GHR Gene Variants within Coding and Intronic Regions in Children with Idiopathic Short Stature.

BALLERINI MG; ROPELATO MG; SCAGLIA P; MARTINEZ A,CEDI; KESELMAN A; BRASLAVSKY D; BERGADÁ I; JASPER HG; ROPELATO MG; DOMENÉ HM

Dublin

Congreso; 53rd Annual ESPE Meeting; 2014

ESPE

Background: Heterozygous GHR gene variants were found in 5?8% of idiopathic short stature (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/IGF1/IGFBPs system. Methods:GHR gene (coding/intronic flanking regions) were PCR-amplified and sequenced in 64 unrelated ISS children (median height, range:K2.88, K4.79 to K2.00). The genotype influence on height and GH/IGF1/IGFBPs system was investigated for SNPs with a minor allele frequency (MAF) O10% (HapMap-Project). ISS children were grouped as: homozygous carriers for the major allele and carriers of one or two copies of the minor allele. IGF1 and IGFBP3 (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, IGF1?SDS,IGFBP3?SDS, or ALS?SDS (PO0.10 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 IGF1?SDS, IGFBP3?SDS, and ALS?SDS levels, two of them with low GHBP (!K1.8 SDS). These variants were not found in 41 control children. Conclusions: The prevalence ofheterozygous uncommon GHR variants was in accordance with previous studies. These variants could be present even in children with normal GHBP and GH-dependent factors. Common SNPs genotypes are distributed as reported in the general population and do not seem to have an impact on height or components of the GH/IGF1/IGFBPs system in ISS.