title: Genetics and epigenetics of parathyroid hormone resistance.
abstract: End-organ resistance to the actions of parathyroid hormone (PTH) is defined as pseudohypoparathyroidism (PHP). Described originally by Fuller Albright and his colleagues in early 1940s, this rare genetic disease is subclassified into two types according to the nephrogenous response to the administration of biologically active PTH. In type I, the PTH-induced urinary excretion of both phosphate and cyclic AMP (cAMP) is blunted. In type II, only the PTH-induced urinary excretion of phosphate is blunted, while the cAMP response is unimpaired. Different subtypes of PHP type I have been described based on the existence of additional clinical features, such as resistance to other hormones and Albright's hereditary osteodystrophy, and underlying molecular defects. Genetic mutations responsible for the different subtypes of PHP type I involve the GNAS complex locus, an imprinted gene encoding the α-subunit of the stimulatory G protein (Gsα) and several other transcripts that are expressed in a parent-of-origin specific manner. Mutations in Gsα-coding GNAS exons cause PHP-Ia and, in some cases, PHP-Ic, while mutations that disrupt the imprinting of GNAS lead to PHP-Ib. PHP type II is less well characterized with respect to its molecular cause. Recently, however, mutations in PRKAR1A, a regulatory subunit of the cAMP-dependent protein kinase, have been identified in several cases of PTH and other hormone resistance and skeletal dysplasia that are considered to be affected by PHP type II due to unimpaired urinary excretion of cAMP following PTH administration.
authors: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA. bastepe@helix.mgh.harvard.edu
authors: Murat
authors: M
authors: Bastepe
mesh_terms: D000818:Animals; D002864:Chromogranins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics / Q000502:physiology; D010281:Parathyroid Hormone / Q000378:metabolism / Q000502:physiology*; D011547:Pseudohypoparathyroidism / Q000145:classification / Q000235:genetics*
chemical_list: D002864:Chromogranins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D010281:Parathyroid Hormone; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs