Genetic identification and functional analysis in Japanese families with a short stature

• Project/Area Number: 24591514
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: The University of Tokushima
• Principal Investigator: ITAKURA Mitsuo 徳島大学, ヘルスバイオサイエンス研究部, 非常勤講師 (60134227)
• Co-Investigator(Kenkyū-buntansha): INOUE Hiroshi 徳島大学, 疾患プロテオゲノム研究センター, 講師 (20294639) ; YAMASHITA Yukiko 徳島大学, 疾患プロテオゲノム研究センター, 技術補佐員 (40532502) ; YOSHIMOTO Katsuhiko 徳島大学, ヘルスバイオサイエンス研究部, 教授 (90201863) ; OYADOMARI Seiichi 徳島大学, 疾患プロテオゲノム研究センター, 教授 (90502534)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 低身長症 / 遺伝子変異 / グレリン受容体遺伝子 / GH放出ホルモン受容体遺伝子

Outline of Final Research Achievements

The genomic DNAs from 127 families with short stature were subjected to genetic studies and further functional studies. We identified two novel compound heterozygous GHRHR gene mutations such as p.G136V substitution (p.G136V) and IVS2+3a>g mutation (IVS2+3a>g) in the patient. Our functional analysis revealed that a p.G136V elicited no transcriptional activity increment in response to GHRH stimulation and the IVS2+3a>g would led to its aberrant splicing. We further analyzed SHOX genes which have not been charicterized in Japanese population, but SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were not identified.

