Selective Deficiency of Gsα and the Possible Role of Alternative Gene Products of GNAS in Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism Type Ia

Abstract

Objective: Albright hereditary osteodystrophy (AHO) and Pseudohypoparathyroidism type Ia (PHPIa) are caused by an inherited deficiency of Gsα, encoded by the GNAS gene. Apart from an exclusive first exon, Gsα shares part of the transcribed regions with NESP55, Exon A/B and XLαs, 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 Gsα, 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 Gsα. The female patient demonstrated a fully expressed AHO and PHPIa phenotype and a decreased Gsα 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 Gsα is sufficient for the expression of an AHO phenotype, which cannot be compensated by alternative products of GNAS.

Albright hereditary osteodystrophy - Pseudohypoparathyroidism type Ia - GNAS mutations

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