Mutations in G proteins and G protein-coupled receptors in endocrine disease.

Naturally occurring mutations in the G protein Gs-α subunit and in a number of G protein-coupled receptors (GPCRs) have been identified in human diseases. Such mutations may lead to loss or gain of function of the encoded protein. Study of such naturally occurring, disease-causing mutations offers unique insights into G protein and GPCR structure and function. In general, diseases caused by GPCR loss-of-function mutations are inherited in autosomal recessive fashion, and those caused by gain-of-function mutations are inherited in autosomal dominant fashion. Endocrine gland dysfunction is the most frequently recognized consequence of GPCR mutation. Loss-of- function mutations in GPCRs for various hormones lead to hormone resistance, manifested as hypofunction of the gland expressing the affected GPCR. Conversely, GPCR gain-of-function mutations lead to hormone-independent activation and hyperfunction of the involved gland.