Hormone resistance caused by mutations in G proteins and G protein-coupled receptors

Abstract

G proteins couple receptors for many hormones to effectors that regulate second messenger metabolism. Several endocrine disorders have been shown to be caused by either loss or gain of function mutations in G proteins or G protein-coupled receptors. Pseudohypoparathyroidism (PHP), the first described example of a hormone resistance disorder, is characterized by renal resistance to parathyroid hormone (PTH) proximal to generation of the second messenger, cAMP. In PHP Ia there is more generalized hormone resistance (PTH, TSH, gonadotropins) and associated abnormal physical features, Albright hereditary osteodystrophy (AHO). Subjects with PHP Ib are normal in appearance and resistant exclusively to PTH. Germline loss of function mutations have been identified in the Gs-alpha gene in PHP Ia, and recent evidence suggests that the Gs-alpha gene is paternally imprinted in a tissue-specific manner. In PHP Ib, several studies have excluded PTH receptor gene mutations, and the molecular basis has not yet been defined.