GHR gene variants within coding and intronic regions in children with idiopathic short stature (ISS)

MARÍA G. BALLERINI; PAULA A. SCAGLIA; ALICIA S. MARTÍNEZ; ANA C. KESELMAN; DEBORA BRASLAVSKY; IGNACIO BERGADA; HÉCTOR G. JASPER; MARIA G ROPELATO; HORACIO M. DOMENÉ

Dublin

Congreso; 53rd Annual Meeting of the European Society for Paediatric Endocrinology; 2014

European Society for Pediatric Endocrinology

Heterozygous GHR gene variants were found in 5-8% of ISS children. Frequent polymorphisms within GHR coding regions, but not intronic SNPs, have been investigated in ISS. Objectives: To characterize GHR gene variants in ISS children, and to test their influence on height and the peripheral GH/IGF-I/IGFBPs system. Methods: GHR gene (coding/intronic flanking regions) were PCR-amplified and sequenced in 64 unrelated ISS children (median height, range: -2.88, -4.79 to -2.00). The genotype influence on height and GH/IGF-I/IGFBPs system was investigated for SNPs with a minor allele frequency (MAF)>10% (HapMap-Project). ISS children were grouped as: homozygous carriers for the major allele and carriers of one or two copies of the minor allele. IGF-I and IGFBP-3 (ICMA), ALS (RIA) and GHBP (in house functional immunofluorometric-assay) were measured1. Hardy-Weinberg equilibrium was verified. Fisher´s exact test and Mann-Whitney analysis were used as appropriate. Results: Eight common polymorphisms were identified: exon-3 deletion (MAF: 26%), rs6179 (exon-6, 23%), rs6180 (exon-10, 42%), rs12521020 (intron-1, 32%), rs10941579 (intron-2, 32%), rs33972388 and rs34223737 (intron-7, 37% and 2%, respectively), rs6880730 (intron-8, 3%). MAF in ISS were not different to the HapMap frequencies. SNPs genotypes were not associated to height, GHBP-SDS, IGF-I-SDS, IGFBP-3-SDS or ALS-SDS (p>0.10 for all analysis). Three heterozygous uncommon variants (exon-7: p.R229H, exon-10: p.R386C and p.C440F) were also identified in 3/64 children (4.7%) with normal IGF-I-SDS, IGFBP-3-SDS and ALS-SDS levels, 2 of them with low GHBP (