ESPE Abstracts (2015) 84 P-2-405

ESPE2015 Poster Category 2 GH & IGF (40 abstracts)

SGA Short Stature Bearing with a Novel Nonsense Mutation (p.W1249X) in the IGF1R Gene

Masanobu Fujimoto a , Yuki Kawashima a , Takashi Hamajima b , Naoki Miyahara a , Rei Nishimura a , Keiichi Hanaki a & Susumu Kanzaki a

aTottori University, Yonago, Japan; bAichi Children’s Health and Medical Center, Obu, Japan

Background: The type I IGF1R plays a role in intrauterine and postnatal growth. Heterozygous IGF1R mutations have been identified in over 20 families. Some of them are linked to the etiology of short stature in previous studies. In addition, we previously reported that a heterozygous nonsense mutation (p.Q1250X) of the IGF1R gene led to decrease IGF1R protein expression through endoplasmic reticulum-associated protein degradation (ERAD) mechanism, resulted in growth failure.

Objective: We aimed to describe the clinical features of the patient with a novel mutation in the IGF1R gene and to evaluate the molecular characteristics of it.

Case presentation and method: A 3-year-old Japanese girl, with a birth weight of 2.110 g (−3.0 SDS) and height of 44.3 cm (−2.8 SDS), had a short stature (−3.1 SDS). At the age of 2.4 years, her basal serum GH level was high (10.5 ng/ml), but serum IGF1 level showed upper limit of normal (185 ng/ml). We analyzed IGF1R gene in the patient, determined the protein expression of mutated IGF1R and performed quantitative RT-PCR of IGF1R mRNA on whole blood cells. The analysis of IGF1R, ALS and IGFBP3 gene by multiplex ligation-dependent probe amplification (MLPA) was performed.

Results: A novel heterozygous nonsense mutations (p.W1249X) was identified in the IGF1R gene. The mutation site of p.W1249X is located next to p.1250X which causes the decrease of IGF1R protein through ERAD. Although this mutation did not affect blood IGF1R mRNA level, the expression of IGF1R protein was significantly decreased in transiently transfected cells. The copy number of IGF1R, ALS and IGFBP3 gene was normal.

Conclusion: It is suggested that the p.W1249X mutation of the IGF1R gene result in short stature through ERAD due to the location of the mutation.

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