Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
Identifieur interne : 006786 ( Main/Exploration ); précédent : 006785; suivant : 006787Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
Auteurs : Stéphanie Maupetit-Mehouas [France] ; Virginie Mariot [France] ; Christelle Reynes [France] ; Guylène Bertrand [France] ; Francois Feillet [France] ; Jean-Claude Carel [France] ; Dominique Simon [France] ; Hélène Bihan [France] ; Vincent Gajdos [France] ; Eve Devouge [France] ; Savitha Shenoy [Royaume-Uni] ; Placide Agbo-Kpati [France] ; Anne Ronan [Australie] ; Catherine Naud-Saudreau [France] ; Anne Lienhardt [France] ; Caroline Silve [France] ; Agnès Linglart [France]Source :
- Journal of medical genetics [ 0022-2593 ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Analyse quantitative, Analyse qualitative, Génétique, Homme.
English descriptors
- KwdEn :
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.
Affiliations:
- Australie, France, Royaume-Uni
- Grand Est, Limousin, Lorraine (région), Nouvelle-Aquitaine, Région Bretagne, Île-de-France
- Bobigny, Limoges, Lorient, Nancy, Paris, Vandœuvre-lès-Nancy
- Université Paris-Descartes
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pseudohypoparathyroidism type Ib</title><author><name sortKey="Maupetit Mehouas, Stephanie" sort="Maupetit Mehouas, Stephanie" uniqKey="Maupetit Mehouas S" first="Stéphanie" last="Maupetit-Mehouas">Stéphanie Maupetit-Mehouas</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul</s1><s2>Paris</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>16 aut.</sZ><sZ>17 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Mariot, Virginie" sort="Mariot, Virginie" uniqKey="Mariot V" first="Virginie" last="Mariot">Virginie Mariot</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul</s1><s2>Paris</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>16 aut.</sZ><sZ>17 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Reynes, Christelle" sort="Reynes, Christelle" uniqKey="Reynes C" first="Christelle" last="Reynes">Christelle Reynes</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion</s1><s2>Paris</s2><s3>FRA</s3><sZ>3 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Bertrand, Guylene" sort="Bertrand, Guylene" uniqKey="Bertrand G" first="Guylène" last="Bertrand">Guylène Bertrand</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique</s1><s2>Paris</s2><s3>FRA</s3><sZ>4 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Feillet, Francois" sort="Feillet, Francois" uniqKey="Feillet F" first="Francois" last="Feillet">Francois Feillet</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Centre de référence des maladies héréditaires du métabolisrne, INSERM U954, CHU Brabois Enfant</s1><s2>Vandoeuvre les Nancy</s2><s3>FRA</s3><sZ>5 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region" nuts="2">Grand Est</region><region type="old region" nuts="2">Lorraine (région)</region><settlement type="city">Vandœuvre-lès-Nancy</settlement><settlement type="city" wicri:auto="agglo">Nancy</settlement></placeName></affiliation></author><author><name sortKey="Carel, Jean Claude" sort="Carel, Jean Claude" uniqKey="Carel J" first="Jean-Claude" last="Carel">Jean-Claude Carel</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital</s1><s2>Paris</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Simon, Dominique" sort="Simon, Dominique" uniqKey="Simon D" first="Dominique" last="Simon">Dominique Simon</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital</s1><s2>Paris</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Bihan, Helene" sort="Bihan, Helene" uniqKey="Bihan H" first="Hélène" last="Bihan">Hélène Bihan</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes</s1><s2>Bobigny</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Bobigny</settlement></placeName></affiliation></author><author><name sortKey="Gajdos, Vincent" sort="Gajdos, Vincent" uniqKey="Gajdos V" first="Vincent" last="Gajdos">Vincent