Pseudohypoparathyroidism: one gene, several syndromes

AbstractPseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complexGNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several sites.GNAS encodes the alpha-subunit of the stimulatory G protein (Gs α) and several splice variants thereof. Heterozygous inactivating mutations involving the maternalGNAS exons 1 –13 cause PHP type Ia (PHP1A). Because of much reduced paternal Gsα expression in certain tissues, such as the proximal renal tubules, thyroid, and pituitary, there is little or no Gsα protein in the presence of maternalGNAS mutations, thus leading to PTH-resistant hypocalcemia and hyperphosphatemia. When located on the paternal allele, the same or similarGNAS mutations are the cause of PPHP. Besides biochemical abnormalities, patients affected by PHP1A show developmental abnormalities, referred to as Albrights hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions withinGNAS orSTX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylatedGNAS exons. LOM at exon A/B and the resulting biallelic expression of A/B transcripts reduces Gs α expression, thus leading to hormonal resistance. Epigenetic changes at all di...
Source: Journal of Endocrinological Investigation - Category: Endocrinology Source Type: research