Selective deficiency of gs and the possible role of alternative gene products of GNAS in albright hereditary osteodystrophy and pseudohypoparathyroidism type Ia

Objective: Albright hereditary osteodystrophy (AHO) and Pseudohypoparathyroidism type Ia (PHPIa) are caused by an inherited deficiency of Gs, encoded by the GNAS gene. Apart from an exclusive first exon, Gs shares part of the transcribed regions with NESP55, Exon A/B and XLs, whose gene products utilize alternative promoter regions of this complex gene locus. However, it is not known, whether the deficiency of all gene products contributes to the AHO and PHPIa phenotype or if they are even causative for some specific symptoms. In these cases, mutations affecting selectively GNAS exon 1, coding only for Gs, would lead to a different phenotype than mutations affecting the common exons 213. Methods: Clinical and molecular genetic analysis of a patient with features of AHO and review of exclusive exon 1 mutations of GNAS. Results: We detected a novel heterozygous 1bp deletion of a guanine in codon 31 in exon 1 of the GNAS gene leading to a frame shift and premature termination of Gs. The female patient demonstrated a fully expressed AHO and PHPIa phenotype and a decreased Gs protein activity of 62% compared to the wild type. Mutations in exon 1 are almost exclusively disruptive and lead to an AHO phenotype that does not show obvious differences from those provoked by missense or nonsense mutations in exon 213. Conclusion: Disruptive mutations in exon 1 indicate that exclusive deficiency of Gs is sufficient for the expression of an AHO phenotype, which cannot be compensated by alternative products of GNAS.