Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: in vitro characterization of a novel mutation (p.Arg511Trp)
Article first published online: 12 MAR 2013
© 2012 Blackwell Publishing Ltd
Volume 78, Issue 4, pages 558–563, April 2013
How to Cite
Leal, A. C., Montenegro, L. R., Saito, R. F., Ribeiro, T. C., Coutinho, D. C., Mendonca, B. B., Arnhold, I. J. P. and Jorge, A. A. L. (2013), Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: in vitro characterization of a novel mutation (p.Arg511Trp). Clinical Endocrinology, 78: 558–563. doi: 10.1111/cen.12048
- Issue published online: 12 MAR 2013
- Article first published online: 12 MAR 2013
- Accepted manuscript online: 21 SEP 2012 08:42AM EST
- Manuscript Accepted: 31 AUG 2012
- Manuscript Revised: 6 AUG 2012
- Manuscript Revised: 11 JUL 2012
- Manuscript Received: 11 JUN 2012
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP). Grant Number: 08/57915-2
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). Grant Numbers: 142062/06-5, 301339/2008-9, 300938/06-3, 475870/2009-3, 301477/2009-4
Insulin-like growth factor 1 insensitivity caused by IGF1R mutations has been previously identified as one of the causes of growth impairment in children born small for gestational age (SGA).
To analyse the IGF1R in children born SGA.
From an initial cohort of 54 sequential children born SGA, without catch-up growth, 25 children were selected for this IGF1R study due to the presence of serum IGF-1 values above the mean for their age and sex.
The proximal IGF1R promoter region, the entire coding region and the exon–intron boundaries were directly sequenced, and multiplex ligation-dependent probe amplification analysis was performed. Fibroblast cultures were developed from one patient with a mutation for the in vitro characterization of IGF-1 insensitivity.
The copy number variation analysis did not identify deletions involving the IGF1R gene. We identified two children carrying heterozygous nucleotide substitutions in IGF1R: c.16G>A/p.Gly6Arg and c.1531C>T/p.Arg511Trp. The first variant (p.Gly6Arg) was identified in control subjects (0·3%) and in a relative with normal growth; thus, it was considered to be a rare benign allelic variation. The second variant (p.Arg511Trp) was not found in 306 alleles from control subjects, and it segregated with the growth impairment phenotype in the patient's family. Fibroblasts obtained from this patient had a significantly reduced proliferative response and AKT phosphorylation after IGF-1 stimulation compared with control fibroblasts.
The identification of an inactivating IGF1R mutation in the present cohort should encourage further studies of larger series to establish the precise frequency of this molecular defect in children with growth impairment of a prenatal onset.