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青山 幸平アオヤマ コウヘイ

所属部署医学研究科新生児・小児医学分野
職名助教
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Last Updated :2020/06/02

研究者基本情報

基本情報

    科研費研究者番号:40812095

学位

  • 医学博士, 名古屋市立大学大学院医学研究科

経歴

  •   2018年10月 - 現在, 名古屋市立大学, 大学院医学研究科, 助教

研究活動情報

研究キーワード

    先天性甲状腺機能低下症, 低ゴナドトロピン性性腺機能低下症

論文

  • Transition from Leigh syndrome to MELAS syndrome in a patient with heteroplasmic MT-ND3 m.10158T>C., Kori A, Hori I, Tanaka T, Aoyama K, Ito K, Hattori A, Ban K, Okazaki Y, Murayama K, Saitoh S, Brain & development, 41, (9) 803 - 807,   2019年10月, 査読有り
  • Congenital goitrous hypothyroidism is caused by dysfunction of the iodide transporter SLC26A7., Ishii J, Suzuki A, Kimura T, Tateyama M, Tanaka T, Yazawa T, Arimasu Y, Chen IS, Aoyama K, Kubo Y, Saitoh S, Mizuno H, Kamma H, Communications biology, 2,   2019年, 査読有り
  • Individual Clinically Diagnosed with CHARGE Syndrome but with a Mutation in KMT2D, a Gene Associated with Kabuki Syndrome: A Case Report, Sonoko Sakata, Satoshi Okada, Kohei Aoyama, Keiichi Hara, Chihiro Tani, Reiko Kagawa, Akari Utsunomiya-Nakamura, Shinichiro Miyagawa, Tsutomu Ogata, Haruo Mizuno, Masao Kobayashi, FRONTIERS IN GENETICS, 8,   2017年12月, 査読有り, We report a Japanese female patient presenting with classic features of CHARGE syndrome, including choanal atresia, growth and development retardation, ear malformations, genital anomalies, multiple endocrine deficiency, and unilateral facial nerve palsy. She was clinically diagnosed with typical CHARGE syndrome, but genetic analysis using the TruSight One Sequence Panel revealed a germline heterozygous mutation in KMT2D with no pathogenic CHD7 alterations associated with CHARGE syndrome. Kabuki syndrome is a rare multisystem disorder characterized by five cardinal manifestations including typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate intellectual disability, and postnatal growth deficiency. Germline mutations in KMT2D underlie the molecular pathogenesis of 52-76% of patients with Kabuki syndrome. This is an instructive case that clearly represents a phenotypic overlap between Kabuki syndrome and CHARGE syndrome. It suggests the importance of considering the possibility of a diagnosis of Kabuki syndrome even if patients present with typical symptoms and meet diagnostic criteria of CHARGE syndrome. The case also emphasizes the impact of non-biased exhaustive genetic analysis by next-generation sequencing in the genetic diagnosis of rare congenital disorders with atypical manifestations.
  • Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome, Kei Ohashi, Takao Togawa, Tokio Sugiura, Koichi Ito, Takeshi Endo, Kohei Aoyama, Yutaka Negishi, Toyoichiro Kudo, Reiko Ito, Shinji Saitoh, ACTA PAEDIATRICA, 106, (11) 1817 - 1824,   2017年11月, 査読有り, Aim: We evaluated combined genetic analyses with targeted next-generation sequencing (NGS), multiplex ligation probe amplification (MLPA) of Jagged1 (JAG1) genes and microarray comparative genomic hybridisation (CGH) in subjects with Alagille syndrome, incomplete clinical features of Alagille syndrome and biliary atresia. Methods: Subjects recruited from April 2013 to December 2015 underwent a targeted NGS analysis, including JAG1 and Notch homolog 2 (NOTCH2). If no mutations were detected in JAG1 or NOTCH2, or if copy number variations were suggested by the NGS analysis, we performed an MLPA analysis of JAG1. We also performed a microarray CGH analysis with whole-exon deletion detected by the MLPA analysis. Results: We analysed 30 subjects with Alagille syndrome, nine with incomplete Alagille syndrome and 17 with biliary atresia and detected pathogenic mutations in JAG1 or NOTCH2 in 24/30 subjects with Alagille syndrome and in 4/9 subjects with incomplete Alagille syndrome. No pathogenic mutations were detected in subjects with biliary atresia. The frequency of JAG1 mutations was as follows: single nucleotide variants (51.9%), small insertion or deletion (29.6%) and gross deletion (18.5%). Conclusion: Combined genetic analyses achieved efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome.
  • Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism, Kohei Aoyama, Haruo Mizuno, Tatsushi Tanaka, Takao Togawa, Yutaka Negishi, Kei Ohashi, Ikumi Hori, Masako Izawa, Takashi Hamajima, Shinji Saitoh, JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, 30, (10) 1111 - 1118,   2017年10月, 査読有り, Background: Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n) CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH. Methods: We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing. Results: We detected 12 potentially pathogenic mutations in 11 families, with three having a mutation in ANOS1 (X-linked recessive); three and four having a mutation in FGFR1 and CHD7, respectively (autosomal dominant); and one having two TACR3 mutations (autosomal recessive). Among four patients with KS carrying a CHD7 mutation, one had perceptive deafness and two had a cleft lip/palate. Conclusions: The frequency of CHH genes in the Japanese was compatible with previous reports, except that CHD7 mutations might be more common. Furthermore, partial phenotype-genotype correlations were demonstrated in our cohort.
