インスリン様成長因子－Ⅰの転写因子と結合蛋白の異常による成長ホルモン不応症の解明

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24591512
• Research Institution: Tottori University
• Principal Investigator: 神崎 晋 鳥取大学, 医学部, 教授 (90224873)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: IGF-I受容体異常症 / 成長ホルモン不応症 / SGA性低身長 / Castleman病 / IL-6 / IGF-I / 小胞体関連分解

Outline of Annual Research Achievements

１． IGF-I受容体（IGF-IR）変異（p.Q1220X）の機能解析：SGAで出生し、著明なIGF-I高値298.4 ng/ml (3.8 SD)をみとめ、SGA性低身長症と診断。変異IGF-IR遺伝子(p.Q1220X)導入細胞は、変異IGF-IR蛋白の著明な発現低下を認めた。細胞はmRNAレベルではナンセンス変異依存性mRNA分解(NMD) pathwayによって、蛋白レベルでは小胞体関連分解(ERAD) pathwayによって、不完全（変異）蛋白の産生を抑制する。Emetine（NMD阻害）添加前後で、WTと変異IGF-IRのmRNAレベルに変化はなく、一方、MG132（ERAD阻害）添加で、変異IGF-IR発現が増加した。従って、変異IGF-IR蛋白の発現低下はERADの機序による。
２．IGF-I受容体（IGF-IR）変異（p.Q1219X）の機能解析：SGAで出生し、SGA性低身長症と診断された。患者末梢血単核球のIGF-IR遺伝子のmRNAの発現量は健常対象と差は無く、p.Q1250X変異では優勢阻害効果を介した蛋白量の低下も認めなかった。本変異はp.Q1220Xの隣であり、ERADを介したIGF-IR発現低下に起因すると考えられた。
３．Castleman病の低身長：低身長（-4.5 SD）と間歇熱で受診し,下腹部に腫瘤を認めた14歳男児。血中IL-6 (97.3 pg/mL, 基準値：<4.0)高値と,IGF-I (28 ng/mL, 基準値：<180)低値をみとめた。腫瘤摘出に伴い、血中IL-6は正常化し,血中IGF-Iの上昇と身長増加の改善がみとめられた。IL-6はIGF-I産生を抑制し,GH不応症の原因となる。

