Heteroplasia, and Pseudohypoparathyroidism Type IB

Abstract

Abstract The heterotrimeric G protein Gs couples receptors for hormones and other extracellular signals to the stimulation of adenylyl cyclase and intracellular cyclic adenosine monophosphate (cAMP) generation. Ligand-bound receptors activate Gs by promoting the exchange GTP for GDP on the Gs α-subunit (Gsα); an intrinsic GTPase activity of Gsα deactivates the G protein by hydrolyzing bound GTP to GDP. Somatic Gsα mutations that disrupt the GTPase activity result in constitutive signaling and lead to endocrine tumors, fibrous dysplasia (FD) of bone, and the McCune–Albright syndrome (MAS) (OMIM 174800). Conversely, heterozygous inactivating mutations may lead to Albright hereditary osteodystrophy (AHO) (OMIM 13580) or, more rarely, to progressive osseous heteroplasia (POH) (OMIM 166350). Within AHO kindreds, paternal transmission of these mutations leads to the AHO phenotype alone [pseudopseudo- hypoparathyroidism (PPHP)], whereas maternal transmission leads to AHO plus multihormone resistance [pseudohypoparathyroidism type IA (PHPIA)]. This is presumably due to the fact that the Gsα gene GNAS is imprinted and in certain hormone-sensitive tissues Gsα is primarily expressed from the maternal allele. Patients with isolated renal resistance to parathyroid hormone (PTH) [pseudohy- poparathyroidism type IB (PHPIB)] (OMIM 603233) have a GNAS imprinting defect that presumably leads to tissue-specific loss of Gsα expression.