  • A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly, Yutaka Negishi, Fuyuki Miya, Ayako Hattori, Yoshikazu Johmura, Motoo Nakagawa, Naoki Ando, Ikumi Hori, Takao Togawa, Kohei Aoyama, Kei Ohashi, Shinobu Fukumura, Seiji Mizuno, Ayako Umemura, Yoko Kishimoto, Nobuhiko Okamoto, Mitsuhiro Kato, Tatsuhiko Tsunoda, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Makoto Nakanishi, Shinji Saitoh, BMC MEDICAL GENETICS, 18, (1) ,   2017年01月, 査読有り, Background: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder. Methods: Thirteen patients with an increased head circumference and neurological symptoms participated in the study. To evaluate the activation of the mTOR pathway, we performed western blot analysis to determine the expression levels of phosphorylated S6 ribosomal protein (phospho-S6 protein) in lymphoblastoid cell lines from 12 patients. Multiplex targeted sequencing analysis for 15 genes involved in the mTOR pathway was performed on 12 patients, and whole-exome sequencing was performed on one additional patient. Clinical features and MRI findings were also investigated. Results: We identified pathogenic mutations in six (AKT3, 1 patient; PIK3R2, 2 patients; PTEN, 3 patients) of the 13 patients. Increased expression of phospho-S6 protein was demonstrated in all five mutation-positive patients in whom western blotting was performed, as well as in three mutation-negative patients. Developmental delay, dysmorphic facial features were observed in almost all patients. Syndactyly/polydactyly and capillary malformations were not observed, even in patients with AKT3 or PIK3R2 mutations. There were no common phenotypes or MRI findings among these patients. Conclusions: A combination of genetic and biochemical methods successfully identified mTOR pathway involvement in nine of 13 (approximately 70%) patients with megalencephaly, indicating a major contribution of the pathway to the pathogenesis of megalencephaly. Our combined approach could be useful to identify patients who are suitable for future clinical trials using an mTOR inhibitor.
  • Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing, Takao Togawa, Tokio Sugiura, Koichi Ito, Takeshi Endo, Kohei Aoyama, Kei Ohashi, Yutaka Negishi, Toyoichiro Kudo, Reiko Ito, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Shigeo Kure, Shinji Saitoh, JOURNAL OF PEDIATRICS, 171, 171 - +,   2016年04月, 査読有り, Objectives To ascertain a molecular genetic diagnosis for subjects with neonatal/infantile intrahepatic cholestasis (NIIC) by the use of next-generation sequencing (NGS) and to perform a genotype-phenotype correlation. Study design We recruited Japanese subjects with NIIC who had no definitive molecular genetic diagnosis. We developed a diagnostic custom panel of 18 genes, and the amplicon library was sequenced via NGS. We then compared clinical data between the molecular genetically confirmed subjects with NIIC. Results We analyzed 109 patients with NIIC ("genetic cholestasis," 31 subjects; "unknown with complications" such as prematurity, 46 subjects; "unknown without complications," 32 subjects), and a molecular genetic diagnosis was made for 28 subjects (26%). The rate of positive molecular genetic diagnosis in each category was 22 of 31 (71%) for the "genetic cholestasis" group, 2 of 46 (4.3%) for the "unknown with complications" group, and 4 of 32 (12.5%) for the "unknown without complications" group. The grouping of the molecular diagnoses in the group with genetic cholestasis was as follows: 12 with Alagille syndrome, 5 with neonatal Dubin-Johnson syndrome, 5 with neonatal intrahepatic cholestasis caused by citrin deficiency, and 6 with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis with low gamma-glutamyl transpeptidase levels. Several clinical datasets, including age of onset, direct bilirubin, and aminotransferases, were significantly different between the disorders confirmed using molecular genetic diagnosis. Conclusion Targeted NGS can be used for molecular genetic diagnosis in subjects with NIIC. Clinical diagnosis should be accordingly redefined in the view of molecular genetic findings.


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