata, Masayo Kagami
    The Journal of clinical endocrinology and metabolism 107 8 e3121-e3133  2022年05月18日 
    CONTEXT: Children born small-for-gestational-age with short stature (SGA-SS) is associated with (epi) genetic defects, including imprinting disorders (IDs), pathogenic copy number variants (PCNVs), and pathogenic variants of genes involved in growth. However, comprehensive studies evaluating these three factors are very limited. OBJECTIVE: To clarify the contribution of PCNVs and candidate pathogenic variants to SGA-SS. DESIGN: Comprehensive molecular analyses consisting of methylation analysis, copy number analysis, and multigene sequencing. PATIENTS AND METHODS: We enrolled 140 patients referred to us for genetic testing for SGA-SS. Among them, we excluded 42 patients meeting Netchine-Harbison clinical scoring system criteria for Silver-Russell syndrome (SRS) and four patients with abnormal methylation levels of the IDs-related differentially methylated regions. Consequently, we conducted copy number analysis and multigene sequencing for 86 SGA-SS patients with sufficient sample volume. We also evaluated clinical phenotypes of patients with PCNVs or candidate pathogenic variants. RESULTS: We identified eight (9.3%) and eleven (12.8%) patients with PCNVs and candidate pathogenic variants, respectively. According to the American College of Medical Genetics standards and guidelines, five variants were classified as pathogenic and the remaining six variants were classified as variants of unknown significance. Genetic diagnosis was made in twelve patients. All patients with PCNVs or candidate pathogenic variants did not correspond perfectly to characteristic clinical features of each specific genetic cause. CONCLUSION: We clarified the contribution of PCNVs and pathogenic variants to SGA-SS without IDs. Comprehensive molecular analyses, including copy number analysis and multigene sequencing, should be considered for patients with unknown SGA-SS etiology.
  • Yuki Ueda, Shuta Fujishige, Takeru Goto, Shuhei Kimura, Noriko Namatame, Masashi Narugami, Sachiko Nakakubo, Midori Nakajima, Kiyoshi Egawa, Naoya Kaneko, Kanako Nakayama, Nozomi Hishimura, Takeshi Yamaguchi, Akie Nakamura, Hideaki Shiraishi
    Epilepsia open 7 1 194 - 200 2022年03月 
    Some patients with developmental and epileptic encephalopathy (DEE) respond to adrenocorticotropic hormone (ACTH) therapy but relapse soon after. While long-term ACTH therapy (LT-ACTH) has been attempted for these patients, no previous studies have carefully assessed adrenal function during LT-ACTH. We evaluated the effectiveness of LT-ACTH, as well as adverse effects (AE), including their adrenal function in three DEE patients. Patients underwent a corticotropin-releasing hormone (CRH) stimulation test during LT-ACTH, and those with peak serum cortisol below 15 μg/dL were considered to be at high risk of adrenal insufficiency (AI). Two of three responded, and their life-threatening seizures with postgeneralized electroencephalogram (EEG) suppression decreased. Although no individuals had serious AE, CRH stimulation test revealed relatively weak responses, without reaching normal cortisol peak level (18 μg/dL). Hydrocortisone replacement during stress was prepared in a case with lower cortisol peak than our cutoff level. LT-ACTH could be a promising treatment option for cases of DEE that relapse soon after effective ACTH treatment. The longer duration and larger cumulative dosage in LT-ACTH than in conventional ACTH could increase the relative risk of AI. Careful evaluation with pediatric endocrinologists, including hormonal stimulation tests, might be useful for continuing this treatment safely.
  • 田島 敏広, 中村 明枝, 山口 健史
    日本マス・スクリーニング学会誌 31 2 197 - 197 (一社)日本マススクリーニング学会 2021年09月
  • Hirohito Shima, Etsuro Tokuhiro, Shingo Okamoto, Mariko Nagamori, Tsutomu Ogata, Satoshi Narumi, Akie Nakamura, Yoko Izumi, Tomoko Jinno, Erina Suzuki, Maki Fukami
    Journal of the Endocrine Society 5 7 bvab056  2021年07月01日 
    Introduction: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. Patients and Methods: A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. Results: Sequence analysis identified 2 heterozygous variants of SOX10 (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1-3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1-3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively. Conclusion: These results provide evidence that SOX10 haploinsufficiency accounts for a small percentage of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH.
  • Gerhard Binder, Akie Nakamura, Roland Schweizer, Tsutomu Ogata, Maki Fukami, Keisuke Nagasaki
    The Journal of clinical endocrinology and metabolism 106 5 1491 - 1500 2021年04月23日 
    CONTEXT: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. OBJECTIVE: The objective was to study long-term treatment effects of an aromatase inhibitor. METHODS: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy. RESULTS: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30). CONCLUSION: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.
  • 中山 加奈子, 菱村 希, 山口 健史, 今 雅史, 中村 美智子, 中村 明枝
    日本内分泌学会雑誌 97 1 356 - 356 (一社)日本内分泌学会 2021年04月
  • Tomoko Fuke, Akie Nakamura, Takanobu Inoue, Sayaka Kawashima, Kaori Isono Hara, Keiko Matsubara, Shinichiro Sano, Kazuki Yamazawa, Maki Fukami, Tsutomu Ogata, Masayo Kagami
    The Journal of clinical endocrinology and metabolism 106 3 802 - 813 2021年03月08日 
    BACKGROUND: (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes. SUBJECTS AND METHODS: To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis. RESULTS: These 249 patients with SGA-SS were classified into the "SRS-compatible group" (n = 148), the "non-SRS with normocephaly or relative macrocephaly at birth group" (non-SRS group) (n = 94), or the "non-SRS with relative microcephaly at birth group" (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the "SRS-compatible group," 21.3% of patients in the "non-SRS group," and 14.3% in the "non-SRS with microcephaly group" had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the "SRS-compatible group" and in 13.8% of patients in the "non-SRS group." CONCLUSION: We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.
  • 母体ヨウ化カリウム内服による胎児甲状腺腫,生後の一過性甲状腺機能低下と,引き続く無痛性甲状腺炎を来した1例
    山口 健史, 中山 加奈子, 菱村 希, 中村 明枝, 古瀬 優太, 長 和俊, 横川 涼介, 長谷河 昌孝, 山田 聡, 伊藤 ゆたか, 八鍬 聡, 衣川 佳数, 植竹 公明
    日本小児科学会雑誌 125 2 219 - 219 (公社)日本小児科学会 2021年02月
  • Keisuke Nagasaki, Akie Nakamura, Takeru Yamauchi, Hotaka Kamasaki, Yosuke Hara, Junko Kanno, Satomi Koyama, Yoshiaki Ohtsu, Ikuko Takahashi, Shigeru Suzuki, Kenichi Kashimada, Toshihiro Tajima
    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 30 2 79 - 84 2021年 
    Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune hypothyroidism without goiter. TSH receptor-blocking antibodies (TSBAb) are involved in its etiology in adults. Reportedly, this disease is extremely rare in children. In this study, we aimed to investigate the prevalence of TSBAb during AAT onset in children using a commercially available cell-based bioassay TSAb kit. We conducted a multicenter retrospective observational study. We collected data of patients with AAT who were < 15 yr old, enrolled in a collaborative research group, and diagnosed since July 2003. AAT was defined as acquired autoimmune hypothyroidism without thyroid enlargement. Eighteen patients (including 15 females) whose TSH receptor antibody (TRAb) or TSBAb levels were measured within a year from the initial visit were included. The median age at diagnosis was 9.3 years, and the estimated time between onset and diagnosis was 2.6 yr. The positive rate for either TSBAb or TRAb was 38.8% (95% confidence interval: 18.3-59.5%). There were no significant differences in age, the estimated time between onset and diagnosis, and FT4 levels at diagnosis between the TSBAb-positive and -negative groups. Unlike previous reports, we showed that the prevalence of TSBAb-positivity in childhood-onset AATs is not rare, as in adults.
  • 発達性てんかん性脳症に対するACTH週1回長期療法時の副腎機能の検討
    植田 佑樹, 木村 修平, 後藤 健, 中久保 佐千子, 生田目 紀子, 鳴神 雅史, 中山 加奈子, 菱村 希, 山口 健史, 中村 明枝, 江川 潔, 白石 秀明
    てんかん研究 38 3 223 - 223 (一社)日本てんかん学会 2021年01月
  • 横川 涼介, 伊藤 ゆたか, 長谷河 昌孝, 山田 聡, 八鍬 聡, 衣川 佳数, 植竹 公明, 山口 健史, 中村 明枝, 古瀬 優太, 長 和俊
    日本内分泌学会雑誌 96 3 595 - 595 (一社)日本内分泌学会 2021年01月
  • 平松 泰好, 植竹 公明, 中山 加奈子, 菱村 希, 山口 健史, 鈴木 滋, 中村 明枝
    日本内分泌学会雑誌 96 3 596 - 596 (一社)日本内分泌学会 2021年01月
  • Takayuki Okamoto, Akie Nakamura, Asako Hayashi, Takeshi Yamaguchi, Yayoi Ogawa, Ken Natsuga, Kumiko Yanagi, Kiyohiko Hotta
    PEDIATRIC TRANSPLANTATION 2021年01月 
    Background ILNEB constitute an autosomal recessive disorder caused by homozygous or compound heterozygous mutation of the gene for the ITGA3. To date, 8 ILNEB patients have been reported, but all 6 neonatal-onset ILNEB patients suffered early death within 2 years. The most common cause of death among previously reported ILNEB patients was exacerbation of the respiratory condition.Methods In this study, we describe a case of ILNEB with neonatal onset in a female patient and the genetic and histopathological testing performed.Results Our patient had a compound heterozygous mutation in ITGA3. Compared to previously reported patients, this patient exhibited milder clinical and histopathological characteristics. After experiencing a life-threatening respiratory infection at 8 months old, the patient started periodic subcutaneous immunoglobulin treatment once every 1-2 weeks for nephrotic-range proteinuria-induced secondary hypogammaglobulinemia. At the age of 3 years, proteinuria gradually increased with severe edema despite strict internal management. Therefore, our patient underwent unilateral nephrectomy and insertion of a peritoneal dialysis catheter followed by another unilateral nephrectomy. One month later, she underwent an ABO-compatible living-donor kidney transplantation at the age of 4 years.Conclusions Our patient is a neonatal-onset ILNEB patient who survived for more than 2 years and underwent successful kidney transplantation.
  • 中山 加奈子, 中村 明枝, 橋本 佳帆子, 鎌田 瑛理, 菱村 希, 山口 健史, 井口 晶裕, 本多 昌平, 木田 毅, 真部 淳
    日本内分泌学会雑誌 96 2 552 - 552 (一社)日本内分泌学会 2020年10月
  • 山口 健史, 山田 聡, 植竹 公明, 中山 加奈子, 菱村 希, 中村 明枝
    日本内分泌学会雑誌 96 2 552 - 552 (一社)日本内分泌学会 2020年10月
  • 中山 加奈子, 菱村 希, 山口 健史, 石津 桂, 山岸 卓也, 田島 敏広, 中村 明枝
    日本内分泌学会雑誌 96 1 251 - 251 (一社)日本内分泌学会 2020年08月
  • 鏡 雅代, 湯野 暁子, 佐野 伸一朗, 中村 明枝, 川嶋 明香, 松原 圭子, 細道 一善, 深見 真紀, 臼井 健, 才津 浩智, 緒方 勤
    日本内分泌学会雑誌 96 1 246 - 246 (一社)日本内分泌学会 2020年08月
  • カテコラミン過剰に伴う症状を契機に診断に至った神経芽腫の1例
    橋本 佳帆子, 中山 加奈子, 山口 健史, 原 和也, 寺下 友佳代, 杉山 未奈子, 長 祐子, 井口 晶裕, 本多 昌平, 中村 明枝, 真部 淳
    日本小児科学会雑誌 124 7 1156 - 1156 (公社)日本小児科学会 2020年07月
  • Kazuki Yamazawa, Takanobu Inoue, Yoshihiro Sakemi, Toshinori Nakashima, Hironori Yamashita, Kaduki Khono, Hideki Fujita, Keisuke Enomoto, Kazuhiko Nakabayashi, Kenichiro Hata, Moeko Nakashima, Tatsuo Matsunaga, Akie Nakamura, Keiko Matsubara, Tsutomu Ogata, Masayo Kagami
    Journal of medical genetics 58 6 427 - 432 2020年06月23日 [査読有り][通常論文]
     
    BACKGROUND: ZNF597, encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of ZNF597 is regulated by the ZNF597:TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of ZNF597 may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported. METHODS: A 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted. RESULTS: Isolated hypomethylation of the ZNF597:TSS-DMR and subsequent loss of imprinting and overexpression of ZNF597 were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically. CONCLUSION: We report the first case of isolated ZNF597 imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the ZNF597 imprinted domain can be speculated.
  • Takanobu Inoue, Akie Nakamura, Megumi Iwahashi-Odano, Kanako Tanase-Nakao, Keiko Matsubara, Junko Nishioka, Yoshihiro Maruo, Yukihiro Hasegawa, Hiroshi Suzumura, Seiji Sato, Yoshiyuki Kobayashi, Nobuyuki Murakami, Kazuhiko Nakabayashi, Kazuki Yamazawa, Tomoko Fuke, Satoshi Narumi, Akira Oka, Tsutomu Ogata, Maki Fukami, Masayo Kagami
    Clinical epigenetics 12 1 86 - 86 2020年06月16日 [査読有り][通常論文]
     
    BACKGROUND: Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype. RESULTS: Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS. CONCLUSIONS: We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.
  • Takeshi Yamaguchi, Akie Nakamura, Kanako Nakayama, Nozomi Hishimura, Shuntaro Morikawa, Katsura Ishizu, Toshihiro Tajima
    The Journal of clinical endocrinology and metabolism 105 8 2020年05月27日 [査読有り][通常論文]
     
    PURPOSE: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, however, its molecular etiology remains poorly understood. METHODS: We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases (57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed). The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern and published evidence. Further, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity. RESULTS: We identified variants in 66.5% cases (111/167) and fifteen genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167), however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that three out of 32 cases with TD (9.4%) had pathogenic variants (two of TSHR and one of TPO), eight out of 57 cases with DH (14.0%) (seven of DUOX2, one of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group. CONCLUSIONS: The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.
  • Taisuke Sato, Takashi Kojima, Osamu Samura, Satoshi Kawaguchi, Akie Nakamura, Masahiro Nakajima, Akiko Tanuma-Takahashi, Kazuhiko Nakabayashi, Kenichiro Hata, Shiro Ikegawa, Gen Nishimura, Aikou Okamoto, Takahiro Yamada
    American journal of medical genetics. Part A 182 4 735 - 739 2020年04月 [査読有り][通常論文]
     
    We present two unrelated Japanese pedigrees with achondrogenesis type 1b (ACG1B), characterized by prenatally lethal fetal hydrops and severe micromelia. The affected members in these pedigrees carried a common homozygous missense point mutation in solute carrier family 26 member 2 (SLC26A2), a gene associated with ACG1B (NM_000112:c.1987G>A). This loss-of-function point mutation causes substitution of glycine 663 with arginine in a highly conserved loop domain of SLC26A2. Interestingly, only a few cases of this mutation have been registered in Japanese genomic databases, and there are no reports of this mutation in any major genomic databases outside Japan. Furthermore, we confirmed the presence of a homozygous stretch of approximately 75 kb surrounding the pathogenic variant. Our findings suggest that this missense point mutation in SLC26A2, which is likely the cause of the ACG1B phenotypes in these unrelated fetuses, is distributed exclusively in Japan.
  • Sho Katayama, Hiroaki Iwata, Yukiko Nomura, Akie Nakamura, Takeshi Yamaguchi, Nozomi Hishimura, Kanako Nakayama, Kahoko Hashimoto, Shohei Honda, Hiroshi Shimizu
    The Journal of dermatology 47 3 e92-e93  2020年03月 [査読有り][通常論文]
  • 中村 明枝, 小林 良二, 鈴木 大介, 堀 大起, 藤倉 かおり, 山口 健史, 菱村 希, 中山 加奈子
    日本内分泌学会雑誌 95 4 1523 - 1523 (一社)日本内分泌学会 2020年02月
  • カテコラミン過剰症状を伴い褐色細胞腫との鑑別を要した神経芽腫の一例
    中山 加奈子, 菱村 希, 山口 健史, 中村 明枝
    日本小児科学会雑誌 124 2 281 - 281 (公社)日本小児科学会 2020年02月
  • 山口 健史, 中村 明枝, 中山 加奈子, 菱村 希, 橋本 佳帆子, 長 祐子, 本多 昌平, 真部 淳
    日本内分泌学会雑誌 95 3 873 - 873 (一社)日本内分泌学会 2020年01月
  • Karl L Insogna, Frank Rauch, Peter Kamenický, Nobuaki Ito, Takuo Kubota, Akie Nakamura, Lin Zhang, Matt Mealiffe, Javier San Martin, Anthony A Portale
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 12 2183 - 2191 2019年12月 
    In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, -54%, osteoid thickness, -32%, osteoid surface/bone surface, -26%, [median] mineralization lag time, -83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
  • 渡邊 さやか, 中村 明枝, 山口 健史, 石津 桂, 田島 敏広
    日本マス・スクリーニング学会誌 29 3 273 - 277 日本マススクリーニング学会 2019年12月 
    21水酸化酵素欠損症(21-hydroxylase deficiency:21-OHD)、特に塩喪失型患者において挙児希望を持たない女性が多いことは、21-OHD女性の妊娠出産率が低い原因の一つである。近年、適切な管理により妊娠分娩に至った21-OHD症例の報告が増加している。今回、良好なコントロールのもと自然妊娠が成立し、無事出産に至った塩喪失型21-OHD成人女性の一例を報告する。症例は28歳の21-OHD女性。疾患に対する理解は良好で、性自認は女性、性的指向は異性であり将来の結婚妊娠の意志があり、24歳時に内服薬をフルドロコルチゾンとデキサメサゾンの併用からプレドニゾロンに変更し、アドヒアランスは良好で月経は規則的に認められていた。26歳で結婚し、28歳で自然妊娠した。妊娠中のコントロールは良好でテストステロンや17α-hydroxyprogesterone(17-OHP)、アルドステロン値は妊婦の正常範囲で経過していた。38週0日で選択的帝王切開にて分娩、身長47.4cm、体重2,950gの男児が出生した。マススクリーニングで児の17-OHPの上昇は認められず、その後の成長発達は良好である。適切な副腎コントロールのもと、小児期・思春期から疾患に対する理解の確認や教育、妊娠出産に向けた情報提供により、良好な妊娠出産経過を得られる21-OHD女性例は増加すると考えられる。21-OHD女性の妊娠管理においては、正常妊婦におけるホルモン値も考慮した上で、慎重な観察と調整が必要である。(著者抄録)
  • 岡本 孝之, 中村 明枝, 林 麻子, 山口 健史, 高橋 俊行, 上田 泰弘, 佐藤 泰征, 柳 久美子, 要 匡, 有賀 正
    日本小児腎臓病学会雑誌 32 2 140 - 140 (一社)日本小児腎臓病学会 2019年11月 [査読有り][通常論文]
  • 中村 明枝, 小林 良二, 鈴木 大介, 堀 大起, 藤倉 かおり, 山口 健史, 菱村 希, 中山 加奈子
    日本マス・スクリーニング学会誌 29 2 227 - 227 日本マススクリーニング学会 2019年10月
  • Takanobu Inoue, Hideaki Yagasaki, Junko Nishioka, Akie Nakamura, Keiko Matsubara, Satoshi Narumi, Kazuhiko Nakabayashi, Kazuki Yamazawa, Tomoko Fuke, Akira Oka, Tsutomu Ogata, Maki Fukami, Masayo Kagami
    Journal of medical genetics 56 6 413 - 418 2019年06月 [査読有り][通常論文]
     
    BACKGROUND: Recently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features. OBJECTIVE: To clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS. METHODS: We studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR. RESULTS: We identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes. CONCLUSION: We suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.
  • 岡本 孝之, 中村 明枝, 林 麻子, 山口 健史, 高橋 俊行, 上田 泰弘, 佐藤 泰征, 柳 久美子, 要 匡, 有賀 正
    日本小児腎臓病学会雑誌 32 1Suppl. 94 - 94 (一社)日本小児腎臓病学会 2019年05月 [査読有り][通常論文]
  • 中山 加奈子, 菱村 希, 山口 健史, 森川 俊太郎, 石津 桂, 依藤 亨, 田島 敏弘, 中村 明枝
    日本内分泌学会雑誌 95 1 351 - 351 (一社)日本内分泌学会 2019年04月
  • 中山 加奈子, 菱村 希, 山口 健史, 森川 俊太郎, 石津 桂, 依藤 亨, 田島 敏弘, 中村 明枝
    日本内分泌学会雑誌 95 1 379 - 379 (一社)日本内分泌学会 2019年04月
  • 山口 健史, 中村 明枝, 中山 加奈子, 菱村 希, 石津 桂, 田島 敏広
    日本内分泌学会雑誌 95 1 397 - 397 (一社)日本内分泌学会 2019年04月
  • 1A型糖尿病におけるインスリン治療開始前の低血糖 後方視的観察研究
    蜂屋 瑠見, 山口 健史, 渡邊 さやか, 澤野 堅太郎, 森川 俊太郎, 中村 明枝, 長谷川 行洋
    糖尿病 62 Suppl.1 S - 286 (一社)日本糖尿病学会 2019年04月
  • Masayo Kagami, Atsuhiro Yanagisawa, Miyuki Ota, Kentaro Matsuoka, Akie Nakamura, Keiko Matsubara, Kazuhiko Nakabayashi, Shuji Takada, Maki Fukami, Tsutomu Ogata
    Clinical epigenetics 11 1 42 - 42 2019年03月07日 [査読有り][通常論文]
     
