Growth hormone insensitivity due to anomalies of insulin-like growth factor systems

• Project/Area Number: 16K09989
• 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(Kenkyū-buntansha): 岡田 晋一 鳥取大学, 医学部, 准教授 (50343281)
• Research Collaborator: KAWASHIMA yuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IGF不応症 / SGA性低身長症 / インスリン様成長因子 / IGF受容体異常症 / インスリン受容体基質１ / IRS1 / acid labile substance / ALS / インスリン受容体基質 / IGF結合蛋白 / SGA性低身長 / 新生児低血糖 / インスリンシグナル / IRS-2 / IGF-1 / 成長障害 / 低出生体重児

Outline of Final Research Achievements

Proband is a 14-year-old Japanese girl with SGA short stature. Her GH treatment did not improve her height. Additionally there was family history of SGA short stature. We decided to analyzed GH/IGF related genes in this family
Heterozygous missense mutation of acid labile subunit (ALS) gene (p.Arg229His) was detected in proband and her father with normal stature. Heterogeneous deletion of IRS1 gene (p.Ser685_Ser686del) was observed in proband, her elder sister and mother who were SGA short stature. We evaluated the function of these two mutated gene. ALS production in mutated IGFALS transfected cells was lower than that of wild type. Mutated IRS1 gene transfected cells decrease the IRS1 expression and phosphorylation of AKT is suppressed compared with wild type.　Her father bearing same ALS mutation has normal stature whereas her sister and mother bearing IRS1 mutation show SGA short stature. Therefore, we believe IRS1 mutation is the cause of short stature of this family.

Academic Significance and Societal Importance of the Research Achievements

体内発育遅延（SGA）性低身長症に対するGH治療が開始されたが、GH治療の効果が乏しい症例も存在する。SGAの原因の大半は胎内での栄養不良状態に起因しているが、IGF KOマウスがSGAを示したことから、IGF系の異常もSGA性低身長の原因となることが明らかになっている。
私たちはIGF受容体異常症でSGA性低身長となった症例を報告してきたが、今回はGH治療が不応であったSGA性低身長症の女児にIGF受容体の下流に存在するIRS1に変異を見出し、それがSGA性低身長の原因となっていることを明らかにした。
IRS1異常はGH治療に抵抗するSGA性低身長症の新しい病因である。

