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Study on IGF-I insensitivity: Function and phenotype of mutated IGF-I receptor gene

IGF-I不敏感性研究：突变IGF-I受体基因的功能和表型

基本信息

批准号：
18591153
负责人：
KANZAKI Susumu
金额：
$ 2.49万
依托单位：
Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591153/
关键词：
insulin-like growth factor IUGR short stature Type 1 IGF receptor IGF insensitivity I型IGF受容体

项目摘要

Context: Insulin-like growth factor (IGF-I) plays key roles in intrauterine fetal growth as well as postnatal growth via IGF-I receptor (IGF-IR). Recently, IGF-IR gene mutations have been reported in four patients with short stature born intrauterine growth retardation (IUGR).Subjects and Methods: We analyzed the nucleotide sequences of IGF-IR gene in 29 patients with IUGR short stature. Mutated IGF-IR gene was transfected in 3T3-like mouse embryo cells with a targeted disruption of the IGF-IR genes (R-cells). Functions of mutated IGF-IR in transfected R-cells were evaluated by IGF-I binding, IGF-I stimulated DNA synthesis and ss-subunit autophosphorylation and internalization analysis.Results: 1) A new heterozygous missense mutation at L2 domain of IGF-IR (R431L) was identified in a 6-year-old Japanese girl with IUGR short stature and her mother. 2) DNA synthesis induced by IGF-I was significantly decreased in R-cells transfected with mutated IGF-IR. 3) IRS-2 phosphorylation in response to IGF-I was decreased in R-cells transfected with mutated IGF-IR. 4) Internalization was decreased in R-cells transfected with mutated IGF-IR.Conclusion: A missense mutation (R431L) causes decreased IGF action by decreased internalization of IGF-IR, and results in growth retardation. The results of this study provide new important information on IUGR short stature with IGF-IR mutation and a role of L2 domain of IGF-IR.

背景：胰岛素样生长因子（IGF-I）通过IGF-I受体（IGF-IR）在胎儿宫内生长和出生后生长中起关键作用。近年来，在4例矮小型胎儿宫内发育迟缓（IUGR）患者中发现了IGF-IR基因突变。将突变的IGF-IR基因转染到具有IGF-IR基因的靶向破坏的3 T3样小鼠胚胎细胞（R细胞）中。结果：1）在一名6岁IUGR矮小日本女孩及其母亲中发现一个新的IGF-IR L2区错义突变（R431 L）。2)在转染突变型IGF-IR的R-细胞中，IGF-I诱导的DNA合成显著减少; 3）在转染突变型IGF-IR的R-细胞中，IRS-2对IGF-I的磷酸化反应降低; 4）在转染突变型IGF-IR的R-细胞中，内化作用降低。错义突变（R431 L）通过降低IGF-IR的内化而导致IGF作用降低，并导致生长迟缓。本研究结果为IUGR矮小症的IGF-IR突变及IGF-IR L2结构域的作用提供了新的重要信息。