Research Products

• [Journal Article] Germline deletion and a somatic mutation of the PRKAR1A gene in a Carney complex-related pituitary adenoma. (2015)
  • Author(s): T Iwata, T Tamanaha, R Koezuka, M Tochiya, H Makino, I Kishimoto, N Mizusawa, S Ono, N Inoshita, S Yamada, A Shimatsu, K Yoshimoto.
  • Journal Title: Eur J Endocrinol. Volume: 172 Issue: 1 Pages: K5-K10
  • DOI: 10.1530/eje-14-0685
  • NAID: 120005708868
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] FGFR4 Polymorphic Variants Modulate Phenotypic Features of Cushing Disease. (2014)
  • Author(s): Nakano-Tateno T, Tateno T, Hlaing MM, Zheng L, Yoshimoto K, Yamada S, Asa SL, Ezzat S.
  • Journal Title: Mol Endocrinol. Volume: 28 Issue: 4 Pages: 525-533
  • DOI: 10.1210/me.2013-1412
  • Peer Reviewed / Open Access
• [Journal Article] A Novel C-terminal Nonsense Mutation, Q315X, of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in a Japanese Familial Isolated Pituitary Adenoma Family. (2014)
  • Author(s): Iwata T, Yamada S, Ito J, Inoshita N, Mizusawa N, Ono S, Yoshimoto K.
  • Journal Title: Endocr Pathol. Volume: 25 Issue: 3 Pages: 273-281
  • DOI: 10.1007/s12022-014-9318-7
  • NAID: 120005708872
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MicroRNAs in Human Pituitary Adenomas. (2014)
  • Author(s): Li XH, Wang EL, Zhou HM, Yoshimoto K, Qian ZR.
  • Journal Title: Int J Endocrinol. Volume: 2014 Pages: 435171-435171
  • DOI: 10.1155/2014/435171
  • NAID: 120005704689
  • Peer Reviewed / Open Access
• [Journal Article] TMEM16E (GDD1) exhibits protein instability and distinct characteristics in chloride channel/pore forming ability. (2014)
  • Author(s): Tran TT, Tobiume K, Hirono C, Fujimoto S, Mizuta K, Kubozono K, Inoue H, Itakura M, Sugita M, Kamata N.
  • Journal Title: J Cell Physiol. Volume: 229(2) Issue: 2 Pages: 181-190
  • DOI: 10.1002/jcp.24431
  • Peer Reviewed
• [Journal Article] Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency. (2013)
  • Author(s): Soneda A, Adachi M, Muroya K, Asakura Y, Takagi M, Hasegawa T, Inoue H, Itakura M
  • Journal Title: Growth Horm IGF Res. Volume: 23 Issue: 4 Pages: 89-97
  • DOI: 10.1016/j.ghir.2013.03.003
  • Peer Reviewed
• [Journal Article] Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population (2013)
  • Author(s): Ikeda M, Aleksic B, Yamada K, Iwayama-Shigeno Y, Matsuo K, Numata S, Watanabe Y, Ohnuma T, Kaneko T, Fukuo Y, Okochi T, Toyota T, Hattori E, Shimodera S, Itakura M, Nunokawa A, Shibata N, Tanaka H, Yoneda H, Arai H, Someya T, Ohmori T, Yoshikawa T, Ozaki N, Iwata N
  • Journal Title: Mol Psychiatry Volume: 18(6) Issue: 6 Pages: 636-638
  • DOI: 10.1038/mp.2012.74
  • Peer Reviewed
• [Journal Article] Association Study of Fat-mass and Obesity-associated Gene and Body Mass Index in Japanese Patients with Schizophrenia and Healthy Subjects (2012)
  • Author(s): Watanabe SY
  • Journal Title: Clin Psychopharmacol Neurosci Volume: 10 Issue: 3 Pages: 185-189
  • DOI: 10.9758/cpn.2012.10.3.185
  • Peer Reviewed
• [Journal Article] Diabetic modifier QTL, Dbm4, affecting elevated fasting blood glucose concentrations in congenic mice. (2012)
  • Author(s): Takeshita S, et al.
  • Journal Title: Genes Genet Syst. Volume: 87 Pages: 341-346
  • Peer Reviewed
• [Journal Article] Bhlhe40, a potential diabetic modifier gene on Dbm1 locus, negatively controls myocyte fatty acid oxidation. (2012)
  • Author(s): Takeshita S,et al.
  • Journal Title: Genes Genet Syst. Volume: 87 Pages: 253-264
  • Peer Reviewed
• [Journal Article] Meta-analysis of association studies between DISC1 missense variants and schizophrenia in Japanese population. (2012)
  • Author(s): Kinoshita M, et al
  • Journal Title: Schizophr Res, Volume: 141(2-3): Issue: 2-3 Pages: 271-273
  • DOI: 10.1016/j.schres.2012.07.020
  • Peer Reviewed
• [Presentation] PRKAR1A を含む広範な胚細胞性欠失を認めた下垂体性巨人症の一例 (2014)
  • Author(s): 肥塚諒、玉那覇民子、菱田藍、橡谷真由、大畑洋子、槇野久士、島津章、岩田武男、吉本勝彦、井下尚子、山田正三、岸本一郎
  • Organizer: 第24回 臨床内分泌代謝Update
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] 成長ホルモン産生腺腫におけるPRKACA遺伝子活性化変異の検討 (2014)
  • Author(s): 小野信二、岩田武男, 水澤典子, 山田正三、吉本勝彦
  • Organizer: 第14回日本内分泌学会四国地方会
  • Place of Presentation: 徳島大学（徳島県徳島市）
  • Year and Date: 2014-09-06
• [Presentation] Mechanisms of tumorigenesis in GH adenomas (2013)
  • Author(s): Katsuhiko Yoshimoto
  • Organizer: 2nd Pituitary Expert Meeting in Asia (PEMA)
  • Place of Presentation: 韓国・ソウル Lotte Hotel Seoul
• [Presentation] 下垂体腫瘍組織にPRKAR1A遺伝子の体細胞変異を認めた下垂体巨人症の一例 (2013)
  • Author(s): 肥塚諒、玉那覇民子、菱田藍、橡谷真由、大畑洋子、槇野久士、島津章、岩田武男、吉本勝彦、井下尚子、山田正三、岸本一郎
  • Organizer: 第８６回京都内分泌同好会
  • Place of Presentation: 京都府・メルパルク京都
• [Book] 改訂版 Acromegaly Handbook (2013)
  • Author(s): 吉本勝彦、岩田武男、水澤典子、小野信二
  • Total Pages: 178
  • Publisher: メディカルレビュー社