Research Products

• [Journal Article] Incidence of diabetes mellitus and neoplasia in Japanese short-statured children treated with growth hormone in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) (2017)
  • Author(s): Yokoya S, Hasegawa T, Ozono K, Tanaka H, Kanzaki S, Tanaka T, Chihara K, Jia N, Child CJ, Ihara K, Funai J, Iwamoto N, Seino Y
  • Journal Title: Clinical Pediatric Endocrinology Volume: 26 Issue: 4 Pages: 229-241
  • DOI: 10.1297/cpe.26.229
  • NAID: 130006105773
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed / Open Access
• [Journal Article] Increased IRS2 mRNA Expression in SGA Neonates: PCR Analysis of Insulin/IGF Signaling in Cord Blood (2017)
  • Author(s): Fujimoto M, Sonoyama YK, Fukushima K, Imamoto A, Miyahara F, Miyahara N, Nishimura R, Yamada Y, Miura M, Adachi K, Nanba E, Hanaki K, Kanzaki S.
  • Journal Title: J Endocr Soc Volume: 1 Issue: 12 Pages: 1408-1416
  • DOI: 10.1210/js.2017-00294
  • Peer Reviewed / Open Access
• [Journal Article] A novel frameshift mutation in <i>NR3C2</i> leads to decreased expression of mineralocorticoid receptor: a family with renal pseudohypoaldosteronism type 1 (2017)
  • Author(s): Kawashima Sonoyama Y, Tajima T, Fujimoto M, Hasegawa A, Miyahara N, Nishimura R, Hashida Y, Hayashi A, Hanaki K, Kanzaki S
  • Journal Title: Endocrine Journal Volume: 64 Issue: 1 Pages: 83-90
  • DOI: 10.1507/endocrj.EJ16-0280
  • NAID: 130005305976
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial respiratory chain complex I deficiency causes intractable gastrointestinal symptoms (2016)
  • Author(s): Kuranobu H, Murakami J, Kuranobu N, Okamoto K, Murayama K, Kanzaki S
  • Journal Title: Pediatr Int Volume: 58 Issue: 12 Pages: 1337-1340
  • DOI: 10.1111/ped.13080
  • Peer Reviewed
• [Journal Article] Effects of financial support on treatment of adolescents with growth hormone deficiency: a retrospective study in Japan (2016)
  • Author(s): Maeda E, Higashi T, Hasegawa T, Yokoya S, Mochizuki T, Ishii T, Ito J, Kanzaki S, Shimatsu A, Takano K, Tajima T, Tanaka H, Tanahashi Y, Teramoto A, Nagai T, Hanew K, Horikawa R, Yorifuji T, Wada N, Tanaka T
  • Journal Title: BMC Health Serv Res Volume: 16 Pages: 602-602
  • Peer Reviewed
• [Journal Article] Growth standard charts for Japanese children with mean and standard deviation (SD) values based on the year 2000 national survey (2016)
  • Author(s): Isojima T, Kato N, Ito Y, Kanzaki S, Murata M
  • Journal Title: Clinical Pediatric Endocrinology Volume: 25 Issue: 2 Pages: 71-76
  • DOI: 10.1297/cpe.25.71
  • NAID: 130005149088
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed
• [Journal Article] Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis. (2016)
  • Author(s): Shima H, Tanaka T, Kamimaki T, Dateki S, Muroya K, Horikawa R, Kanno J, Adachi M, Naiki Y, Tanaka H, Mabe H, Yagasaki H, Kure S, Matsubara Y, Tajima T, Kashimada K, Ishii T, Asakura Y, Fujiwara I, Soneda S, Nagasaki K, Hamajima T, Kanzaki S, Jinno T, Ogata T, Fukami M
  • Journal Title: J Hum Genet Volume: 未定 Issue: 7 Pages: 585-591
  • DOI: 10.1038/jhg.2016.18
  • NAID: 40020883994
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 胎児期の成長のメカニズムー最近の知見ー (2018)
  • Author(s): 神崎 晋
  • Organizer: 第28回臨床内分泌代謝update
  • Invited
• [Presentation] 新生児期早期の血糖値とインスリン/IGFシグナル の検討 (2017)
  • Author(s): 藤本正伸、鞁嶋有紀、澤由起子、宮原直樹、西村玲、足立香織、難波英二、花木啓一、神崎晋
  • Organizer: 第90回日本内分泌学会学術集会
  • Place of Presentation: 京都市勧業館みやこめっせ（京都府京都市）
  • Year and Date: 2017-04-20
• [Presentation] Insulin and IGF1 receptor signaling (2017)
  • Author(s): Kanzaki S
  • Organizer: 10th International Meeting of Pediatric Endocrinology
  • Int'l Joint Research / Invited
• [Presentation] IGFALS遺伝子及びIRS1遺伝子異常が同定されたSGA性低身長の一家系；新たな成長障害の解明 (2016)
  • Author(s): 鞁嶋有紀、長谷川亜紀子、藤本正伸、宮原直樹、西村玲、花木啓一、神崎晋
  • Organizer: 第50回日本小児内分泌学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-11-16
• [Book] 別冊日本臨床 内分泌症候群 Ⅳ 第3版 (2019)
  • Author(s): 神崎 晋
  • Total Pages: 641
  • Publisher: 日本臨床社
• [Book] 小児科診療ガイドライン 第4版 (2019)
  • Author(s): 長石純一、花木啓一、神崎 晋
  • Total Pages: 758
  • Publisher: 総合医学社
• [Book] 内分泌代謝科専門医研修ガイドブック (2018)
  • Author(s): 神崎 晋
  • Total Pages: 761
  • Publisher: 診断と治療社
• [Book] 成長曲線活用の実際 (2018)
  • Author(s): 村田光範、田中敏章、加藤則子、神崎晋
  • Total Pages: 98
  • Publisher: 日本学校保健会
• [Book] SHOX異常症 (2017)
  • Author(s): 緒方勤、神崎晋、深見真紀
  • Total Pages: 45
  • Publisher: 診断と治療社
  • ISBN: 9784787823175
• [Book] ヌーナン症候群のマネジメント (2017)
  • Author(s): 緒方勤、神崎晋 他
  • Total Pages: 117
  • Publisher: メディカルレビュー社
  • ISBN: 9784779220029
• [Book] 小児内分泌学第２版 分担：成長とその制御 (2016)
  • Author(s): 神崎晋
  • Total Pages: 7
  • Publisher: 診断と治療社