Endocrine Abstracts (2011) 26 P542

Pseudohypoparathyroidism and GNAS epigenetic alterations: quantitative analysis of methylation defects and correlation with clinical characteristics

F M Elli1, A M Barbieri1, L de Sanctis2, V Bollati3, P Beck-Peccoz1, A Spada1 & G Mantovani1


1Department of Medical Sciences, Endocrinology and Diabetology Unit, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 2Department of Pediatrics, Regina Margherita Children’s Hospital, University of Turin, Turin, Italy; 3Department of Environmental and Occupational Health, Center of Molecular and Genetic Epidemiology, Università degli Studi di Milano and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.


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) and resistance toward multiple hormones (PTH/TSH/GHRH/gonadotropins), whereas PHP-Ib patients classically display hormone resistance limited to PTH and TSH. Incoming data suggest that the two diseases share more genetic and clinical similarities than previously thought. In particular, methylation defects have been detected in a subset of patients with PHP and AHO, but the correlation between molecular findings and the severity of the disease has not been investigated yet.

In the present study, we included 30 patients with either classical PHP-Ib (N=16) or PHP with different degrees of AHO (N=14), all found to have broad GNAS methylation defects in the absence of mutations. Differential methylation of GNAS DMRs A/B, AS, XL, NESP was assessed using highly quantitative analysis based on PCR-pyrosequencing. The data obtained were correlated with the following clinical characteristics: age at diagnosis, endocrine function (PTH, TSH, FT4, calcium, phosphorus levels) and the presence or absence of AHO signs (short stature, brachydactyly, round face, ectopic ossifications, mental retardation).

No statistical difference was observed between the group of patients with classical PHP-Ib and the group with PHP plus AHO. In particular, the degree of the imprinting defect (percentage of methylation at each DMR expressed in respect with a pool of 20 normal subjects age- and gender-related) did not correlate with the onset of the disease, the severity of endocrine resistances, nor with the presence/absence of specific AHO signs.

In conclusion, similar molecular alterations may lead to a broad spectrum of diseases, from isolated PTH resistance to complete PHP-Ia. Our study further confirms the existence of an overlap between molecular and clinical features of PHP-Ia/Ib, highlighting the need of an updated classification that takes into account the recent knowledge on the molecular basis underlying these defects.

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