Gajdos</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère</s1><s2>Clamart</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Clamart</wicri:noRegion><wicri:noRegion>Hôpital Beclère</wicri:noRegion><wicri:noRegion>Clamart</wicri:noRegion></affiliation></author><author><name sortKey="Devouge, Eve" sort="Devouge, Eve" uniqKey="Devouge E" first="Eve" last="Devouge">Eve Devouge</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Service de Pédiatrie, Hôpital d'Arras</s1><s3>FRA</s3><sZ>10 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Hôpital d'Arras</wicri:noRegion><wicri:noRegion>Service de Pédiatrie, Hôpital d'Arras</wicri:noRegion></affiliation></author><author><name sortKey="Shenoy, Savitha" sort="Shenoy, Savitha" uniqKey="Shenoy S" first="Savitha" last="Shenoy">Savitha Shenoy</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Leicester Royal Infirmary</s1><s2>Leicester</s2><s3>GBR</s3><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Leicester Royal Infirmary</wicri:noRegion></affiliation></author><author><name sortKey="Agbo Kpati, Placide" sort="Agbo Kpati, Placide" uniqKey="Agbo Kpati P" first="Placide" last="Agbo-Kpati">Placide Agbo-Kpati</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Service de Pédiatrie, Hôpital de Lagny</s1><s2>Lagny</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Lagny</wicri:noRegion><wicri:noRegion>Hôpital de Lagny</wicri:noRegion><wicri:noRegion>Lagny</wicri:noRegion></affiliation></author><author><name sortKey="Ronan, Anne" sort="Ronan, Anne" uniqKey="Ronan A" first="Anne" last="Ronan">Anne Ronan</name><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Hunter Genetics Unit</s1><s2>Waratah, New South Wales</s2><s3>AUS</s3><sZ>13 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Hunter Genetics Unit</wicri:noRegion></affiliation></author><author><name sortKey="Naud Saudreau, Catherine" sort="Naud Saudreau, Catherine" uniqKey="Naud Saudreau C" first="Catherine" last="Naud-Saudreau">Catherine Naud-Saudreau</name><affiliation wicri:level="3"><inist:fA14 i1="12"><s1>Service de Pédiatrie Bretagne sud</s1><s2>Lorient</s2><s3>FRA</s3><sZ>14 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Région Bretagne</region><region type="old region">Région Bretagne</region><settlement type="city">Lorient</settlement></placeName></affiliation></author><author><name sortKey="Lienhardt, Anne" sort="Lienhardt, Anne" uniqKey="Lienhardt A" first="Anne" last="Lienhardt">Anne Lienhardt</name><affiliation wicri:level="3"><inist:fA14 i1="13"><s1>Centre de référence des maladies rares du métabolisme du calcium et du phosphore, Service de Pédiatrie, Hôpital de la mère et de l'enfant</s1><s2>Limoges</s2><s3>FRA</s3><sZ>15 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Nouvelle-Aquitaine</region><region type="old region">Limousin</region><settlement type="city">Limoges</settlement></placeName></affiliation></author><author><name sortKey="Silve, Caroline" sort="Silve, Caroline" uniqKey="Silve C" first="Caroline" last="Silve">Caroline Silve</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul</s1><s2>Paris</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>16 aut.</sZ><sZ>17 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique</s1><s2>Paris</s2><s3>FRA</s3><sZ>4 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnès" last="Linglart">Agnès Linglart</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul</s1><s2>Paris</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>16 aut.</sZ><sZ>17 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="14"><s1>Assistance Publique-Hôpitaux de Paris, Endocrinologie-diabétologie Pédiatrique et Centre de reference des maladies rares du métabolisme du calcium et du phosphore, Hôpital St-Vincent de Paul</s1><s2>Paris</s2><s3>FRA</s3><sZ>17 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Journal of medical genetics</title><title level="j" type="abbreviated">J. med. genet.