ESPE Abstracts (2014) 82 P-D-2-1-410

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

María Gabriela Ballerini, Paula Scaglia, Alicia Martínez, Ana Keselman, Débora Braslavsky, Ignacio Bergadá, Héctor Guillermo Jasper, María Gabriela Ropelato & Horacio Domené


Centro de Investigaciones Endocrinológicas ‘Dr César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina


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: −2.88, −4.79 to −2.00). The genotype influence on height and GH/IGF1/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. 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 (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 IGF1–SDS, IGFBP3–SDS, and ALS–SDS levels, two of them with low GHBP (<−1.8 SDS). These variants were not found in 41 control children.

Conclusions: The prevalence of heterozygous 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.

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