GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders.

Manuel C Lemos,Rajesh V Thakker

doi:10.1002/humu.22696

Abstract

Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of Albright's hereditary osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to pseudopseudohypoparathyroidism (PPHP) characterized by AHO alone, or to progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, P < 0.0001). This mutation update and respective genotype–phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders.

Highlights

Pseudohypoparathyroidism (PHP) is characterized by hypocalcaemia and hyperphosphataemia due to parathyroid hormone (PTH) resistance
Sporadic de novo cases were more frequent in progressive osseous heteroplasia (POH) than in the other phenotypes (24.3% familial, 48.6% sporadic; 27.0% unknown; Fisher’s exact test, P = 0.003), and this may reflect a reduced reproductive fitness associated with the severity of POH
Exon A/B, located 2.5 kb upstream from exon 1, can splice onto exons 2–13 to produce a noncoding RNA involved in the imprinting of the GNAS locus, there is evidence for an amino terminally truncated form of Gs-alpha that is derived from this transcript and may have inhibitory activity [Puzhko et al, 2011]

Summary

Introduction

GTP-binding protein (Gs-alpha), which is a downstream signaling protein of the PTH receptor and of other G protein-coupled hormone receptors [Thakker, 2011]. Patients with pseudopseudohypoparathyroidism (PPHP) exhibit most of the somatic features of AHO in the absence of PTH resistance Both PHP1a and PPHP result from inherited inactivating mutations of GNAS and can coexist in the same family, but never in the same sibship. Patients with PHP1b do not have mutations within GNAS exons that encode Gs-alpha, but have methylation and imprinting defects resulting in the absence of expression of the maternal Gs-alpha [Turan et al, 2013] Another related disorder is PHP1c, which is identical to PHP1a in terms of the presence of AHO and hormone resistance, but in. The three reported cases with isolated OC (i.e., superficial heterotopic ossification without AHO or hormone resistance) and a GNAS mutation were all infants (aged 1, 3, and 6 years) [Elli et al, 2013a; Huh et al, 2014], so it remains to be confirmed whether this is a true GNAS-associated phenotypic category or rather the first manifestation of POH. For practical reasons, the term “germline mutation” is used throughout this article, one cannot exclude the possibility that some sporadic cases may be mosaics for a somatic mutation

GNAS Locus and Transcripts

Imprinting Defects of GNAS

Animal Models

Clinical and Diagnostic Relevance

Findings

Future Prospects