    BACKGROUND: The human chromosome 14q32.2 imprinted region harbors the primary MEG3/DLK1:IG-differentially methylated region (DMR) and secondary MEG3:TSS-DMR. The MEG3:TSS-DMR can remain unmethylated only in the presence of unmethylated MEG3/DLK1:IG-DMR in somatic tissues, but not in the placenta, because of a hierarchical regulation of the methylation pattern between the two DMRs. METHODS: We performed molecular studies in a 4-year-old Japanese girl with Temple syndrome (TS14). RESULTS: Pyrosequencing analysis showed extremely low methylation levels of five CpGs at the MEG3:TSS-DMR and grossly normal methylation levels of four CpGs at the MEG3/DLK1:IG-DMR in leukocytes. HumanMethylation450 BeadChip confirmed marked hypomethylation of the MEG3:TSS-DMR and revealed multilocus imprinting disturbance (MLID) including mild hypomethylation of the H19/IGF2:IG-DMR and mild hypermethylation of the GNAS A/B:TSS-DMR in leukocytes. Bisulfite sequencing showed markedly hypomethylated CpGs at the MEG3:TSS-DMR and irregularly and non-differentially methylated CpGs at the MEG3/DLK1:IG-DMR in leukocytes and apparently normal methylation patterns of the two DMRs in the placenta. Maternal uniparental disomy 14 and a deletion involving this imprinted region were excluded. CONCLUSIONS: Such a methylation pattern of the MEG3/DLK1:IG-DMR has not been reported in patients with TS14. It may be possible that a certain degree of irregular hypomethylation at the MEG3/DLK1:IG-DMR has prevented methylation of the MEG3:TSS-DMR in somatic tissues and that a hypermethylation type MLID has occurred at the MEG3/DLK1:IG-DMR to yield the apparently normal methylation pattern in the placenta.
  • Takeshi Yamaguchi, Rumi Hachiya, Sayaka Watanabe-Yamamoto, Kentaro Sawano, Shuntaro Morikawa, Akie Nakamura, Yukihiro Hasegawa
    Diabetes research and clinical practice 147 87 - 92 2019年01月 
    AIMS: There are as yet no cohort studies of hypoglycemia in type 1 diabetes before starting insulin therapy. Our aim was to determine the frequency and clinical features of hypoglycemia in patients with type 1A diabetes prior to commencing insulin therapy. METHODS: Eighty-seven patients with type 1A diabetes were enrolled, and a retrospective chart review of the patients was conducted. RESULTS: Hypoglycemia before insulin therapy occurred in six of 87 patients (6.9%). The HbA1c levels at the diagnosis of type 1A diabetes in the hypoglycemia group were lower than in the non-hypoglycemia group (median: 7.3% (56 mmol/mol) vs. 11.9% (106 mmol/mol), p < 0.0001). Similarly, the 24-hour urinary C-peptide (UCPR) levels of the former group were higher than those of the latter group (16.5 μg/day/m2 vs. 7.0 μg/day/m2, p = 0.0075). Hypoglycemic episodes occurred mostly in the postprandial period and gradually disappeared with a decrease in insulin secretion. CONCLUSIONS: We demonstrated that some patients with type 1A diabetes experience hypoglycemic episodes before insulin therapy. Patients with early-stage type 1A diabetes with relatively low HbA1c or high UCPR have a risk of hypoglycemia. These findings may impact when and how insulin is introduced in the treatment of early-stage type 1A diabetes.
  • Toshihiro Tajima, Akie Nakamura, Makiko Oguma, Masayo Yamazaki
    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 28 3 69 - 79 2019年 
    Congenital central hypothyroidism (C-CH) is caused by defects in the secretion of thyrotropin-releasing hormone (TRH) and/or TSH, leading to an impairment in the release of hormones from the thyroid. The causes of C-CH include congenital anomalies of the hypothalamic-pituitary regions and several genetic defects. In terms of endocrinology, C-CH is divided into two categories: (1) accompanied by another pituitary hormone deficiency and called combined pituitary hormone deficiency, and (2) isolated C-CH, showing mainly TSH deficiency. For isolated C-CH, a mutation in the TSH gene (TSHB) encoding the β-subunit of the protein was first found in 1990 by Japanese researchers, and thereafter several mutations in TSHB have been reported. Mutations in the thyrotropin-releasing hormone receptor gene (TRHR), as well as genetic defects in immunoglobulin superfamily 1 (IGSF1), have also been identified. It was recently found that isolated C-CH is caused by mutations in transducin β-like 1 X-linked and insulin receptor substrate 4. It is noted that all patients with TSHB deficiency and some with IGSF1 deficiency show severe hypothyroidism soon after birth. Among the causes of C-CH, high frequency of mutations in IGSF1 is the most prevalent. This review focuses on recent findings on isolated C-CH.
  • Erina Suzuki, Hirohito Shima, Masayo Kagami, Shun Soneda, Toshiaki Tanaka, Shuichi Yatsuga, Junko Nishioka, Yuji Oto, Toshiya Kamiya, Yasuhiro Naiki, Tsutomu Ogata, Yasuko Fujisawa, Akie Nakamura, Sayaka Kawashima, Shuntaro Morikawa, Reiko Horikawa, Shinichiro Sano, Maki Fukami
    Human genome variation 6 7 - 7 2019年 [査読有り][通常論文]
     
    We sequenced MKRN3, the major causative gene of central precocious puberty in Western countries, in 24 Japanese or Chinese patients and examined the DNA methylation and copy-number statuses of this gene in 19 patients. We identified no (epi)genetic defects except for one previously reported mutation. These results, together with reports from Korea, indicate that MKRN3 defects are rare in Asian populations. The ethnic differences likely reflect Western country-specific founder mutations and the rarity of de novo mutations.
  • Akie Nakamura, Koji Muroya, Hiroko Ogata-Kawata, Kazuhiko Nakabayashi, Keiko Matsubara, Tsutomu Ogata, Kenji Kurosawa, Maki Fukami, Masayo Kagami
    Journal of medical genetics 55 8 567 - 570 2018年08月 [査読有り][通常論文]
     
    BACKGROUND: Paternal uniparental disomy for chromosome 7 (upd(7)pat) is extremely rare, and only four cases have been previously reported. As these cases were accompanied by autosomal-recessive disorders which are likely to be involved in growth restriction, the relevance of upd(7)pat to the overgrowth phenotype remains unclear. Here we describe one case of upd(7)pat with no additional genetic diseases, which may answer the question. METHODS: A 5-year-old Japanese boy presented with a tall stature of unknown causes. To detect the genetic cause of the tall stature, we performed Sanger sequencing, targeted resequencing, comparative genomic hybridisation and single-nucleotide polymorphism (SNP) array analyses, methylation analysis and microsatellite analysis. RESULTS: We could not detect pathogenic variants in causative genes for overgrowth syndrome or apparent copy number alterations. DNA methylation analysis revealed hypomethylation at the GRB10, PEG1 and PEG10 differentially methylated regions. SNP array and microsatellite analyses suggested paternal uniparental isodisomy for chromosome 7. Furthermore, we could not identify homozygous mutations of known causative genes for inherited disorders on chromosome 7. CONCLUSION: We report the first case of upd(7)pat with an overgrowth phenotype.
  • 渡邊 さやか, 中村 明枝, 山口 健史, 石津 桂, 田島 敏広
    日本マス・スクリーニング学会誌 28 2 245 - 245 日本マススクリーニング学会 2018年07月
  • Shigeru Nakamura, Yoshitomo Kobori, Yoshihiko Ueda, Yoko Tanaka, Hiromichi Ishikawa, Atsumi Yoshida, Momori Katsumi, Kazuki Saito, Akie Nakamura, Tsutomu Ogata, Hiroshi Okada, Hideo Nakai, Mami Miyado, Maki Fukami
    Human mutation 39 6 830 - 833 2018年06月 [査読有り][通常論文]
     
    STX2 encodes a sulfoglycolipid transporter. Although Stx2 nullizygosity is known to cause spermatogenic failure in mice, STX2 mutations have not been identified in humans. Here, we performed STX2 mutation analysis for 131 Japanese men clinically diagnosed with nonobstructive azoospermia. As a result, we identified a homozygous frameshift mutation [c.8_12delACCGG, p.(Asp3Alafs*8)] in one patient. The mutation-positive patient exhibited loss-of-heterozygosity for 58.4 Mb genomic regions involving STX2, suggesting possible parental consanguinity. The patient showed azoospermia, relatively small testes, and a mildly elevated follicle stimulating hormone level, but no additional clinical features. Testicular histology of the patient showed universal maturation arrest and multinucleated spermatocytes, which have also been observed in mice lacking Stx2. PCR-based cDNA screening revealed wildtype STX2 expression in various tissues including the testis. Our results indicate that STX2 nullizygosity results in nonsyndromic maturation arrest with multinucleated spermatocytes, and accounts for a small fraction of cases with nonobstructive azoospermia.
  • Sayaka Kawashima, Akie Nakamura, Takanobu Inoue, Keiko Matsubara, Reiko Horikawa, Keiko Wakui, Kyoko Takano, Yoshimitsu Fukushima, Toshi Tatematsu, Seiji Mizuno, Junko Tsubaki, Shigeo Kure, Yoichi Matsubara, Tsutomu Ogata, Maki Fukami, Masayo Kagami
    The Journal of clinical endocrinology and metabolism 103 6 2083 - 2088 2018年06月01日 [査読有り][通常論文]
     
    Context: Maternal uniparental disomy for chromosome 20 [UPD(20)mat], resulting in aberrant expression of imprinted transcripts at the GNAS locus, is a poorly characterized condition. These patients manifested a phenotype similar to that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS); however, the etiological relationship between UPD(20)mat and SRS/SGA-SS remains unclear. Moreover, no report has described endocrinological assessment of UPD(20)mat patients, although paternal UPD(20), the mirror image entity of UPD(20)mat, is known to cause multiple hormone resistance reflecting reduced α-subunit of the stimulatory G protein expression. Participants: Patients 1 to 5 showed nonmosaic heterodisomy and/or isodisomy for the entire chromosome 20. Patients 1 to 3 and 4 were identified through UPD(20)mat screening for 55 patients with etiology-unknown SRS and 96 patients with SGA-SS, respectively. Patient 5 was identified through molecular analysis for patients with developmental defects. Patients 1 to 5 manifested postnatal growth failure and feeding problems, with or without developmental delay, and other clinical features. Patients 1 to 4 were born SGA. Patients 4 and 5 exhibited hypercalcemia and low or low-normal parathyroid hormone levels. Patient 1 showed constantly decreased thyroid-stimulating hormone (TSH) levels after 12 years of age, although she had a normal TSH level at 5.2 years of age. Conclusion: The results suggest that UPD(20)mat underlies growth failure and feeding problems with additional features and could account for >5% of etiology-unknown SRS and small percentages of SGA-SS. Most important, this study provides an indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age.
  • 田島 敏広, 中村 明枝, 山口 健史, 渡邊 さやか, 小熊 真紀子
    日本内分泌学会雑誌 94 1 170 - 170 (一社)日本内分泌学会 2018年04月
  • 山本 さやか, 山口 健史, 森川 俊太郎, 本多 昌平, 中村 明枝
    日本内分泌学会雑誌 94 1 276 - 276 (一社)日本内分泌学会 2018年04月
  • 山口 健史, 蜂屋 瑠見, 山本 さやか, 森川 俊太郎, 中村 明枝, 長谷川 行洋
    日本内分泌学会雑誌 94 1 334 - 334 (一社)日本内分泌学会 2018年04月
  • Takeshi Yamaguchi, Tomoyuki Hothubo, Shuntaro Morikawa, Akie Nakamura, Toshihiko Mori, Toshihiro Tajima
    Journal of pediatric endocrinology & metabolism : JPEM 31 3 355 - 359 2018年03月28日 [査読有り][通常論文]
     
    BACKGROUND: IGSF1 abnormality causes diverse symptoms, including congenital central hypothyroidism (CCH), prolactin hyposecretion, testicular enlargement and delayed puberty. CASE PRESENTATION: Here, we report a case of a male patient who visited our hospital with a chief complaint of abdominal pain and short stature, in whom we identified a novel IGSF1 mutation. He was closely examined because of chronic constipation since infancy, persistent abdominal pain at 14 years of age and marked short stature (-4.7 standard deviation [SD] for normal Japanese boys). He was diagnosed with CCH. Decreased prolactin (PRL) secretion was also observed. IGSF1 analysis revealed a novel mutation at the splicing donor site (c.2065+1G>A) in intron 11. In silico analysis predicted this mutation to be a non-functional splice donor site. After thyroid hormone replacement, his thyroid function, constipation and growth rate improved. CONCLUSIONS: This is the first report of a patient in whom constipation and short stature led to a diagnosis of CCH with a novel IGSF1 mutation.
  • M. Okuno, T. Ayabe, I. Yokota, I. Musha, K. Shiga, T. Kikuchi, N. Kikuchi, A. Ohtake, A. Nakamura, K. Nakabayashi, K. Okamura, Y. Momozawa, M. Kubo, J. Suzuki, T. Urakami, T. Kawamura, S. Amemiya, T. Ogata, S. Sugihara, M. Fukami, The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes
    Diabetic Medicine 35 3 376 - 380 2018年03月01日 [査読有り][通常論文]
     
    Aim: To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. Methods: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. Results: One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. Conclusions: The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation.
  • Ushijima K, Yatsuga S, Matsumoto T, Nakamura A, Fukami M, Kagami M
    Journal of human genetics 63 3 377 - 381 2018年03月01日 [査読有り][通常論文]
     
