Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
| Autor: | Agnès Linglart, Virginie Mariot, Anne Ronan, Caroline Silve, Catherine Naud-Saudreau, Dominique Simon, Stéphanie Maupetit-Méhouas, Hélène Bihan, François Feillet, Savitha Shenoy, Anne Lienhardt, Eve Devouge, Vincent Gajdos, Christelle Reynes, Jean-Claude Carel, Placide Agbo-Kpati, Guylène Bertrand |
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| Přispěvatelé: | Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie hormonale, métabolique et génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie, maladies métaboliques [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Service de pédiatrie, Hôpital d'Arras, Leicester Royal Infirmary, University Hospitals Leicester, Hôpital de Lagny, Hunter Genetics Unit, Service de Pédiatrie, CH Bretagne Sud, Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique ( U986 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Molécules Thérapeutique in silico, Recherche de molécules à visée thérapeutique par approches In Silico ( MTI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Centre de référence des maladies rares du métabolisme du calcium et du phosphore, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Peer, Hal |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male musculoskeletal diseases medicine.medical_specialty Adolescent 030209 endocrinology & metabolism Locus (genetics) Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Endocrinology Combined bisulfite restriction analysis Molecular genetics Chromogranins GTP-Binding Protein alpha Subunits Gs Genetics GNAS complex locus medicine Humans natural sciences Epigenetics Child Genetics (clinical) Pseudohypoparathyroidism Genes Dominant 030304 developmental biology 0303 health sciences biology Sequence Analysis DNA Methylation DNA Methylation medicine.disease Phenotype biology.protein Female STX16 |
| Zdroj: | Journal of Medical Genetics Journal of Medical Genetics, BMJ Publishing Group, 2010, 48 (1), pp.55. ⟨10.1136/jmg.2010.081356⟩ Journal of Medical Genetics, BMJ Publishing Group, 2010, 48 (1), pp.55. 〈10.1136/jmg.2010.081356〉 |
| ISSN: | 0022-2593 1468-6244 |
| DOI: | 10.1136/jmg.2010.081356⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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