Growth hormone insensitivity due to disorders of insulin like growth factor system

• Project/Area Number: 24591512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tottori University
• Principal Investigator: KANZAKI Susumu 鳥取大学, 医学部, 教授 (90224873)
• Co-Investigator(Renkei-kenkyūsha): OKADA Shin-ichi 鳥取大学, 医学部, 准教授 (50343281) ; MURAKAMI Jun 鳥取大学, 医学部附属病院, 講師 (90362889) ; HANAKI Keiichi 鳥取大学, 医学部, 教授 (20238041) ; SONOYAMA Yuki (KAWASHIMA Yuki) 鳥取大学, 医学部, 講師 (20403412)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: IGF-I受容体異常症 / 成長ホルモン不応症 / SGA性低身長 / IGF-I / 小胞体関連分解 / Castleman病 / IL-6 / 偽性副甲状腺機能低下症 / 遺伝子変異

Outline of Final Research Achievements

We identified two novel heterozygous nonsense mutations of type 1 IGF receptor (IGF-IR) gene in 9-year-old boy (p.Q1220X) and 3-year-old girl (p.W1219X) with SGA short stature. The cells transfected with these mutated IGF-1R genes showed an extremely low level of the IGF-1R protein compared to those with wild type. These mutations cause premature stop codon (PTC) in exon 21, and result in the absence of the carboxyl terminal fragment of IGF-1R. Quality of protein production is usually controlled by two mechanism; nonsense-mediated mRNA decay (NMD) in mRNA stage and endoplasmic reticulum associated degradation (ERAD) in protein production. Emetine, that blocks NMD, did not improve IGF-IR mRNA expression in transfected cells. Whereas, addition of MG132, that blocks ERAD, could rescue the reduced IGF-IR protein productio. From the above results, we speculated that the mutation (p.W1219X and p.Q1220X) lead to decrease IGF-1R protein expression through ERAD, result in growth failure.