    The predominant symptoms of trisomy 14 mosaicism are prenatal and postnatal growth failure, ear abnormalities, congenital heart disease, developmental delay, and genitourinary abnormalities. Maternal uniparental disomy of chromosome 14 (upd(14)mat) presents discernible clinical features such as prenatal and postnatal growth failure, hypotonia, precocious puberty, and obesity. Given the small number of previously reported patients with a combination of trisomy 14 mosaicism and upd(14)mat, the detailed clinical features of these patients remain to be elucidated. Here we report a severely short-statured girl with feeding difficulties and failure to thrive, ear abnormalities, deafness, small hands, and developmental delay. Karyotyping, FISH analysis, methylation analysis, and microsatellite marker analysis using her leukocytes and buccal cells showed that she had a combination of trisomy 14 mosaicism and upd(14)mat. Furthermore, a comparison of the clinical features of this patient with those of previously reported patients with genetic anomalies including the combination of trisomy 14 mosaicism and upd(14)mat or upd(14)mat suggested that the severe short stature observed in patients with a combination of trisomy 14 mosaicism and upd(14)mat stemmed from the synergic effect of these two events. In severely short-statured patients with trisomy 14 mosaicism, we should be aware of the possible coexistence of upd(14)mat.
  • Kikumi Ushijima, Maki Fukami, Tadayuki Ayabe, Satoshi Narumi, Misako Okuno, Akie Nakamura, Toshikazu Takahashi, Kenji Ihara, Kazuhiro Ohkubo, Emiko Tachikawa, Shoji Nakayama, Junichi Arai, Nobuyuki Kikuchi, Toru Kikuchi, Tomoyuki Kawamura, Tatsuhiko Urakami, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Shin Amemiya, Tsutomu Ogata, Ichiro Yokota, Shigetaka Sugihara
    Pediatric diabetes 19 2 243 - 250 2018年03月 [査読有り][通常論文]
     
    BACKGROUND: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). OBJECTIVES: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. METHODS: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. RESULTS: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. CONCLUSIONS: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.
  • Noriko Namatame-Ohta, Shuntaro Morikawa, Akie Nakamura, Kumihiro Matsuo, Masahide Nakajima, Kazuhiro Tomizawa, Yusuke Tanahashi, Toshihiro Tajima
    Case reports in pediatrics 2018 6561952 - 6561952 2018年 
    Almost 90% of nephrogenic diabetes insipidus (NDI) is caused by mutations in the arginine vasopressin receptor 2 gene (AVPR2) on the X chromosome. Herein, we reported clinical and biochemical parameters in four cases of three unrelated Japanese families and analyzed the status of the AVPR2. Two of the four patients had poor weight gain. However, in the male and female sibling cases, neither had poor weight gain while toddlers, but in the male sibling, episodes of recurrent fever, polyuria, and polydipsia led to the diagnosis of NDI at 4 years of age. Analysis of AVPR2 identified two nonsense mutations (c.299_300insA; p.K100KfsX91 and c.296G > A; p.W99X) and one missense mutation (c.316C > T; p.R106C). These mutations were previously reported. The patient with c.316C > T; p.R106C had milder symptoms consistent with previous reports. Of the familial cases, the sister was diagnosed as having NDI, but a skewed X-inactivation pattern in her peripheral blood lymphocytes was not identified. In conclusion, our study expands the spectrum of phenotypes and characterized mutations in AVPR2 in NDI.
  • 山口 健史, 渡邊 さやか, 中村 明枝, 有賀 正, 齋 秀二
    The Lipid 29 1 116 - 116 (株)メディカルレビュー社 2018年01月
  • Shinichiro Sano, Akie Nakamura, Keiko Matsubara, Keisuke Nagasaki, Maki Fukami, Masayo Kagami, Tsutomu Ogata
    Journal of the Endocrine Society 2 1 9 - 23 2018年01月01日 [査読有り][通常論文]
     
    Context: Pseudohypoparathyroidism type I (PHP-I) is divided into PHP-Ia with Albright hereditary osteodystrophy and PHP-Ib, which usually shows no Albright hereditary osteodystrophy features. Although PHP-Ia and PHP-Ib are typically caused by genetic defects involving α subunit of the stimulatory G protein (Gsα)-coding GNAS exons and methylation defects of the GNAS differentially methylated regions (DMRs) on the maternal allele, respectively, detailed phenotypic characteristics still remains to be examined. Objective: To clarify phenotypic characteristics according to underlying (epi)genetic causes. Patients and Methods: We performed (epi)genotype-phenotype analysis in 69 Japanese patients with PHP-I; that is, 28 patients with genetic defects involving Gsα-coding GNAS exons (group 1) consisting of 12 patients with missense variants (subgroup A) and 16 patients with null variants (subgroup B), as well as 41 patients with methylation defects (group 2) consisting of 21 patients with broad methylation defects of the GNAS-DMRs (subgroup C) and 20 patients with an isolated A/B-DMR methylation defect accompanied by the common STX16 microdeletion (subgroup D). Results: Although (epi)genotype-phenotype findings were grossly similar to those reported previously, several important findings were identified, including younger age at hypocalcemic symptoms and higher frequencies of hyperphosphatemia in subgroup C than in subgroup D, development of brachydactyly in four patients of subgroup C, predominant manifestation of subcutaneous ossification in subgroup B, higher frequency of thyrotropin resistance in group 1 than in group 2, and relatively low thyrotropin values in four patients with low T4 values and relatively low luteinizing hormone/follicle-stimulating hormone values in five adult females with ovarian dysfunction. Conclusion: The results imply the presence of clinical findings characteristic of each underlying cause and provide useful information on the imprinting status of Gsα.
  • Inoue Takanobu, Yagasaki Hideaki, Nishioka Junko, Nakamura Akie, Matsubara Keiko, Narumi Satoshi, Nakabayashi Kazuhiko, Yamazawa Kazuki, Fuke Tomoko, Oka Akira, Ogata Tsutomu, Fukami Maki, Kagami Masayo
    HORMONE RESEARCH IN PAEDIATRICS 90 122 - 123 2018年 [査読有り][通常論文]
  • Kawashima Sayaka, Nakamura Akie, Inoue Takanobu, Matsubara Keiko, Horikawa Reiko, Wakui Keiko, Takano Kyoko, Fukushima Yoshimitsu, Tatematsu Toshi, Mizuno Seiji, Tsubaki Junko, Kure Shigeo, Matsubara Yoichi, Ogata Tsutomu, Nagasaki Keisuke, Fukami Maki, Kagami Masayo
    HORMONE RESEARCH IN PAEDIATRICS 90 432  2018年 [査読有り][通常論文]
  • Katoh-Fukui Y, Yatsuga S, Shima H, Hattori A, Nakamura A, Okamura K, Yanagi K, Iso M, Kaname T, Matsubara Y, Fukami M
    Human genome variation 5 18006 - 18006 2018年 [査読有り][通常論文]
     
    CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous CHD7 mutations. A de novo variant in a CHD7 splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an "unclassified variant" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.
  • 田島 敏広, 中村 明枝, 森川 俊太郎, 山口 健史
    日本内分泌学会雑誌 93 4 1295 - 1295 (一社)日本内分泌学会 2017年12月
  • Shuntaro Morikawa, Toshihiro Tajima, Akie Nakamura, Katsura Ishizu, Tadashi Ariga
    PEDIATRIC DIABETES 18 8 934 - 941 2017年12月 [査読有り][通常論文]
     
    BackgroundWolfram syndrome (WS) is a disorder characterized by the association of insulin-dependent diabetes mellitus (DM), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum (ER). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as ER stress. This is attenuated by the unfolded protein response (UPR), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11-month-old Japanese female WS patient with insulin-dependent DM, congenital cataract and severe bilateral hearing loss. ObjectiveAnalyze the WFS1 and functional consequence of the patient WFS1 in vitro. ResultsThe patient WFS1 contained a heterozygous 4 amino acid in-frame deletion (p.N325_I328del). Her mutant WFS1 increased GRP78 and ATF6 promoter activities in the absence of thapsigargin, indicating constitutive ER stress and nuclear factor of activated T-cell reporter activity, reflecting elevated cytosolic Ca2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca2+ transport ATPase 2b (SERCA2b) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca2+ homeostasis, decreased SERCA2b expression might affect ER Ca2+ efflux, causing cell apoptosis. ConclusionA novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6 activation and ER Ca2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM.
  • Masayo Kagami, Keisuke Nagasaki, Rika Kosaki, Reiko Horikawa, Yasuhiro Naiki, Shinji Saitoh, Toshihiro Tajima, Tohru Yorifuji, Chikahiko Numakura, Seiji Mizuno, Akie Nakamura, Keiko Matsubara, Maki Fukami, Tsutomu Ogata
    Genetics in medicine : official journal of the American College of Medical Genetics 19 12 1356 - 1366 2017年12月 [査読有り][通常論文]
     
    PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14.MethodsWe performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported.ResultsWe identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader-Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS-like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older.ConclusionThese results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2.
  • 坂本 沙織, 本多 昌平, 宮城 久之, 湊 雅嗣, 鈴木 麻由, 中村 明枝, 森川 俊太郎, 山口 健史, 武冨 紹信
    日本小児血液・がん学会雑誌 54 4 327 - 327 (一社)日本小児血液・がん学会 2017年10月 [査読有り][通常論文]
  • Takanobu Inoue, Akie Nakamura, Keiko Matsubara, Hiromi Nyuzuki, Keisuke Nagasaki, Akira Oka, Maki Fukami, Masayo Kagami
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 173 10 2847 - 2850 2017年10月 [査読有り][通常論文]
  • 森川 俊太郎, 山口 健史, 石津 桂, 本間 桂子, 長谷川 奉延, 田島 敏広, 中村 明枝
    日本マス・スクリーニング学会誌 27 2 204 - 204 日本マススクリーニング学会 2017年07月
  • S. Nakamura, M. Miyado, K. Saito, M. Katsumi, A. Nakamura, Y. Kobori, Y. Tanaka, H. Ishikawa, A. Yoshida, H. Okada, K. Hata, K. Nakabayashi, K. Okamura, H. Ogata, Y. Matsubara, T. Ogata, H. Nakai, M. Fukami
    Andrology 5 4 824 - 831 2017年07月01日 [査読有り][通常論文]
     
    Azoospermia affects up to 1% of adult men. Non-obstructive azoospermia is a multifactorial disorder whose molecular basis remains largely unknown. To date, mutations in several genes and multiple submicroscopic copy-number variations (CNVs) have been identified in patients with non-obstructive azoospermia. The aim of this study was to clarify the contribution of nucleotide substitutions in known causative genes and submicroscopic CNVs in the genome to the development of non-obstructive azoospermia. To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization. We studied 40 Japanese patients with idiopathic non-obstructive azoospermia. Functional significance of molecular alterations was assessed by in silico analyses. As a result, we identified four putative pathogenic mutations, four rare polymorphisms possibly associated with disease risk, and four probable neutral variants in 10 patients. These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia. Copy-number analysis detected five X chromosomal or autosomal CNVs of unknown clinical significance, in addition to one known pathogenic Y chromosomal microduplication. Five patients carried multiple molecular alterations. The results indicate that monogenic and oligogenic mutations, including those in SOHLH1 and TEX11, account for more than 10% of cases of idiopathic non-obstructive azoospermia. Furthermore, this study suggests possible contributions of substitutions in various genes as well as submicroscopic CNVs on the X chromosome and autosomes to non-obstructive azoospermia, which require further validation.
  • Takanobu Inoue, Akie Nakamura, Tomoko Fuke, Kazuki Yamazawa, Shinichiro Sano, Keiko Matsubara, Seiji Mizuno, Yoshika Matsukura, Chie Harashima, Tatsuji Hasegawa, Hisakazu Nakajima, Kumi Tsumura, Zenro Kizaki, Akira Oka, Tsutomu Ogata, Maki Fukami, Masayo Kagami
    CLINICAL EPIGENETICS 9 2017年05月 [査読有り][通常論文]
     
