Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib. Issue 1 (23rd October 2010)

• Record Type: Journal Article
• Authors: Maupetit-Méhouas, Stéphanie; Mariot, Virginie; Reynès, Christelle; Bertrand, Guylène; Feillet, Francois; Carel, Jean-Claude; Simon, Dominique; Bihan, Hélène; Gajdos, Vincent; Devouge, Eve; Shenoy, Savitha; Agbo-Kpati, Placide; Ronan, Anne; Naud-Saudreau, Catherine; Lienhardt, Anne; Silve, Caroline; Linglart, Agnès
• Is Part Of: Journal of medical genetics. Volume 48:Issue 1(2011)
• Page Start: 55
• Page End: 63
• Publication Date: 2010-10-23
• Subjects: Pseudohypoparathyroidism -- quantitative methylation -- subtypes -- somatic mosaicism -- endocrinology -- molecular genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2010.081356
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR. Objective: To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib. Design and methods: In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA. Results: A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR. Conclusion: Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients.