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Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
  1. Stéphanie Maupetit-Méhouas1,
  2. Virginie Mariot1,
  3. Christelle Reynès2,
  4. Guylène Bertrand3,
  5. Francois Feillet4,
  6. Jean-Claude Carel5,
  7. Dominique Simon5,
  8. Hélène Bihan6,
  9. Vincent Gajdos7,
  10. Eve Devouge8,
  11. Savitha Shenoy9,
  12. Placide Agbo-Kpati10,
  13. Anne Ronan11,
  14. Catherine Naud-Saudreau12,
  15. Anne Lienhardt13,
  16. Caroline Silve1,3,
  17. Agnès Linglart1,14
  1. 1INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France
  2. 2MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion, Paris, France
  3. 3Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France
  4. 4Centre de référence des maladies héréditaires du métabolisme, INSERM U954, CHU Brabois Enfant, Vandoeuvre les Nancy, France
  5. 5Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France
  6. 6Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes, Bobigny, France
  7. 7Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère, Clamart, France
  8. 8Service de Pédiatrie, Hôpital d'Arras, France
  9. 9Leicester Royal Infirmary, Leicester, UK
  10. 10Service de Pédiatrie, Hôpital de Lagny, Lagny, France
  11. 11Hunter Genetics Unit, Waratah, New South Wales, Australia
  12. 12Service de Pédiatrie Bretagne sud, Lorient, France
  13. 13Centre de référence des maladies rares du métabolisme du calcium et du phosphore, Service de Pédiatrie, Hôpital de la mère et de l'enfant, Limoges, France
  14. 14Assistance Publique-Hôpitaux de Paris, Endocrinologie-diabétologie Pédiatrique et Centre de référence des maladies rares du métabolisme du calcium et du phosphore, Hôpital St-Vincent de Paul, Paris, France
  1. Correspondence to Agnès Linglart, INSERM U986, Hôpital Saint Vincent de Paul, 82 avenue Denfert-Rochereau, 75014 Paris, France; agnes.linglart{at}


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.

  • Pseudohypoparathyroidism
  • quantitative methylation
  • subtypes
  • somatic mosaicism
  • endocrinology
  • molecular genetics

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  • Funding This work was supported by INSERM funding. SM-M was supported by a fellowship from the Paris Descartes University.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the local ethic committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.