GNAS

GNAS refers to the GNAS complex locus on human chromosome 20q13.3, which encodes the Gs alpha subunit (Gsα) of heterotrimeric G proteins. Gsα activates adenylyl cyclase, increasing intracellular cAMP in response to many receptors, and thereby participates in a wide range of hormonal signal transduction pathways. The locus expresses multiple overlapping transcripts through alternative promoters and differential imprinting, including Gsα, XLαs, NESP55, and an antisense A/B transcript. In most tissues Gsα is biallelic, but in several tissues (for example renal proximal tubules, certain endocrine tissues) the paternal GNAS allele is epigenetically silenced, so the expressed product is mainly from the maternal allele. This imprinting underlies parent-of-origin effects in disease.

Mutations and epigenetic changes at GNAS cause pseudohypoparathyroidism and related disorders. Inactivating mutations in the maternal GNAS allele lead to pseudohypoparathyroidism type 1A, with resistance to PTH and often other hormones, together with Albright hereditary osteodystrophy features such as short stature and skeletal anomalies. The related pseudohypoparathyroidism type 1B is primarily due to epigenetic alterations at the GNAS locus and may present with hormone resistance with or without skeletal changes; pseudopseudohypoparathyroidism refers to Albright-like features without hormone resistance.

A different mechanism, activating post-zygotic mutations in GNAS, underlies McCune–Albright syndrome, which shows mosaic distribution and includes fibrous dysplasia of bone, café-au-lait skin spots, and various endocrinopathies.

Activating GNAS mutations are also found in other tumors and endocrine lesions, reflecting constitutive Gsα signaling.