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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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)

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Author(s):
Leal, Andrea C. [1, 2] ; Montenegro, Luciana R. [2] ; Saito, Renata F. [3] ; Ribeiro, Tamaya C. [2] ; Coutinho, Debora C. [2] ; Mendonca, Berenice B. [2] ; Arnhold, Ivo J. P. [2] ; Jorge, Alexander A. L. [1, 2]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Fac Med, Lab Endocrinol Celular & Mol LIM 25, Hosp Clin, Unidade Endocrinol Genet, Disciplina Endocrinol, BR-01246903 Sao Paulo - Brazil
[2] Univ Sao Paulo, Fac Med, Lab Hormonios & Genet Mol LIM 42, Hosp Clin, Unidade Endocrinol Desenvolvimento, Disciplina End, BR-01246903 Sao Paulo - Brazil
[3] Univ Sao Paulo, Fac Med, Dept Radiol, Grp Adesao Celular, Lab Oncol Expt, BR-01246903 Sao Paulo - Brazil
Total Affiliations: 3
Document type: Journal article
Source: CLINICAL ENDOCRINOLOGY; v. 78, n. 4, p. 558-563, APR 2013.
Web of Science Citations: 11
Abstract

Background 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). Objective To analyse the IGF1R in children born SGA. Subjects 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. Methods The proximal IGF1R promoter region, the entire coding region and the exonintron 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. Results 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 center dot 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. Conclusion 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. (AU)