</title><idno type="ISSN">0022-2593</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of medical genetics</title><title level="j" type="abbreviated">J. med. genet.</title><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Genetics</term><term>Human</term><term>Locus</term><term>Methylation</term><term>Pseudohypoparathyroidism</term><term>Qualitative analysis</term><term>Quantitative analysis</term><term>Sporadic</term><term>Subtype</term><term>Typing</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Pseudohypoparathyroïdie</term><term>Analyse quantitative</term><term>Analyse qualitative</term><term>Méthylation</term><term>Locus</term><term>Soustype</term><term>Typage</term><term>Sporadique</term><term>Génétique</term><term>Homme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Analyse quantitative</term><term>Analyse qualitative</term><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Royaume-Uni</li></country><region><li>Grand Est</li><li>Limousin</li><li>Lorraine (région)</li><li>Nouvelle-Aquitaine</li><li>Région Bretagne</li><li>Île-de-France</li></region><settlement><li>Bobigny</li><li>Limoges</li><li>Lorient</li><li>Nancy</li><li>Paris</li><li>Vandœuvre-lès-Nancy</li></settlement><orgName><li>Université Paris-Descartes</li></orgName></list><tree><country name="France"><region name="Île-de-France"><name sortKey="Maupetit Mehouas, Stephanie" sort="Maupetit Mehouas, Stephanie" uniqKey="Maupetit Mehouas S" first="Stéphanie" last="Maupetit-Mehouas">Stéphanie Maupetit-Mehouas</name></region><name sortKey="Agbo Kpati, Placide" sort="Agbo Kpati, Placide" uniqKey="Agbo Kpati P" first="Placide" last="Agbo-Kpati">Placide Agbo-Kpati</name><name sortKey="Bertrand, Guylene" sort="Bertrand, Guylene" uniqKey="Bertrand G" first="Guylène" last="Bertrand">Guylène Bertrand</name><name sortKey="Bihan, Helene" sort="Bihan, Helene" uniqKey="Bihan H" first="Hélène" last="Bihan">Hélène Bihan</name><name sortKey="Carel, Jean Claude" sort="Carel, Jean Claude" uniqKey="Carel J" first="Jean-Claude" last="Carel">Jean-Claude Carel</name><name sortKey="Devouge, Eve" sort="Devouge, Eve" uniqKey="Devouge E" first="Eve" last="Devouge">Eve Devouge</name><name sortKey="Feillet, Francois" sort="Feillet, Francois" uniqKey="Feillet F" first="Francois" last="Feillet">Francois Feillet</name><name sortKey="Gajdos, Vincent" sort="Gajdos, Vincent" uniqKey="Gajdos V" first="Vincent" last="Gajdos">Vincent Gajdos</name><name sortKey="Lienhardt, Anne" sort="Lienhardt, Anne" uniqKey="Lienhardt A" first="Anne" last="Lienhardt">Anne Lienhardt</name><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnès" last="Linglart">Agnès Linglart</name><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnès" last="Linglart">Agnès Linglart</name><name sortKey="Mariot, Virginie" sort="Mariot, Virginie" uniqKey="Mariot V" first="Virginie" last="Mariot">Virginie Mariot</name><name sortKey="Naud Saudreau, Catherine" sort="Naud Saudreau, Catherine" uniqKey="Naud Saudreau C" first="Catherine" last="Naud-Saudreau">Catherine Naud-Saudreau</name><name sortKey="Reynes, Christelle" sort="Reynes, Christelle" uniqKey="Reynes C" first="Christelle" last="Reynes">Christelle Reynes</name><name sortKey="Silve, Caroline" sort="Silve, Caroline" uniqKey="Silve C" first="Caroline" last="Silve">Caroline Silve</name><name sortKey="Silve, Caroline" sort="Silve, Caroline" uniqKey="Silve C" first="Caroline" last="Silve">Caroline Silve</name><name sortKey="Simon, Dominique" sort="Simon, Dominique" uniqKey="Simon D" first="Dominique" last="Simon">Dominique Simon</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Shenoy, Savitha" sort="Shenoy, Savitha" uniqKey="Shenoy S" first="Savitha" last="Shenoy">Savitha Shenoy</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Ronan, Anne" sort="Ronan, Anne" uniqKey="Ronan A" first="Anne" last="Ronan">Anne Ronan</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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