In:
Clinical Endocrinology, Wiley, Vol. 83, No. 6 ( 2015-12), p. 834-841
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0300-0664
,
1365-2265
DOI:
10.1111/cen.2015.83.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2004597-9
Permalink