GNAS Epigenetic Defects and Pseudohypoparathyroidism: Time for a New Classification?

Abstract

The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1–13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO), together with end-organ resistance to the action of different hormones that activate the Gs-coupled pathways, primarily PTH, TSH, gonadotropins, and GHRH. In PHP-Ib patients AHO is classically absent, Gsα activity in erythrocytes and fibroblast is normal and hormone resistance is limited to PTH and TSH, the latter being essentially always subclinical. This disorder is caused by the disruption of long-range imprinting control elements in GNAS locus. In particular, the most consistent defect is the loss of imprinting at the exon A/B differenzially methylated region (DMR), with consequent decreased Gsα transcription in tissues where this protein is derived from the maternal allele only. The familial form of the disease (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR due to microdeletions disrupting the upstream STX16 gene. In addition, deletions removing the entire NESP55 DMR, located within GNAS, have been identified in some AD-PHP-Ib kindreds in whom affected individuals show loss of all the maternal GNAS imprints. Conversely, most sporadic PHP-Ib cases have GNAS imprinting abnormalities that involve multiple DMRs, but the genetic lesion underlying these defects remains to be discovered. Recently, methylation defects have been detected in a subset of patients with PHP-Ia and variable degrees of AHO, indicating a molecular overlap between the two forms. Imprinting defects do not seem to be associated with the severity of AHO neither with specific AHO signs.