Objective: Albright hereditary osteodystrophy (AHO) and Pseudohypoparathyroidism type Ia (PHPIa) are caused by an inherited deficiency of Gsalpha, encoded by the GNAS gene. Apart from an exclusive first exon, Gsalpha shares part of the transcribed regions with NESP55, Exon A/B and XLalphas, 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 Gsalpha, would lead to a different phenotype than mutations affecting the common exons 2-13.
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 1 bp deletion of a guanine in codon 31 in exon 1 of the GNAS gene leading to a frame shift and premature termination of Gsalpha. The female patient demonstrated a fully expressed AHO and PHPIa phenotype and a decreased Gsalpha 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 2-13.
Conclusion: Disruptive mutations in exon 1 indicate that exclusive deficiency of Gsalpha is sufficient for the expression of an AHO phenotype, which cannot be compensated by alternative products of GNAS.
J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart. New York.