Pseudohypoparathyroidism: complex disease variants with unfortunate names.

Abstract

Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's Hereditary Osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant (AD) pseudohypoparathyroidism type Ib (AD-PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several Differentially Methylated Regions (DMR) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss-of-methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B (sporPHP1B), the most frequent variant of this disorder, remains unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain-of-methylation at the NESP DMR. Multiple genetic or epigenetic GNAS abnormalities thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events down-stream of various Gsα-coupled receptors.

• Authors: Harald Jüppner
• Journal: Journal of molecular endocrinology (J Mol Endocrinol) (Nov 01 2023) ISSN: 1479-6813 [Electronic] England
• PMID: 37965945 (Publication Type: Journal Article, Review)