    Background: Silver-Russell syndrome (SRS) is a rare congenital disorder characterized by pre- and postnatal growth failure and dysmorphic features. Recently, pathogenic copy number variations (PCNVs) and imprinting defects other than hypomethylation of the H19-differentially methylated region (DMR) and maternal uniparental disomy chromosome 7 have been reported in patients with the SRS phenotype. This study aimed to clarify the frequency and clinical features of patients with SRS phenotype caused by PCNVs. Methods: We performed array comparative genomic hybridization analysis using a catalog array for 54 patients satisfying the Netchine-Harbison clinical scoring system (NH-CSS) (SRS-compatible) and for 28 patients presenting with three NH-CSS items together with triangular face and/or fifth finger clinodactyly and/or brachydactyly (SR-Slike) without abnormal methylation levels of 9 DMRs related to known imprinting disorders. We then investigated the clinical features of patients with PCNVs. Results: Three of the 54 SRS-compatible patients (5.6%) and 2 of the 28 SRS-like patients (7.1%) had PCNVs. We detected 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, and 3.77-4.00 Mb deletion in 19q13.11-12 in SRS-compatible patients, and 1.41-1.97 Mb deletion in 7q11.23 in both SRS-like patients. Congenital heart diseases (CHDs) were identified in two patients and moderate to severe global developmental delay was observed in four patients. Conclusions: Of the patients in our study, 5.6% of SRS-compatible and 7.1% of SRS-like patients had PCNVs. All PCNVs have been previously reported for genetic causes of contiguous deletion syndromes or mosaic trisomy 18. Our study suggests patients with PCNVs, who have a phenotype resembling SRS, show a high tendency towards CHDs and/or apparent developmental delay.
  • 山口 健史, 田島 敏広, 森川 俊太郎, 石津 桂, 中村 明枝, 五十嵐 麻希, 深見 真紀
    日本内分泌学会雑誌 93 1 308 - 308 (一社)日本内分泌学会 2017年04月
  • 佐野 伸一朗, 中村 明枝, 松原 圭子, 長崎 啓介, 深見 真紀, 緒方 勤, 鏡 雅代
    日本内分泌学会雑誌 93 1 198 - 198 (一社)日本内分泌学会 2017年04月 [査読有り][通常論文]
  • 佐野 伸一朗, 長崎 啓介, 松原 圭子, 中村 明枝, 深見 真紀, 緒方 勤
    日本内分泌学会雑誌 93 1 265 - 265 (一社)日本内分泌学会 2017年04月 [査読有り][通常論文]
  • Masayo Kagami, Keiko Matsubara, Kazuhiko Nakabayashi, Akie Nakamura, Shinichiro Sano, Kohji Okamura, Kenichiro Hata, Maki Fukami, Tsutomu Ogata
    GENETICS IN MEDICINE 19 4 476 - 482 2017年04月 [査読有り][通常論文]
     
    Purpose: Recent studies have identified multilocus imprinting disturbances (MLIDs) in a subset of patients with imprinting diseases (IDs) caused by epimutations. We examined MLIDs in patients with Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14). Methods: We studied four TS14 patients (patients 1-4) and five KOS14 patients (patients 5-9) with epimutations. We performed HumanMethylation450 BeadChip (HM450k) analysis for 43 differentially methylated regions (DMRs) (753 CpG sites) and pyrosequencing for 12 DMRs (62 CpG sites) using leukocyte genomic DNA (Leu-gDNA) of patients 1-9, and performed HM450k analysis for 43 DMRs (a slightly different set of 753 CpG sites) using buccal cell gDNA (Buc-gDNA) of patients 1,3, and 4. We also performed mutation analysis for six causative and candidate genes for MLIDs and quantitative expression analysis using immortalized lymphocytes in MLID-positive patients. Results: Methylation analysis showed hypermethylated ZDBF2DMR and ZNF597/NAA60-DMR, hypomethylated ZNF597-DMR in both Leu-gDNA and Buc-gDNA, and hypomethylated PPIEL-DMR in Buc-gDNA of patient 1, and hypermethylated GNAS-A/B-DMR in Leu-gDNA of patient 3. No mutations were detected in the six genes for MLIDs. Expression patterns of ZDBF2, ZNF597, and GNAS-A/B were consistent with the identified MLIDs. Conclusion: This study indicates the presence of MLIDs in TS14 patients but not in KOS14 patients.
  • 田島 敏広, 山口 健史, 森川 俊太郎, 石津 桂, 中村 明枝, 五十嵐 麻希, 深見 真紀
    日本内分泌学会雑誌 92 3 800 - 800 (一社)日本内分泌学会 2017年01月
  • Mami Miyado, Kenji Miyado, Akihiro Nakamura, Maki Fukami, Gen Yamada, Sen-Ichi Oda
    Reproduction 153 2 187 - 195 2017年 [査読有り][通常論文]
     
    Reciprocal epithelial-mesenchymal interactions and several signalling pathways regulate the development of the genital tubercle (GT), an embryonic primordium of external genitalia. The morphology of the adult male external genitalia of the Asian house musk shrew Suncus murinus (hereafter, laboratory name: suncus) belonging to the order Eulipotyphla (the former order Insectivora or Soricomorpha) differs from those of mice and humans. However, the developmental process of the suncus GT and its regulatory genes are unknown. In the present study, we explored the morphological changes and gene expression patterns during the development of the suncus GT. Morphological observations suggested the presence of common (during the initial outgrowth) and species-specific (during the sexual differentiation of GT) developmental processes of the suncus GT. In gene expression analysis, fibroblast growth factor 8 (Fgf8) and sonic hedgehog (Shh), an indicator and regulator of GT development in mice respectively, were found to be expressed in the cloacal epithelium and the developing urethral epithelium of the suncus GT. This pattern of expression specifically in GT epithelium is similar to that observed in the developing mouse GT. Our results indicate that the mechanism of GT formation regulated by the FGF and SHH signalling pathways is widely conserved in mammals.
  • Yamamoto Sayaka, Nakamura Akie, Aoyagi Hayato, Shida Satoru, Ueda Yasuhiro, Yamaguchi Takeshi, Morikawa Shuntaro, Ishizu Katsura, Kagami Masayo, Fukami Maki, Tajima Toshihiro
    HORMONE RESEARCH IN PAEDIATRICS 88 382  2017年 [査読有り][通常論文]
  • Hattori Atsushi, Shima Hirohito, Katoh-Fukui Yuko, Nakamura Akie, Suzuki Erina, Matsubara Keiko, Adachi Masanori, Dateki Sumito, Hamajima Takashi, Horikawa Reiko, Ida Shinobu, Kamimaki Tsutomu, Mitani Marie, Muroya Koji, Ogata Tsutomu, Tajima Toshihiro, Tanaka Hiroyuki, Uetake Kimiaki, Yagasaki Hideaki, Yoshida Shinobu, Tanaka Toshiaki, Fukami Maki
    HORMONE RESEARCH IN PAEDIATRICS 88 487 - 488 2017年 [査読有り][通常論文]
  • Takanobu Inoue, Akie Nakamura, Tomoko Fuke, Kazuki Yamazawa, Shinichiro Sano, Keiko Matsubara, Seiji Mizuno, Yoshika Matsukura, Chie Harashima, Tatsuji Hasegawa, Hisakazu Nakajima, Kumi Tsumura, Zenro Kizaki, Akira Oka, Tsutomu Ogata, Maki Fukami, Masayo Kagami
    Clinical epigenetics 9 52 - 52 2017年 [査読有り][通常論文]
     
    BACKGROUND: Silver-Russell syndrome (SRS) is a rare congenital disorder characterized by pre- and postnatal growth failure and dysmorphic features. Recently, pathogenic copy number variations (PCNVs) and imprinting defects other than hypomethylation of the H19-differentially methylated region (DMR) and maternal uniparental disomy chromosome 7 have been reported in patients with the SRS phenotype. This study aimed to clarify the frequency and clinical features of patients with SRS phenotype caused by PCNVs. METHODS: We performed array comparative genomic hybridization analysis using a catalog array for 54 patients satisfying the Netchine-Harbison clinical scoring system (NH-CSS) (SRS-compatible) and for 28 patients presenting with three NH-CSS items together with triangular face and/or fifth finger clinodactyly and/or brachydactyly (SRS-like) without abnormal methylation levels of 9 DMRs related to known imprinting disorders. We then investigated the clinical features of patients with PCNVs. RESULTS: Three of the 54 SRS-compatible patients (5.6%) and 2 of the 28 SRS-like patients (7.1%) had PCNVs. We detected 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, and 3.77-4.00 Mb deletion in 19q13.11-12 in SRS-compatible patients, and 1.41-1.97 Mb deletion in 7q11.23 in both SRS-like patients. Congenital heart diseases (CHDs) were identified in two patients and moderate to severe global developmental delay was observed in four patients. CONCLUSIONS: Of the patients in our study, 5.6% of SRS-compatible and 7.1% of SRS-like patients had PCNVs. All PCNVs have been previously reported for genetic causes of contiguous deletion syndromes or mosaic trisomy 18. Our study suggests patients with PCNVs, who have a phenotype resembling SRS, show a high tendency towards CHDs and/or apparent developmental delay.
  • Hirohito Shima, Akira Ishii, Yasunori Wada, Junya Kizawa, Tadashi Yokoi, Noriyuki Azuma, Yoichi Matsubara, Erina Suzuki, Akie Nakamura, Satoshi Narumi, Maki Fukami
    ENDOCRINE JOURNAL 64 8 813 - 817 2017年 [査読有り][通常論文]
     
    Hypogonadotropic hypogonadism (HH) is a genetically heterogeneous condition that occurs either as an isolated disorder or as a component of congenital malformation syndromes. SOX2 is a causative gene of syndromic HH characterized by anophthalmia, microphthalmia, or coloboma and other neurological defects such as epilepsy. To date, the causal relationship between SOX2 abnormalities and non-syndromic HH remains speculative. Here, we identified a nonsense mutation of SOX2 in a male patient clinically diagnosed with non-syndromic HH. The patient had epilepsy but no additional clinical features. Ophthalmological examination revealed no abnormalities except for decreased thickness of the retinal nerve fiber layer. Audiometry showed mild sensorineural hearing impairment of both ears. Hormonal evaluation suggested isolated gonadotropin deficiency. Next-generation sequencing-based mutation screening of 13 major causative genes for HH identified a p.Lys35* mutation in SOX2 and excluded pathogenic mutations in other tested genes. The p.Lys35* mutation appeared to encode a non-functioning SOX2 protein that lacks 283 of 317 amino acids. The SOX2 mutation was absent in the maternal DNA sample, while a paternal sample was unavailable for sequence analysis. These results expand the clinical consequences of SOX2 haploinsufficiency to include non-syndromic HH. Systematic mutation screening using a next-generation sequencer and detailed evaluation of nonspecific ocular/neurological features may help identify SOX2 mutation-positive individuals among HH patients.
  • Atsushi Hattori, Yuko Katoh-Fukui, Akie Nakamura, Keiko Matsubara, Tsutomu Kamimaki, Hiroyuki Tanaka, Sumito Dateki, Masanori Adachi, Koji Muroya, Shinobu Yoshida, Shinobu Ida, Marie Mitani, Keisuke Nagasaki, Tsutomu Ogata, Erina Suzuki, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Satoshi Narumi, Toshiaki Tanaka, Maki Fukami
    ENDOCRINE JOURNAL 64 10 947 - 954 2017年 [査読有り][通常論文]
     
    Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.
  • Toshihiro Tajima, Shuntaro Morikawa, Akie Nakamura
    Clinical Pediatric Endocrinology 26 3 109 - 117 2017年 [査読有り][通常論文]
     
