Molecular Analysis of Growth Hormone Releasing Hormone Receptor Gene (GHRH-R) in isolated growth hormone deficiency: identification of a likely etiological mutation in the signal peptide

The coding sequence, the intron-exon boundaries and the proximal promoter of the growth hormone releasing hormone receptor gene (GHRH-R) were screened for sequence variations in 22 unrelated Italian patients with isolated growth hormone deficiency (IGHD). Six single nucleotide variations were detected in the 5′ flanking region, five in the intronic sequences and five leading to amino acid substitutions. All the variations had comparable frequencies in the patients and in controls except for T29C, leading to a Val10Gly substitution in the signal peptide, which was present in the heterozygous state in one patient and was never detected in 1,226 control chromosomes. Gly has different physio-chemical properties from Val and Ile commonly present in the homologous position in closely related species, and it is never found in the corresponding position of eukaryotic signal peptides. Thus this missense substitution might represent a new IGHD etiological dominant mutation acting through a pathophysiological mechanism involving the signal peptide.