Premium
Heterozygous nonsense mutations near the C‐terminal region of IGF1R in two patients with small‐for‐gestational‐age‐related short stature
Author(s) -
Fujimoto Masanobu,
Kawashima Sonoyama Yuki,
Hamajima Naoki,
Hamajima Takashi,
Kumura Yumiko,
Miyahara Naoki,
Nishimura Rei,
Adachi Kaori,
Nanba Eiji,
Hanaki Keiichi,
Kanzaki Susumu
Publication year - 2015
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.12791
Subject(s) - insulin like growth factor 1 receptor , endocrinology , medicine , short stature , nonsense mutation , biology , mutation , receptor , genetics , gene , growth factor , missense mutation
Summary Objective 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. Patients and Methods 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 m RNA expression in whole blood cells. Results Two novel heterozygous nonsense mutations (case 1: p.Q1250X and case 2: p.W1249X) were identified. Although these mutations did not affect blood IGF1R m RNA levels, they significantly decreased the expression of IGF1R protein in transiently transfected cells. Treatment with the proteasome inhibitor MG 132 showed significantly increased IGF1R protein. Conclusions 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.