Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia and hyperphosphatemia due to end-organ resistance to the action of PTH. The two main subtypes of PHP, PHP type Ia and Ib are caused by heterozygous loss-of-function mutations in GNAS exons 113, which encode Gsα, and by methylation defects in the imprinted GNAS cluster, respectively. Individuals affected with PHP-Ia typically show clinical abnormalities referred to as Albright hereditary osteodystrophy (AHO) together with resistance toward several additional hormones, such as TSH, gonadotropins and GHRH. PHP-Ib differs from PHP-Ia in that affected patients do not have the AHO phenotype and hormone resistance appears to be limited to the actions of PTH and, occasionally, TSH. About 30% of patients with PHP-Ia features lack GNAS coding mutations. We investigated the presence of typical PHP-Ib epigenetic defects at GNAS differentially-methylated regions (DMRs) in 10 PHP-Ia cases lacking GNAS mutations. We found loss of methylation at A/B DMR in 6 cases and defects at other GNAS DMRs in 3 of them. In one patient we found the presence of STX16 gene 3.3 kb deletion, that characterizes familial PHP-Ib cases.
In conclusion, we confirm that GNAS methylation defects can explain about 50% of PHP-Ia cases lacking GNAS coding mutations and suggest that PHP-Ia patients should be screened not only for GNAS coding mutations but for epigenetic defects at the same locus as well.