    Pseudohypoaldosteronism (PHA) type 1 is a disease showing mineralocorticoid resistance in the kidney and/or other mineralocorticoid target tissues. Patients with PHA1 present very high plasma aldosterone and renin levels, but they develop excessive salt wasting. There are three types of PHA1. The systemic form of PHA1 is inherited in an autosomal recessive manner and causes severe life-long salt loss in multiple target tissues, such as sweat glands, salivary glands, the colonic epithelium, and the lung. In the systemic form of PHA1, life-long salt supplementation is necessary. The second type is the renal form, where aldosterone resistance is shown only in the kidney, and its inheritance is autosomal dominant. In the renal form of PHA1, salt supplementation generally becomes unnecessary by 1–3 yr of age. The third type is the secondary PHA1, which is strongly associated with urinary tract infections and/or urinary tract malformations. This review summarizes the clinical features and molecular basis of PHA1. Understanding of its pathogenesis can be helpful for the early diagnosis and clinical care of affected children with PHA1.
  • Motohide Goto, Yukiyo Yamamoto, Masahiro Ishii, Akie Nakamura, Shinichiro Sano, Masayo Kagami, Maki Fukami, Reiko Saito, Shunsuke Araki, Kazuyasu Kubo, Rinko Kawagoe, Yasusada Kawada, Koichi Kusuhara
    PEDIATRICS INTERNATIONAL 58 11 1229 - 1231 2016年11月 [査読有り][通常論文]
     
    Pseudohypoparathyroidism type 1b (PHP-1b) is usually diagnosed on various symptoms of hypocalcemia. Previous studies reported a few cases of autosomal dominant pattern PHP-1b identified on familial analysis with asymptomatic hypocalcemia. Herein we report the case of a 6-year-old male patient with sporadic PHP-1b incidentally detected on preoperative examination. He had neither characteristic findings of Albright hereditary osteodystrophy nor evidence of tetany. Sporadic PHP-1b was diagnosed on the basis of clinical observation and laboratory examination. In addition, genetic testing using methylation-specific multiplex ligation-dependent probe amplification indicated broad methylation abnormalities and confirmed the sporadic form of PHP-1b. Sporadic PHP-1b might often be overlooked when diagnosis is done simply on definitive clinical features. To avoid this, DNA sequencing and methylation analysis should be performed even in the absence of definitive clinical features.
  • Wolfram症候群における成長障害メカニズムの解明 小胞体ストレスによるGH分泌への影響
    森川 俊太郎, 山口 健史, 石津 桂, 有賀 正, 田島 敏広, 中村 明枝
    成長科学協会研究年報 39 139 - 146 (公財)成長科学協会 2016年09月 
    Wolfram症候群(WS)における成長障害メカニズムについて検討した。野生型hWFS1 cDNAが挿入されたpcDNA3.1プラスミドを用いた。同定した患児の変異(p.N325_M328del;Del)の他、既報のp.Q194Xとp.L543R変異を作成した。患児の変異は、小胞体ストレス誘導剤であるタプシガルギンの有無に関わらず、ERSEプロモーター活性を上昇させ、「恒常的な小胞体ストレス」を誘導し、優性阻害効果があることが示唆された。野生型WFS1と既報の二つのWFS1変異は、小胞体と細胞内局在が一致したが、患児の変異は、一部は小胞体の局在と一致するものの細胞形態が変化し、早期にアポトーシスなどを生じている可能性が示唆された。患児の変異を発現した細胞では、他の変異と比較しても有意に強いアポトーシスが誘導されていることが示された。患児の変異では切断されたATF6タンパクが増大していることを確認した。患児の変異では細胞質内Ca2+の上昇を認めた。RT-PCRでSERCA2b mRNA量について検討し、患児の変異においてはSERCA2b発現量の有意な低下を認めた。
  • Ho-Ming Luk, Fai-Man Ivan Lo, Shinichiro Sano, Keiko Matsubara, Akie Nakamura, Tsutomu Ogata, Masayo Kagami
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 170 7 1938 - 1941 2016年07月 [査読有り][通常論文]
  • Akie Nakamura, Erika Hamaguchi, Reiko Horikawa, Yasuyuki Nishimura, Keiko Matsubara, Shinichiro Sand, Keisuke Nagasaki, Yoichi Matsubara, Akihiro Umezawa, Toshihiro Tajima, Tsutomu Ogata, Masayo Kagami, Kohji Okamura, Maki Fukami
    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 101 7 2623 - 2627 2016年07月 [査読有り][通常論文]
     
    Context: Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory alpha subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNAS region were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary. Case Description: A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XL alpha s, and exon A/B-DMR but not STX16 or the Gs alpha coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XL alpha s-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions. Conclusions: Our results indicate that maternally derived copy-number gains in the GNAS region mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation.
  • 森川 俊太郎, 中村 明枝, 石津 桂, 田島 敏広
    日本内分泌学会雑誌 92 1 201 - 201 (一社)日本内分泌学会 2016年04月
  • 佐野 伸一朗, 長崎 啓祐, 中村 明枝, 松原 圭子, 深見 真紀, 緒方 勤, 鏡 雅代
    日本内分泌学会雑誌 92 1 221 - 221 (一社)日本内分泌学会 2016年04月 [査読有り][通常論文]
  • 偽性副甲状腺機能低下症における分子遺伝学的分類に基づいたTSH抵抗性に関する検討
    佐野 伸一朗, 長崎 啓祐, 中村 明枝, 松原 圭子, 深見 真紀, 緒方 勤, 鏡 雅代
    日本小児科学会雑誌 120 2 298 - 298 (公社)日本小児科学会 2016年02月 [査読有り][通常論文]
  • Shima Hirohito, Yatsuga Shuichi, Nakamura Akie, Sano Shinichiro, Sasaki Takako, Katsumata Noriyuki, Suzuki Erina, Ogata Tsutomu, Fukami Maki
    HORMONE RESEARCH IN PAEDIATRICS 86 118 - 119 2016年 [査読有り][通常論文]
  • Hirohito Shima, Shuichi Yatsuga, Akie Nakamura, Shinichiro Sano, Takako Sasaki, Noriyuki Katsumata, Erina Suzuki, Kenichiro Hata, Kazuhiko Nakabayashi, Yukihide Momozawa, Michiaki Kubo, Kohji Okamura, Shigeo Kure, Yoichi Matsubara, Tsutomu Ogata, Satoshi Narumi, Maki Fukami
    SEXUAL DEVELOPMENT 10 4 205 - 209 2016年 [査読有り][通常論文]
     
    NR0B1 is the causative gene for X-linked adrenal hypoplasia congenita, characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and infertility. We identified an NR0B1 frameshift mutation in a boy with precocious puberty who had no signs of adrenal insufficiency. Blood examination revealed elevated testosterone levels and gonadotropin hyperresponses to gonadotropin releasing hormone (GnRH) stimulation, together with normal adrenal hormone levels. GnRH analog treatment partially ameliorated his clinical features. Molecular analysis identified a p.Glu3fsAla*16 in NR0B1. These results expand the clinical manifestations of NR0B1 mutations to include central precocious puberty without adrenal insufficiency. NR0B1 mutations likely underlie androgen overproduction via GnRH-dependent and -independent mechanisms. (C) 2016 S. Karger AG, Basel.
  • Gul Yesiltepe Mutlu, Heves Kirmizibekmez, Akie Nakamura, Maki Fukami, Sukru Hatun
    JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY 7 4 344 - 348 2015年12月 [査読有り][通常論文]
     
    Hypoparathyroidism, deafness, and renal dysplasia (HDR; OMIM 146255) syndrome is a rare disease, inherited dominantly and found to be related with GATA3 (GATA binding protein 3) gene mutations. A 13-year and 8-month-old boy who presented with hypocalcemia was diagnosed with hypoparathyroidism. He also had dysmorphic facial features, renal anomaly (pelvic kidney), and mild sensorineural hearing loss. His cranial computed tomography revealed multiple calcifications in bilateral centrum semiovale, corona radiata, and basal ganglions suggesting a persistent hypoparathyroidism. Thus, the presence of triad of HDR syndrome was considered, and genetic analysis using a next-generation sequencer identified a novel de novo missense mutation in exon 4 p.R276Q (c.827G>A) of GATA3 gene. This is the second patient who was reported to have a mutation in GATA3 gene from Turkey. In conclusion, although HDR syndrome is a rare condition, it should be kept in mind in patients with hypoparathyroidism. Classical triad can easily be identified if patients diagnosed with hypoparathyroidism are also evaluated with a urinary tract ultrasound and an audiometer.
  • 阿部 清美, 鳴海 覚志, 三井 俊賢, 長崎 啓祐, 中村 明枝, 田島 敏広, 湯野 暁子, 臼井 健, 室谷 浩二, 朝倉 由美, 安達 昌功, 長谷川 奉延
    日本内分泌学会雑誌 91 2Suppl. 74 - 74 (一社)日本内分泌学会 2015年11月
  • Mami Miyado, Kenji Miyado, Momori Katsumi, Kazuki Saito, Akihiro Nakamura, Daizou Shihara, Tsutomu Ogata, Maki Fukami
    Scientific reports 5 14705 - 14705 2015年10月05日 [査読有り][通常論文]
     
    In mice, the onset of parturition is triggered by a rapid decline in circulating progesterone. Progesterone withdrawal occurs as a result of functional luteolysis, which is characterized by an increase in the enzymatic activity of 20α-hydroxysteroid dehydrogenase (20α-HSD) in the corpus luteum and is mediated by the prostaglandin F2α (PGF2α) signaling. Here, we report that the genetic knockout (KO) of Mamld1, which encodes a putative non-DNA-binding regulator of testicular steroidogenesis, caused defective functional luteolysis and subsequent parturition failure and neonatal deaths. Progesterone receptor inhibition induced the onset of parturition in pregnant KO mice, and MAMLD1 regulated the expression of Akr1c18, the gene encoding 20α-HSD, in cultured cells. Ovaries of KO mice at late gestation were morphologically unremarkable; however, Akr1c18 expression was reduced and expression of its suppressor Stat5b was markedly increased. Several other genes including Prlr, Cyp19a1, Oxtr, and Lgals3 were also dysregulated in the KO ovaries, whereas PGF2α signaling genes remained unaffected. These results highlight the role of MAMLD1 in labour initiation. MAMLD1 likely participates in functional luteolysis by regulating Stat5b and other genes, independent of the PGF2α signaling pathway.
  • Maki Fukami, Yasuhiro Naiki, Koji Muroya, Takashi Hamajima, Shun Soneda, Reiko Horikawa, Tomoko Jinno, Momori Katsumi, Akie Nakamura, Yumi Asakura, Masanori Adachi, Tsutomu Ogata, Susumu Kanzaki
    JOURNAL OF HUMAN GENETICS 60 9 553 - 556 2015年09月 [査読有り][通常論文]
     
    Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.
  • Osamu Kawano, Akie Nakamura, Shuntaro Morikawa, Kimiaki Uetake, Katsura Ishizu, Toshihiro Tajima
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 167 7 1578 - 1581 2015年07月 [査読有り][通常論文]
     
    Spondyloepiphyseal dysplasia congenita (SEDC) is a group of rare inherited chondrodysplasias characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. SEDC is usually caused by substitution of glycine residue with another amino acid in the triple helical domains of alpha 1 chains, which consist of type II collagen (COL2A1). Herein, we describe a unique case of SEDC with mild coxa vara (SEDC-M) caused by double de novo COL2A1 mutations located on the same allele. One mutation, p.G504S, was previously described in patients with SEDC, whereas the other, p.G612A, was a novel mutation; both were located in the triple helical domain. Neither mutation was identified in the parents and appeared to be de novo. To the best of our knowledge, this is the first study involving a patient with a type II collagenopathy with two COL2A1 mutations on the same allele. The case was characterized by a more severe phenotype compared with previously reported cases involving a single p.G504S mutation, which may have been the result of the double mutation. (C) 2015 Wiley Periodicals, Inc.
  • 中村 明枝, 森川 俊太郎, 石津 桂, 田島 敏広
    日本内分泌学会雑誌 91 1 182 - 182 (一社)日本内分泌学会 2015年04月
  • 森川 俊太郎, 田島 敏広, 石津 桂, 中村 明枝, 藤倉 かおり, 福士 勝
    日本内分泌学会雑誌 91 1 306 - 306 (一社)日本内分泌学会 2015年04月
  • 森川 俊太郎, 中村 明枝, 石津 桂, 久間木 悟, 田島 敏広
    日本内分泌学会雑誌 91 1 369 - 369 (一社)日本内分泌学会 2015年04月
  • 佐野 伸一朗, 松原 圭子, 中村 明枝, 深見 真紀, 緒方 勤
    日本内分泌学会雑誌 91 1 286 - 286 (一社)日本内分泌学会 2015年04月 [査読有り][通常論文]
  • マススクリーニングの歴史と展望 内分泌疾患の新しい知見
    田島 敏広, 森川 俊太郎, 石津 桂, 中村 明枝
    日本小児科学会雑誌 119 2 195 - 195 (公社)日本小児科学会 2015年02月
  • Tajima T, Nakamura A, Morikawa S, Ishizu K
    Annals of pediatric endocrinology & metabolism 19 3 117 - 121 2014年09月 [査読有り][通常論文]
     
    Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.
  • Akie Nakamura, Shuntaro Morikawa, Hayato Aoyagi, Katsura Ishizu, Toshihiro Tajima
    PEDIATRIC RESEARCH 75 6 749 - 753 2014年06月 [査読有り][通常論文]
     
    BACKGROUND: Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population. METHODS: We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells. RESULTS: We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type. CONCLUSION: We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.
  • 田島 敏広, 森川 俊太郎, 中村 明枝, 石津 桂
    日本内分泌学会雑誌 90 1 338 - 338 (一社)日本内分泌学会 2014年04月
  • Shuntaro Morikawa, Akie Nakamura, Kaori Fujikura, Masaru Fukushi, Tomoyuki Hotsubo, Jun Miyata, Katsura Ishizu, Toshihiro Tajima
    Clinical Pediatric Endocrinology 23 2 35 - 43 2014年 [査読有り][通常論文]
     
    The primary goal of newborn mass screening (MS) for congenital adrenal hyperplasia (CAH) is the prevention of life-threatening salt-wasting crisis in the most severe forms of CAH, and MS for CAH has been implemented in several countries. We summarize here our experience and results from newborn CAH MS from 1982 to 2010 in Sapporo City. During these 28 yr, the level of 17-hydroxyprogesterone (17-OHP) was determined in MS of samples from 498,147 newborns. During this period, 26 individuals (19 females and 7 males) with 21-hydroxylase deficiency (21-OHD) were detected. Of the 26 CAH, 20 were classified as having the salt-wasting (SW) form, 4 were classified as having the simple virilizing (SV) form, and 2 were classified as having the noncalssic (NC) form. Therefore, the frequency of the classical type of CAH was 1 in 20,756. In order to improve the effectiveness, we employed high-performance liquid chromatography (HPLC) as a second tier test from 2000. During this period, among the recalled babies, 75.4% were born prior to the 37th wk of gestation age, and the recall rate was 5.38% for premature neonates and 0.06% for mature neonates. MS for CAH in Sapporo is effective for the identification of the SW and SV forms of 21-OHD. However, the recall rate of premature babies is still high after the introduction of HPLC as a second tier test. © 2014 by The Japanese Society for Pediatric Endocrinology.
  • 【小児内分泌学の進歩2014】甲状腺 腹痛、低身長を契機として診断に至ったIGSF1遺伝子異常症の14歳男児例
    土山 厚志, 母坪 智行, 森川 俊太郎, 中村 明枝, 石津 桂, 田島 敏広, 森 俊彦
    ホルモンと臨床 61 12 949 - 953 (有)医学の世界社 2013年12月 
    IGSF1(Immunoglobulin superfamily member 1)遺伝子異常による先天性中枢性甲状腺機能低下症(C-CH)が2012年に初めて報告されて以降、本邦においても報告例が増えてきた。今回著者等は、幼少期からの便秘と3年前からの腹痛を主訴に当科受診し、高度な低身長を認めたため精査を行いC-CHの診断に至った14歳男児例を経験した。長期に無治療であった貴重な症例と思われたので報告した。患児は消化器症状のほかに肥満と不登校があり、LT4補充治療によって消化器症状と肥満は速やかに改善した。一方、不登校は続き、その理由として14年間無治療であったために不可逆性の心理社会的不適応を生じ、LT4補充が無効であった可能性が示唆された。
  • Daisuke Takahashi, Hiroyuki Kobayashi, Kanako Kubota, Yasuto Suzuki, Akie Nakamura, Katsura Ishizu, Masanori Nakanishi, Tetsuro Nagashima, Toshihiro Tajima
    JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM 26 9-10 949 - 953 2013年10月 [査読有り][通常論文]
     
    We report an 18-year-old Japanese male with a lack of secondary sex characterization and growth failure caused by a rare association between Rathke's cyst and hypophysitis. He was referred to us because of delayed secondary sex characterization. Endocrinological examination showed panhypopituitarism, and the replacement of hydrocortisone, levothyroxine, and desmopressin acetate (DDAVP) was initiated. Brain magnetic resonance imaging (MRI) showed a suprasellar region and a swollen pituitary stalk. The mass was partially resected using the transsphenoidal approach. The pathological diagnosis was hypophysitis and Rathke's cyst. Follow-up MRI performed 1 year after surgery showed that the size of sellar region had not changed. After surgery, in addition to pre-operative hormonal replacement, growth hormone and testosterone were initiated. Two years later, the size of sellar region remains unchanged. In conclusion, while an association between Rathke's cyst and hypophysitis is rare, we suggest that this condition should be included in differential diagnosis of the sellar region, even in adolescents.
  • Akie Nakamura, Tomoyuki Hotsubo, Keiji Kobayashi, Hiroshi Mochizuki, Katsura Ishizu, Toshihiro Tajima
    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 98 10 E1692 - E1701 2013年10月 [査読有り][通常論文]
     
    Objective: Activating mutations in the calcium-sensing receptor (CASR) gene cause autosomal dominant hypoparathyroidism, and heterozygous inactivating CASR mutations cause familial hypocalciuric hypercalcemia. Recently, there has been a focus on the use of allosteric modulators to restore the functional activity of mutant CASRs. In this study, the effect of allosteric modulators NPS R-568 and NPS 2143 on CASR mutants was studied in vitro. Methods: DNA sequence analysis of the CASR gene was undertaken in autosomal dominant hypoparathyroidism and familial hypocalciuric hypercalcemia Japanese patients, and the functional consequences for the Gi-MAPK pathway and cell surface expression of CASR were determined. Furthermore, we studied the effect of NPS R-568 and NPS 2143 on the signal transduction activity and cell surface expression of each mutant CASR. Results: We identified 3 activating mutations (S122C, P569H, and I839T) and 2 inactivating mutations (A110T and R172G) in patients. The activating and inactivating mutations caused leftward and rightward shifts, respectively, in the dose-response curves of the signaling pathway. NPS R-568 rescued the signal transduction capacity of 2 inactivating mutants without increasing cell surface expression levels. NPS 2143 suppressed the enhanced activity of the activating mutants without altering cell surface expression levels, although A843E, which is a constitutively active mutant, was suppressed to a lesser degree. Conclusions: We have identified 4 novel mutations of CASR. Moreover, our results indicate that allosteric modulators can restore the activity of the loss-and gain-of-function mutant CASRs, identified in this study.
  • Akie Nakamura, Beata Bak, Tanya L. R. Silander, Jessica Lam, Tomoyuki Hotsubo, Toru Yorifuji, Katsura Ishizu, Daniel J. Bernard, Toshihiro Tajima
    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 98 10 E1682 - E1691 2013年10月 [査読有り][通常論文]
     
    Context: Congenital central hypothyroidism (C-CH) is a rare disease. We investigated the molecular basis of unexplained C-CH in 4 Japanese boys. Patients and Methods: C-CH was diagnosed by low free T-4 and/or T-3 and low basal TSH concentrations. We used whole-exome sequencing of one patient with C-CH to identify potential disease-causing mutations. Thereafter, PCR direct sequencing was performed to Identify genetic defects underlying C-CH in 3 more patients. We then assessed the effects of mutations identified in the Ig superfamily, member 1 (IGSF1), gene on protein expression and membrane trafficking. Results: All patients had congenital hypothyroidism, and 2 had definitive prolactin deficiency. Two patients were detected by neonatal screening. The other patients were diagnosed by short stature and failure to thrive. We identified a novel nonsense variant in IGSF1 by whole-exome sequencing in patient 1, which was confirmed by PCR direct sequencing (p.R1189X). PCR direct sequencing identified the identical nonsense mutation in patient 2. Patients 3 and 4 harbored distinct missense (p.V1082E) or nonsense (p.Q645X) mutations in IGSF1. The mothers of patients 1, 3, and 4 were heterozygous for these mutations. The R1189X mutant, which lacks the transmembrane domain, failed to traffic to the plasma membrane. V1082E could be observed at the cell surface, but at greatly diminished levels relative to the wild-type form of the protein. The severely truncated Q645X mutant could not be detected by Western blot. Conclusion: Our findings provide additional genetic evidence that loss-of-function mutations in IGSF1 cause an X-linked form of C-CH and variable prolactin deficiency.
  • 石津 桂, 森川 俊太郎, 中村 明枝, 藤倉 かおり, 福士 勝, 母坪 智行, 花井 潤師, 宮田 淳, 田島 敏広
    日本内分泌学会雑誌 89 2 624 - 624 (一社)日本内分泌学会 2013年09月
  • 田島 敏広, 石津 桂, 中村 明枝, 森川 俊太郎, 藤倉 かおり, 山岸 卓弥, 田上 泰子, 花井 潤師, 宮田 淳, 福士 勝
    日本マス・スクリーニング学会誌 23 2 225 - 225 (一社)日本マススクリーニング学会 2013年08月
  • Maruyama H, Shinno Y, Fujiwara K, Nakamura A, Tajima T, Nakamura M, Kageyama M
    AJP reports 3 1 21 - 24 2013年05月 [査読有り][通常論文]
  • Toshihiro Tajima, Akie Nakamura, Katsura Ishizu
    ENDOCRINE JOURNAL 60 2 245 - 249 2013年02月 [査読有り][通常論文]
     
    Congenital central hypothyroidism (C-CH) is a rare disease known to be caused by mutations of the genes encoding TSH beta or the TRH receptor gene, although the cause of the disease in a number of patients has not yet been clarified. Recently, mutations and deletions of the immunoglobulin superfamily member 1 (IGSF1) gene have been reported to be the cause of C-CH. Here we report a Japanese male patient with C-CH due to a novel IGSF1 mutation. He was detected by neonatal mass screening of simultaneous TSH and free T4 measurements and levothyroxine was initiated. At 6 years of age he underwent I-123 scintigraphy after levothyroxine treatment had been discontinued for one month and his thyroid and pituitary function were evaluated. Since TSH and PRL responses after TRH stimulation were low, his diagnosis of C-CH was confirmed. During follow up, whereas onset of his puberty was delayed, his secondary sex characterization completed at 17 years old. In this patient we analyzed IGSF1 and TRHR. As results, we identified a novel insertion mutation in IGSF1 (c.3528-3529insC), resulting in a premature stop codon (p.Pro1082Trpfs39X). In conclusion, we identified a novel mutation of IGSF1 in a Japanese male patient with C-CH.
  • Eisuke Kondo, Akie Nakamura, Keiko Homma, Tomonobu Hasegawa, Takeshi Yamaguchi, Masahiko Narugami, Tetsuo Hattori, Hayato Aoyagi, Katsura Ishizu, Toshihiro Tajima
    Endocrine Journal 60 1 51 - 55 2013年 [査読有り][通常論文]
     
