RT Journal Article
SR Electronic
T1 Quantification of the methylation at the <em>GNAS</em> locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 55
OP 63
DO 10.1136/jmg.2010.081356
VO 48
IS 1
A1 Maupetit-Méhouas, Stéphanie
A1 Mariot, Virginie
A1 Reynès, Christelle
A1 Bertrand, Guylène
A1 Feillet, Francois
A1 Carel, Jean-Claude
A1 Simon, Dominique
A1 Bihan, Hélène
A1 Gajdos, Vincent
A1 Devouge, Eve
A1 Shenoy, Savitha
A1 Agbo-Kpati, Placide
A1 Ronan, Anne
A1 Naud-Saudreau, Catherine
A1 Lienhardt, Anne
A1 Silve, Caroline
A1 Linglart, Agnès
YR 2011
UL http://jmg.bmj.com/content/48/1/55.abstract
AB 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.