GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders

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.