    Isolated hypoaldosteronism is a rare and occasionally life-threatening cause of salt wasting in infancy. A 2-month-old Japanese boy of unrelated parents was examined for failure to thrive and poor weight gain. Laboratory findings were hyponatremia, hyperkalemia, high plasma renin and low aldosterone levels. Spot urine analysis by gas chromatography-mass spectrometry (GC-MS) showed that urinary excretion of corticosterone metabolites was elevated. Whereas excretion of 18-hydroxycortricosterone metabolites was within the normal range, excretion of aldosterone metabolites was undetectable. The patient was therefore suspected to have aldosterone synthase deficiency type 1. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (CYP11B2), showed that the patient was a compound heterozygote for c.168G> A, p.W56X in exon 1 and c.1149C> T, p.R384X in exon 7. p.W56X was inherited from his mother and p.R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition. To our knowledge, this is the first Japanese patient in which the molecular basis of aldosterone synthase deficiency type 1 has been clarified. This case also indicates that spot urinary steroid analysis is useful for diagnosis. ©The Japan Endocrine Society.
  • Yoriko Hatta, Akie Nakamura, Shinya Hara, Takashi Kamijo, Junko Iwata, Takashi Hamajima, Marie Abe, Mari Okada, Masanobu Ushio, Kazumichi Tsuyuki, Toshihiro Tajima
    Endocrine Journal 60 3 299 - 304 2013年 [査読有り][通常論文]
     
    Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of NR3C2 in the renal form of PHA1. © The Japan Endocrine Society.
  • Wakako Jo, Satoko Sudo, Akie Nakamura, Daisuke Endo, Yosuke Konno, Katsura Ishizu, Toshihiro Tajima
    Clinical Pediatric Endocrinology 22 2 33 - 38 2013年 [査読有り][通常論文]
     
    Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease. © 2013 by The Japanese Society for Pediatric Endocrinology.
  • Toshihiro Tajima, Katsura Ishizu, Akie Nakamura
    Clinical Pediatric Endocrinology 22 2 15 - 23 2013年 [査読有り][通常論文]
     
    The pituitary gland produces hormones that play important roles in both the development and homeostasis of the body. Ontogeny of the anterior and posterior pituitary is orchestrated by inputs from neighboring tissues, cellular signaling molecules and transcription factors. Disruption of expression or function of these factors has been implicated in the etiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, OTX2, SOX2, SOX3 and GLI2. This review focuses on summarizing most recent mutations in LHX4 and OTX2 responsible for pituitary hormone deficiency. In both genetic defects of LHX4 and OTX2, there is high variability in clinical manifestations even in the same family. In addition, there is no clear phenotype-genotype correlation. These findings indicate that the other genetic and/or environmental factors influence the phenotype. In addition, the variability might reflect a plasticity during pituitary development and maintenance. Over the past two decades, a genetic basis for pituitary hormone deficiency and the mechanism of pituitary development have been clarified. It should be kept in mind that this review is not comprehensive, and defects of other transcriptional factors have been described in patients with CPHD. Furthermore, the causes in many patients with CPHD have not yet been determined. Therefore, continuing efforts for the clarification of the etiology are necessary. © 2013 by The Japanese Society for Pediatric Endocrinology.
  • Hiroko Nihei, Hidenori Tada, Yuki Naruse, Masako Izawa, Manji Kato, Hiroaki Okuno, Akie Nakamura, Katsura Ishizu, Takashi Hamajima, Toshihiro Tajima
    JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY 5 4 270 - 272 2013年 [査読有り][通常論文]
     
    In many countries, methimazole (MMI) therapy is the first-line treatment in children with Graves' disease (GD). The rate of side effects of antithyroid drugs (ATDs) in children has been reported to range between 6% and 35%. Of these side effects, polyarthritis is uncommon but serious, and can also develop as a part of the antineutrophil cytoplasmic antibody-associated vasculitis that is induced by ATDs. Here, we describe two GD girl patients aged 15 years and 11 years who developed polyarthritis. The onset of polyarthritis in these patients was 24 days and 28 days after the initiation of MMI therapy, respectively. MMI was suspected of causing the polyarthritis in the two patients and was withdrawn. The symptoms of polyarthritis disappeared rapidly following cessation of treatment. Subsequently, one patient was treated with I-131 therapy and the other patient was subjected to thyroidectomy. Although it rarely occurs in pediatric GD patients, severe polyarthritis is a serious side effect of MMI and is an indication for prompt cessation of treatment.
  • Akie Nakamura, Katsura Ishidu, Toshihiro Tajima
    JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY 4 2 104 - 106 2012年 [査読有り][通常論文]
     
    Maturity-onset diabetes of the young type 3 (MODY3) is caused by heterozygous mutation in the HNF1A gene. Liver adenomatosis has been reported in MODY3 patients. The patient reported in this paper is a Japanese girl who first developed hepatomegaly, fatty liver, and hepatic dysfunction at age 5 years. Liver biopsy demonstrated steatosis and degeneration of hepatocytes. At that time, blood glucose and HbA1c levels were within normal ranges. Elevated HbA1c was noticed 4 years later, but islet cell and glutamic acid decarboxylase antibodies were not detected in the serum. Therefore, MODY3 was suspected and subsequent analysis of the HNF1A gene identified a heterozygous germline splice donor-site mutation in intron 9. MODY3 patients should be screened by non-invasive liver imaging, and careful follow-up of liver disease should be performed.
  • 石津 桂, 中村 明枝, 城 和歌子, 工藤 正尊, 田島 敏広
    日本マス・スクリーニング学会誌 = Journal of Japanese Society for Mass-screening 21 3 243 - 246 2011年12月01日 [査読無し][通常論文]
  • Kuniko Takanashi, Yashuto Suzuki, Ayumu Noro, Minako Sugiyama, Masanori Nakanishi, Tetsuro Nagashima, Akie Nakamura, Ishizu Katsura, Toshihiro Tajima
    Pediatric reports 3 3 e20  2011年06月30日 [査読有り][通常論文]
     
    The clinical phenotype of congenital pituitary hormone deficiency is variable and can be associated with a number of structural abnormalities of the central nervous system. We report three Japanese patients with congenital pituitary hormone deficiency and ophthalmological anomalies. Two of the patients initially showed strabismus and unilateral optic nerve hypoplasia. Thereafter, growth failure became evident, leading to the diagnosis of pituitary hormone deficiency. The other patient had severe congenital hypopituitarism with respiratory distress and hypoglycemia from the first day of life. In addition, he had prolonged jaundice and impaired liver function with bilateral optic nerve hypoplasia. Neuroimaging of the pituitary region in all three patients demonstrated a small anterior pituitary lobe and no pituitary stalk. Our findings indicate that clinical variability of congenital hypopituitarism must be considered. In a patient with ophthalmological symptoms, endocrine evaluation and neuroimaging of the CNS including the pituitary region should be considered.
  • Akie Nakamura, Fumie Fujiwara, Yukihiro Hasegawa, Katsura Ishizu, Akiyo Mabe, Hiroyasu Nakagawa, Keisuke Nagasaki, Wakako Jo, Toshihiro Tajima
    ENDOCRINE JOURNAL 58 2 123 - 130 2011年02月 [査読有り][通常論文]
     
    GATA3 is a member of the GATA family of transcription factors. Heterozygous GATA3 abnormalities are associated with hypoparathyroidism, sensorineural deafness, and renal abnormality (HDR syndrome). However, this triad of symptoms does not occur in all HDR patients and other clinical features may be present in some cases. We report the clinical phenotypes and the molecular analysis of GATA 3 in five Japanese HDR patients, including two familial cases. All five patients had hypoparathyroidism and sensorineural deafness, however renal abnormalities were absent in four patients. In addition, two patients with different mutations of GATA3 had female genital tract abnormalities. Sequence analysis of GATA3 demonstrated three novel (R262G, c1063delC and C318) and two reported mutations (c.432insG and c.1051-1G > T). Transient transfection assay using the GATA3 activating reporter system revealed that the transactivating activity of the R262G, c.1063delC, C318S and c.432insG mutants were markedly decreased, indicating that all four mutations are loss-of-function. In conclusion, this study reiterates the clinical variability in HDR syndrome and identifies three novel mutations of GATA3.
  • Wakako Jo, Machiko Endo, Katura Ishizu, Akie Nakamura, Toshihiro Tajima
    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 223 2 113 - 118 2011年02月 [査読有り][通常論文]
     
    Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous type of diabetes mellitus, characterized by early onset (often before 25 years of age) and absence of pancreatic autoimmunity markers. Paired-homeodomain transcription factor 4 (PAX4) functions as a transcriptional repressor and is involved in the differentiation of insulin-secreting beta-cells. Here we identified a novel PAX4 mutation in a Japanese patient with MODY. A 15-year-old, non-obese boy was admitted to our hospital because of polyuria and polydipsia. Laboratory evaluation showed an elevated fasting glucose level; however, islet cell antibodies and glutamic acid decarboxylase antibodies were not detected in the patient's serum. The proband's father had been diagnosed as having type 2 diabetes at age of 30 years. We therefore analyzed several candidate genes of MODY, and identified a novel mutation of a 39-base heterozygous deletion in exon 3 (c.374-412 de139) of PAX4 in the proband and his father. This mutation may cause exon 3 skipping that results in a frameshift, thereby producing a premature stop codon in exon 5. As this mutant PAX4 lacks a part of the homeodomain that is critical for binding to the target gene, this mutant was thought to lose the transcriptional repressor function. As expected, luciferase-reporter assays revealed that the mutant PAX4 could not repress the activities of insulin and glucagon gene promoters, unlike the wild-type PAX4 that repressed the promoter activities. The present study demonstrates that a novel mutation of PAX4 is likely to be associated with diabetes in this Japanese family.
  • Akie Nakamura, Tomoyuki Hostubo, Wakako Jo, Katsura Ishizu, Toshihiro Tajima
    Clinical Pediatric Endocrinology 20 1 21 - 23 2011年 [査読有り][通常論文]
  • 城 和歌子, 中村 明枝, 石津 桂, 田島 敏広
    日本内分泌学会雑誌 85 0 74 - 75 2009年08月20日 [査読無し][通常論文]

その他活動・業績

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2016年04月 -2018年03月 
    代表者 : 中村 明枝
     
    我々は偽性副甲状腺機能低下症の症例を集積し、分子遺伝学的要因を同定した。更に、GNAS A/B領域の軽度低メチル化を呈する兄妹例において、次世代シークエンサーを用いた全ゲノム解析によりXLASとA/B領域の間に1100bpのレトロトランスボゾン由来の挿入配列を確認した。ドロップレットデジタルPCRを用いた遺伝子発現解析によりNESP55発現低下傾向を認めたが、今後、更に詳細な遺伝子解析を確認するため、RNA-Seq解析を行う予定である。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2014年04月 -2016年03月 
    代表者 : 中村 明枝
     
    我々はカルシウム代謝異常(高カルシウム血症、低カルシウム血症、高カルシウム尿症)を呈する24症例を集積し、次世代シークエンサーを用いたカルシウム代謝に関与する遺伝子解析を施行した。低カルシウム血症を呈する家族例1例、弧発例1例に新規のCASR遺伝子変異を同定した。更に、新規のCLDN16遺伝子、FAM111A遺伝子、GATA3遺伝子変異を同定した。また、複雑な染色体構造異常を呈するPHP1b家族例も同定した。

教育活動情報

主要な担当授業

  • 基本医学研究
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 発達、小児医療、周産期医療、がんプロフェッショナル development, pediatric care, perinatal care, cancer professional
  • 基本医学総論
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 発達、小児医療、周産期医療、がんプロフェッショナル development, pediatric care, perinatal care, cancer professional
  • 基盤医学研究
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 発達、小児医療、周産期医療、がんプロフェッショナル
  • 臨床医学研究
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 発達、小児医療、周産期医療、がんプロフェッショナル
  • 医学総論
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 発達、小児医療、周産期医療、がんプロフェッショナル
  • 小児科学・小児外科学
    開講年度 : 2021年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : 小児科学


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