Pseudohypoparathyroidism: new insight into Gsα

Abstract

Pseudohypoparathyroidism (PHP) is an endocrinopathy characterized by resistance to parathyroid hormone (PTH) in target tissues, resulting in hypocalcaemia and hyperphosphataemia despite increased secretion of PTH. PHP is subclassified according to additional biochemical and clinical criteria. In PHP type Ia, patients commonly show resistance to thyroid stimulating hormone (TSH) and luteinizing hormone (LH), as well as to PTH, and have clinical features known as Albright hereditary osteodystrophy (AHO) characterized by round faces, short stature and shortened fingers and toes. At the molecular level, PHPIa is known to result from heterozygous inactivating mutations in the gene GNAS1, which encodes the α-subunit of the heterotrimeric G-protein, Gs. Gs couples the receptors for various hormones, including PTH, TSH and LH, to activation of intracellular adenylyl cyclase. Patients with PHPIa show a 50% reduction in Gsα activity in their cell membranes.By contrast, PHP type Ib is characterized by isolated resistance to PTH, normal Gsα activity and absence of AHO. It was originally hypothesized that PHPIb would result from mutations of the PTH receptor gene, but extensive analysis failed to confirm this. Recently, PHPIb was localized to a region of chromosome 20 very close to GNAS1. Wu et al. 1xSee all References1 now describe an intriguing novel mutation in GNAS1 that leads to PHPIb rather than PHPIa. The mutation was identified in three affected brothers and results in deletion of one amino acid at the C-terminus of Gsα, a region important for receptor interaction. In vitro expression assays confirmed that the mutation selectively uncouples Gsα from the PTH receptor without affecting its interaction with receptors for TSH or LH, thus explaining the PTH-specific phenotype. The mutation was not found in 15 additional unrelated patients and is therefore not a common cause of PHPIb. Other possible mechanisms include promoter mutations with tissue-specific effects, or mutations in alternative Gsα transcripts. GNAS1 is already known to be a complex imprinted locus and this report underlines the molecular complexities of Gsα expression and function.