Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 16 P588

Paediatric endocrinology

Epigenetic defects at GNAS DMRs in PHP-Ia patients lacking coding GNAS mutations

Sara Bondioni1, Giovanna Mantovani1, Pamela Labarile1, Luisa de Sanctis2, Erika Peverelli1, Andrea Lania1, Paolo Beck-Peccoz1 & Anna Spada1


1Endocrine Unit, Department of Medical Sciences, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy; 2Department of Pediatrics, Regina Margherita Children’s Hospital, University of Turin, Turin, Italy.


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 1–13, 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.

Article tools

My recent searches

No recent searches.

My recently viewed abstracts

No recent abstracts.