GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders

Pseudohypoparathyroidism type 1a ( PHP 1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of A lbright's hereditary osteodystrophy ( AHO ). PHP 1a is caused by maternally inherited inactivating mutations of G s‐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 PHP 1a and its related disorders are reviewed together with the 343 kindreds with G s‐alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode G s‐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 PHP 1a/ 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.