57 - Pseudohypoparathyroidism, Albright’s Hereditary Osteodystrophy, and Progressive Osseous Heteroplasia: Disorders Caused by GNAS Mutations that Reduce Gsα Activity

Abstract

Pseudohypoparathyroidism (PHP) refers to disorders of multihormone resistance primarily involving the actions of parathyroid hormone (PTH) in the proximal tubule and often resistance to other agonists in several additional tissues. These agonists, including PTH, exert their actions via receptors that couple primarily to the alpha-subunit of the stimulatory G protein (Gsα). The genetic cause of PHP1 and related disorders are inactivating mutations affecting the GNAS complex locus, the gene encoding Gsα and splice variants thereof. These mutations cause diminished expression/activity of Gsα. An important determinant of the clinical phenotype is the nature and the parental origin of the mutation. GNAS is an imprinted gene comprising multiple differentially methylated regions. Maternal mutations that affect coding Gsα exons (PHP1A) usually lead to broader clinical features than maternal mutations that alter parent-specific GNAS methylation (PHP1B). However, these features become apparent only because the paternal Gsα allele is subject to tissue-specific silencing, therefore highlighting, for these tissues, the importance of maternally-derived Gsα. Albright’s hereditary osteodystrophy (AHO) typically occurs after both maternal and paternal transmission of coding Gsα mutations, although some AHO features also follow a parental origin-specific inheritance. Pseudopseudohypoparathyroidism (PPHP) is a term used to describe patients with AHO who lack any evidence of hormone resistance. AHO features vary markedly among patients, and an extreme manifestation is progressive osseous heteroplasia (POH), a disorder of heterotopic ossification that not only occurs subcutaneously but also invades skeletal muscle and deep connective tissue. In a great majority of cases, POH develops when the Gsα mutation is present on the paternal allele. PHP2 is characterized by a lack of receptor-dependent functions despite sufficient agonist-stimulated cAMP formation. The molecular determinants of several of these PHP2 variants, which show concurrent skeletal dysplasia, i.e. acrodysostosis, involve the regulatory subunit of protein kinase-A or cAMP phosphodiesterases.