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Clin Endocrinol (Oxf). 2015 Dec;83(6):834-41. doi: 10.1111/cen.12791. Epub 2015 May 11.

Heterozygous nonsense mutations near the C-terminal region of IGF1R in two patients with small-for-gestational-age-related short stature.

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Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago, Japan.
Department of Pediatrics, Nagoya City West Medical Center, Nagoya, Japan.
Department of Pediatric Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Obu, Japan.
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
Department of Women's & Children's Family Nursing, Tottori University Faculty of Medicine, Yonago, Japan.



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.

[Indexed for MEDLINE]

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