Research Products

• [Journal Article] 11ヵ月の男児に発症した乳瘤の1例 (2015)
  • Author(s): 宮原 直樹, 鞁嶋 有紀, 藤本 正伸, 西村 玲, 花木 啓一, 神崎 晋
  • Journal Title: 小児科 Volume: 56 Pages: 211-215
  • Peer Reviewed
• [Journal Article] Morphological diagnosis of Alport syndrome and thin basement membrane nephropathy by low vacuum scanning electron microscopy (2014)
  • Author(s): Okada S, Inaga S, Kitamoto K, Kawaba Y, Nakane H, Naguro T, Kaidoh T, Kanzaki S
  • Journal Title: Biomedical Research Volume: 35 Pages: 345-350
  • Peer Reviewed
• [Journal Article] Clinical overview of nephrogenic diabetes insipidus based on a nationwide survey in Japan (2014)
  • Author(s): Fujimoto M, Okada S, Kawashima Y, Nishimura R, Miyahara N, Kawaba Y, Hanaki K, Nanba E, Kondo Y, Igarashi T, Kanzaki S
  • Journal Title: Yonago Acta Medica Volume: 57 Pages: 85-91
  • Peer Reviewed
• [Journal Article] A rare CYP 21 mutation (p.E431K) induced deactivation of CYP 21A2 and resulted in congenital adrenal hyperplasia (2014)
  • Author(s): Kawashima Y, Usui T, Fujimoto M, Miyahara N, Nishimura R, Hanaki K, Kanzaki S
  • Journal Title: Endocrine Journal Volume: 62 Pages: 101-106
  • DOI: 10.1507/endocrj.EJ14-0437
  • Peer Reviewed
• [Journal Article] Early predictors of status epilepticus-associated mortality and morbidity in children (2014)
  • Author(s): Maegaki Y, Kurozawa Y, Tamasaki A, Togawa M, Tamura A, Hirao M, Nagao A, Kouda T, Okada T, Hayashibara H, Harada Y, Urushibara M, Sugiura C, Sejima H, Tanaka Y, Matsuda-Ohtahara H, Kasai T, Kishi K, Kaji S, Toyoshima M, Kanzaki S, Ohno K; Status Epilepticus Study Group
  • Journal Title: Brain and Development Volume: 37 Pages: 478-486
  • DOI: 10.1016/j.braindev.2014.08.004
  • Peer Reviewed
• [Journal Article] A novel approach to the histological diagnosis of pediatric nephrotic syndrome by low vacuum scanning electron microscopy (2014)
  • Author(s): Okada S, Inaga S, Kawaba Y, Hanada T, Hayashi A, Nakane H, Naguro T, Kaidoh T, Kanzaki S
  • Journal Title: Biomedical Research Volume: 35 Pages: 227-236
  • Peer Reviewed
• [Journal Article] Effect of growth hormone treatment on quality of life in Japanese children with growth hormone deficiency: an analysis from a prospective observational study (2014)
  • Author(s): Tanaka T, Hasegawa T, Ozono K, Tanaka H, Kanzaki S, Yokoya S, Chihara K, Iwamoto N, Seino Y
  • Journal Title: Clinical Pediatric Endocrinology Volume: 23 Pages: 83-92
  • DOI: 10.1297/cpe.23.83
  • Peer Reviewed
• [Journal Article] Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism (2014)
  • Author(s): Izumi Y, Suzuki E, Kanzaki S, Yatsuga S, Kinjo S, Igarashi M, Maruyama T, Sano S, Horikawa R, Sato N, Nakabayashi K, Hata K, Umezawa A, Ogata T, Yoshimura Y, Fukami M
  • Journal Title: Fertility and Sterility Volume: 102 Pages: 1130-1136
  • DOI: 10.1016/j.fertnstert.2014.06.017
  • Peer Reviewed
• [Journal Article] Gender differences in childhood food preference: evaluation using a subjective picture choice method (2014)
  • Author(s): Kimura S, Endo Y, Minamimae K, Kanzaki S, Hanaki K
  • Journal Title: Pediatrics International Volume: 56 Pages: 389-394
  • DOI: 10.1111/ped.12276
  • Peer Reviewed
• [Journal Article] 【神経症候群(第2版)-その他の神経疾患を含めて-】 先天異常/先天奇形 染色体異常・先天奇形症候群 Leprechaunism(Donohue症候群) (2014)
  • Author(s): 西村 玲, 神崎 晋
  • Journal Title: 日本臨床 Volume: 別冊神経症候群IV Pages: 594-597
• [Journal Article] 【最新肥満症学-基礎・臨床研究の最前線-】 症候性肥満の成因と病態 遺伝性肥満 Alstroem症候群 (2014)
  • Author(s): 木下 朋絵, 花木 啓一, 神崎 晋
  • Journal Title: 日本臨床 Volume: 72 Pages: 370-374
• [Journal Article] 日本人における臍帯血中多価不飽和脂肪酸の特徴 (2014)
  • Author(s): 宮原 史子, 松下 博亮, 美野 陽一, 三浦 真澄, 船田 裕昭, 村上 潤, 神崎 晋
  • Journal Title: 日本周産期・新生児医学会雑誌 Volume: 50 Pages: 256-262
  • Peer Reviewed
• [Presentation] Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency Derived from Novel Compound Heterozygous Mutations (IVS2-13 A/C>G and p.E431K) (2014)
  • Author(s): Kawashima Y, Okayama Y, Fujimoto F, Miyahara N, Nishimura R, Hanaki K, Usui T, Kanzaki S
  • Organizer: The Endocrine Society's 96th Annual Meeting & Expo
  • Place of Presentation: McCormick Place (Chicago), USA
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] Three Novel Heterozygous Mutations Were Found in Exon 1 and Intron 1 of GNAS Gene in Patients with Pseudohypoparathyroidism Type 1a (2014)
  • Author(s): Nishimura R, Usui T, Okayama Y, Fujimoto M, Miyahara M, Kawashima Y, Hanaki k, Kanzaki S
  • Organizer: The Endocrine Society's 96th Annual Meeting & Expo
  • Place of Presentation: McCormick Place (Chicago), USA
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] SGA Short Stature Bearing with a Novel Nonsense Mutation (p.W1219X) in the IGF1R Gene (2014)
  • Author(s): Fujimoto M, Kawashima Y, Hamajima T, Okayama Y, Miyahara M, Nishimura R, Hanaki K, Kanzaki S
  • Organizer: The Endocrine Society's 96th Annual Meeting & Expo
  • Place of Presentation: McCormick Place (Chicago), USA
  • Year and Date: 2014-06-21 – 2014-06-24