Research Products

• [Journal Article] A rare <i>CYP 21</i> mutation (p.E431K) induced deactivation of CYP 21A2 and resulted in congenital adrenal hyperplasia (2015)
  • Author(s): Kawashima Y, Usui T, Fujimoto M, Miyahara N, Nishimura R, Hanaki K, Kanzaki S
  • Journal Title: Endocrine Journal Volume: 62 Issue: 1 Pages: 101-106
  • DOI: 10.1507/endocrj.EJ14-0437
  • NAID: 130004699222
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [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
  • NAID: 130004701685
  • 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
  • NAID: 120005463512
  • 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 Issue: 5 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
  • NAID: 130004678578
  • 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 Issue: 3 Pages: 83-92
  • DOI: 10.1297/cpe.23.83
  • NAID: 130004677665
  • ISSN: 0918-5739, 1347-7358
  • 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: Fertil Steril Volume: 102(4) Issue: 4 Pages: 1130-1136
  • DOI: 10.1016/j.fertnstert.2014.06.017
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 3 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
• [Journal Article] Instability of KCNE1-D85N that Causes Long QT Syndrome: Stabilization by Verapamil (2014)
  • Author(s): Sakata S, Kurata Y, Li P, Notsu T, Morikawa K, Miake J, Higaki K, Yamamoto Y, Yoshida A, Shirayoshi Y, Yamamoto K, Horie M, Ninomiya H, Kanzaki S, Hisatome I.
  • Journal Title: Pacing Clinical Electrophysiology Volume: Epub ahead of print Issue: 7 Pages: 1-11
  • DOI: 10.1111/pace.12360
  • Peer Reviewed / Open Access
• [Journal Article] Familial short stature is associated with a novel dominant-negative heterozygous insulin-like growth factor 1 receptor (IGF1R) mutation (2014)
  • Author(s): Kawashima Y, Hakuno F, Okada SI, Hotsubo T, Kinoshita T, Fujimoto M, Nishimura R, Fukushima T, Hanaki K, Takahashi SI, Kanzaki S
  • Journal Title: Clinical Endocrinology (Oxf) Volume: Epub ahead of print Issue: 2 Pages: 1-3
  • DOI: 10.1111/cen.12317
  • Peer Reviewed
• [Journal Article] 小児の心房中隔欠損症におけるcrochetageパターンの年齢群別の差異および血行動態との関係の検討 (2014)
  • Author(s): 船田 裕昭, 坂田 晋史, 倉信 裕樹, 橋田 祐一郎, 美野 陽一, 辻 靖博, 神崎 晋
  • Journal Title: 日本小児循環器学会雑誌 Volume: 30 Pages: 22-29
  • NAID: 130003398231
  • Peer Reviewed
• [Journal Article] 小児科から内科へのシームレスな診療をめざして: 疾患各論 代謝・内分泌 (2013)
  • Author(s): 神崎 晋, 藤本 正伸, 西村 玲
  • Journal Title: 診断と治療 Volume: 101 Pages: 1813-1818
• [Journal Article] 小児における負荷試験とは? (2013)
  • Author(s): 藤本正伸 鞁嶋有紀 花木啓一 神崎 晋
  • Journal Title: 小児内科 Volume: 45 Pages: 780-783
• [Journal Article] 腎性尿崩症 何故バソプレシン不応になるのか (2013)
  • Author(s): 岡田 晋一, 西村 玲 神崎 晋
  • Journal Title: Fluid Management Renaissance Volume: 3 Pages: 168-173
• [Journal Article] oncologic emergencyを呈して発見された縦隔原発非ホジキンリンパ腫 (2013)
  • Author(s): 橋田 祐一郎, 上山 潤一, 米田 尚弘, 佐野 仁志, 奥野 啓介, 神崎 晋
  • Journal Title: 小児科 Volume: 54 Pages: 1977-1982
• [Journal Article] EBNA-2 -deleted Epstein-Barr virus from P3HR-1 can infect rabbits with lower efficiency than prototype Epstein-Barr virus from B95-8. (2013)
  • Author(s): Sano H, Nagata K, Kato K, Kanai K, Yamamoto K, Okuno K, Kuwamoto S, Higaki-Mori H, Sugihara H,Kato M, Murakami I, Kanzaki S, Hayashi K.
  • Journal Title: Intervirology Volume: 56 Issue: 2 Pages: 114-21
  • DOI: 10.1159/000343753
  • Peer Reviewed
• [Journal Article] An observational study of the effectiveness and safety of growth hormone (Humatrope(R)) treatment in Japanese children with growth hormone deficiency or Turner syndrome (2013)
  • Author(s): Tai S
  • Journal Title: Endocrine Journal Volume: 60 Pages: 57-64
  • Peer Reviewed
• [Journal Article] Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene. (2013)
  • Author(s): Kawashima Y
  • Journal Title: Endocrine Journal Volume: 60 Pages: 107-112
  • NAID: 10031156729
  • Peer Reviewed
• [Journal Article] Castleman disease in a child with short stature (2012)
  • Author(s): Hanada T, Okuno K, Okada S, Fujimoto M, Kuranobu H, Hashida Y, Ueyama J, Murakami J, Hayashi A, Hanaki K, Kanzaki S.
  • Journal Title: Pediatr Int Volume: 54(5) Issue: 5 Pages: 720-4
  • DOI: 10.1111/j.1442-200x.2012.03589.x
  • Peer Reviewed
• [Journal Article] Eisk factors for mother-to-child transmission of hepatitis C virus : Maternal high viral load and fetal exposure in the birth canal (2012)
  • Author(s): Murakami J
  • Journal Title: Hepatology Research Volume: (印刷中) Issue: 7 Pages: 648-657
  • DOI: 10.1111/j.1872-034x.2012.00968.x
  • Peer Reviewed
• [Journal Article] Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation (2012)
  • Author(s): Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi JI, Hanaki K, Nanba E, Takahashi SI, Kanzaki S
  • Journal Title: Clin.Endocrinol. Volume: (in press) Issue: 2 Pages: 246-54
  • DOI: 10.1111/j.1365-2265.2012.04357.x
  • Peer Reviewed
• [Journal Article] Familial short stature with IGF-I receptor gene anomaly. (2012)
  • Author(s): Kawashima Y
  • Journal Title: Endocrine Journal Volume: 59 Pages: 179-185
  • NAID: 10030748947
  • 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
• [Presentation] A nonsense mutation at the carboxyl terminal region of IGF1R (p.Q1220X) leads to reduction in IGF-1R protein level, and results in SGA short stature (2013)
  • Author(s): Masanobu Fujimoto, Yuki Kawashima, Naoki Hamajima, Rei Nishimura, Keiichi Hanaki and Susumu Kanzaki
  • Organizer: The Endocrine Society's 95th Annual meeting & Expo
  • Place of Presentation: Moscone Center (San Francisco, USA)
• [Presentation] A novel nonsense mutation at carboxyl terminal region of IGF-1R (p.Q1220X) causes reduction of the IGF-1R protein, and results in SGA short stature (2013)
  • Author(s): Masanobu Fujimoto; Yuki Kawashima; Naoki Hamajima; Rei Nishimura; Keiichi Hanaki; Susumu Kanzaki
  • Organizer: 9th Joint Meeting of Paediatric Endocrinology
  • Place of Presentation: Milano Congressi (Milan, Italy)
• [Presentation] Congenital adrenal hyperplasia due to 21-hydroxylase deficiency derived from novel compound heterozygous mutations (IVS2-13 A/ C>G and p.E431K) (2013)
  • Author(s): Yuki Kawashima; Yoshiki Okayama; Masanobu Fujimoto; Naoki Miyahara; Rei Nishimura; Keiichi Hanaki; Takeshi Usui; Susumu Kanzaki
  • Organizer: 9th Joint Meeting of Paediatric Endocrinology
  • Place of Presentation: Milano Congressi (Milan, Italy)
• [Presentation] IGF-I受容体遺伝子に新規変異を認めたSGA性低身長の１例 (2012)
  • Author(s): 鞁嶋有紀
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
• [Presentation] A novel mutation (p.D1105E) of IGF1R detected in a family of short stature has dominant negative effect to IGF1R, not to IR (2012)
  • Author(s): Kawashima Y
  • Organizer: Sixth International Congress of the GRS and the IGF Society
  • Place of Presentation: The Gasteig (Munich, Germany)
• [Presentation] SGA short stature bearing with a nonsense mutation (p.Q1220X) of the IGF-I receptor (2012)
  • Author(s): Fujimoto M
  • Organizer: The Endocrine Society's 94th Annual Meeting
  • Place of Presentation: Houston Convention Center (Houston, USA)
• [Book] 標準小児科学 第8版 (2013)
  • Author(s): 神崎 晋
  • Publisher: 医学書院
• [Book] 今日の小児治療指針 (2012)
  • Author(s): 大関武彦
  • Publisher: 医学書院