Fujimoto Masanobu, Kawashima Sonoyama Yuki, Hamajima Naoki, Hamajima Takashi, Kumura Yumiko, Miyahara Naoki, Nishimura Rei, Adachi Kaori, Nanba Eiji, Hanaki Keiichi, Kanzaki Susumu
Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago, Japan.
Department of Pediatrics, Nagoya City West Medical Center, Nagoya, Japan.
Clin Endocrinol (Oxf). 2015 Dec;83(6):834-41. doi: 10.1111/cen.12791. Epub 2015 May 11.
The type I insulin-like growth factor I receptor (IGF1R) plays an important role in growth. We aimed to evaluate the detailed mechanism underlying the effect of IGF1R on human growth.
We have performed sequence analysis of IGF1R in 55 patients with SGA short stature in Japan, since 2004, and identified novel heterozygous nonsense mutations in 2 patients: an 8-year-old Japanese boy (case 1), with a birthweight of 2228 g (-3·3 SDS) and height of 46 cm (-2·1 SDS), and a 3-year-old Japanese girl (case 2), with a birthweight of 2110 g (-3·0 SDS) and height of 44·3 cm (-2·8 SDS). Both patients had a short stature (-3·2 SDS, -3·1 SDS). We determined the protein expression of mutated IGF1R, assessed the effect of the endoplasmic reticulum-associated degradation (ERAD) pathway on mutated IGF1R, assessed the dominant-negative effect of IGF1R and performed quantitative RT-PCR analysis of IGF1R mRNA expression in whole blood cells.
Two novel heterozygous nonsense mutations (case 1: p.Q1250X and case 2: p.W1249X) were identified. Although these mutations did not affect blood IGF1R mRNA levels, they significantly decreased the expression of IGF1R protein in transiently transfected cells. Treatment with the proteasome inhibitor MG132 showed significantly increased IGF1R protein.
Heterozygous nonsense mutations affecting the C-terminal region (p.Q1250X, p.W1249X) of IGF1R decreased the expression of IGF1R through the ERAD pathway. Our study revealed the importance of the C-terminal region and the dosage of this receptor for growth.
I型胰岛素样生长因子I受体（IGF1R）在生长过程中发挥重要作用。我们旨在评估IGF1R对人类生长影响的详细机制。
自2004年以来，我们对55名日本SGA身材矮小患者的IGF1R进行了序列分析，并在2名患者中鉴定出新型杂合无义突变：一名8岁日本男孩（病例1），出生体重2228 g（-3.3 SDS），身高46 cm（-2.1 SDS）；一名3岁日本女孩（病例2），出生体重2110 g（-3.0 SDS），身高44.3 cm（-2.8 SDS）。两名患者均身材矮小（-3.2 SDS，-3.1 SDS）。我们测定了突变型IGF1R的蛋白表达，评估了内质网相关降解（ERAD）途径对突变型IGF1R的影响，评估了IGF1R的显性负效应，并对全血细胞中IGF1R mRNA表达进行了定量RT-PCR分析。
鉴定出两个新型杂合无义突变（病例1：p.Q1250X，病例2：p.W1249X）。虽然这些突变不影响血液中IGF1R mRNA水平，但它们显著降低了瞬时转染细胞中IGF1R蛋白的表达。用蛋白酶体抑制剂MG132处理后，IGF1R蛋白显著增加。
影响IGF1R C末端区域（p.Q1250X，p.W1249X）的杂合无义突变通过ERAD途径降低了IGF1R的表达。我们的研究揭示了C末端区域和该受体剂量对生长的重要性。
