Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
Identifieur interne : 000078 ( Istex/Corpus ); précédent : 000077; suivant : 000079Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib
Auteurs : Stéphanie Maupetit-Méhouas ; Virginie Mariot ; Christelle Reynès ; Guylène Bertrand ; Francois Feillet ; Jean-Claude Carel ; Dominique Simon ; Hélène Bihan ; Vincent Gajdos ; Eve Devouge ; Savitha Shenoy ; Placide Agbo-Kpati ; Anne Ronan ; Catherine Naud-Saudreau ; Anne Lienhardt ; Caroline Silve ; Agnès LinglartSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2011-01.
English descriptors
- KwdEn :
- Albright osteodystrophy, Allele, Bastepe, Biochemical characteristics, Body mass index, Clin, Clin endocrinol metab, Cytosine, Defect, Deletion, Different patterns, Differentially, Differentially methylated regions, Dmrs, Endocrinol, Epigenetic, Epigenetic changes, Epigenetic defects, Euclidean distance, Genet, Gnas, Gnas locus, Gnas1, Gure, Hopital, Hormonal resistance, Imprinting, Juppner, Linglart, Locus, Metab, Methylated, Methylation, Methylation abnormalities, Methylation changes, Methylation defects, Methylation patterns, Mosaicism, Nesp, Nesp dmrs, Nesp exon, Normal range, Nucleic acids, Osteodystrophy, Parathyroid hormone, Parental imprinting, Php1, Php4, Primer, Principal component analysis, Proc natl acad, Pseudohypoparathyroidism, Pseudohypoparathyroidism type, Quantitative method, Restriction analysis, Somatic mosaicism, Sporadic pseudohypoparathyroidism type, Sporphplb, Unmethylated.
- Teeft :
- Albright osteodystrophy, Allele, Bastepe, Biochemical characteristics, Body mass index, Clin, Clin endocrinol metab, Cytosine, Defect, Deletion, Different patterns, Differentially, Differentially methylated regions, Dmrs, Endocrinol, Epigenetic, Epigenetic changes, Epigenetic defects, Euclidean distance, Genet, Gnas, Gnas locus, Gnas1, Gure, Hopital, Hormonal resistance, Imprinting, Juppner, Linglart, Locus, Metab, Methylated, Methylation, Methylation abnormalities, Methylation changes, Methylation defects, Methylation patterns, Mosaicism, Nesp, Nesp dmrs, Nesp exon, Normal range, Nucleic acids, Osteodystrophy, Parathyroid hormone, Parental imprinting, Php1, Php4, Primer, Principal component analysis, Proc natl acad, Pseudohypoparathyroidism, Pseudohypoparathyroidism type, Quantitative method, Restriction analysis, Somatic mosaicism, Sporadic pseudohypoparathyroidism type, Sporphplb, Unmethylated.
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.
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DOI: 10.1136/jmg.2010.081356
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last="Silve">Caroline Silve</name><affiliation><mods:affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnès" last="Linglart">Agnès Linglart</name><affiliation><mods:affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance 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</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: agnes.linglart@inserm.fr</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:04167EA3EC5F03CA000338C4FC82163CCE831147</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1136/jmg.2010.081356</idno><idno type="url">https://api.istex.fr/document/04167EA3EC5F03CA000338C4FC82163CCE831147/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000078</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000078</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</title><author><name sortKey="Maupetit Mehouas, Stephanie" sort="Maupetit Mehouas, Stephanie" uniqKey="Maupetit Mehouas S" first="Stéphanie" last="Maupetit-Méhouas">Stéphanie Maupetit-Méhouas</name><affiliation><mods:affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Mariot, Virginie" sort="Mariot, Virginie" uniqKey="Mariot V" first="Virginie" last="Mariot">Virginie Mariot</name><affiliation><mods:affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Reynes, Christelle" sort="Reynes, Christelle" uniqKey="Reynes C" first="Christelle" last="Reynès">Christelle Reynès</name><affiliation><mods:affiliation>MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Bertrand, Guylene" sort="Bertrand, Guylene" uniqKey="Bertrand G" first="Guylène" last="Bertrand">Guylène Bertrand</name><affiliation><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Feillet, Francois" sort="Feillet, Francois" uniqKey="Feillet F" first="Francois" last="Feillet">Francois Feillet</name><affiliation><mods:affiliation>Centre de référence des maladies héréditaires du métabolisme, INSERM U954, CHU Brabois Enfant, Vandoeuvre les Nancy, France</mods:affiliation></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><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Simon, Dominique" sort="Simon, Dominique" uniqKey="Simon D" first="Dominique" last="Simon">Dominique Simon</name><affiliation><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Bihan, Helene" sort="Bihan, Helene" uniqKey="Bihan H" first="Hélène" last="Bihan">Hélène Bihan</name><affiliation><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes, Bobigny, France</mods:affiliation></affiliation></author><author><name sortKey="Gajdos, Vincent" sort="Gajdos, Vincent" uniqKey="Gajdos V" first="Vincent" last="Gajdos">Vincent Gajdos</name><affiliation><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère, Clamart, France</mods:affiliation></affiliation></author><author><name sortKey="Devouge, Eve" sort="Devouge, Eve" uniqKey="Devouge E" first="Eve" last="Devouge">Eve Devouge</name><affiliation><mods:affiliation>Service de Pédiatrie, Hôpital d'Arras, France</mods:affiliation></affiliation></author><author><name sortKey="Shenoy, Savitha" sort="Shenoy, Savitha" uniqKey="Shenoy S" first="Savitha" last="Shenoy">Savitha Shenoy</name><affiliation><mods:affiliation>Leicester Royal Infirmary, Leicester, UK</mods:affiliation></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><mods:affiliation>Service de Pédiatrie, Hôpital de Lagny, Lagny, France</mods:affiliation></affiliation></author><author><name sortKey="Ronan, Anne" sort="Ronan, Anne" uniqKey="Ronan A" first="Anne" last="Ronan">Anne Ronan</name><affiliation><mods:affiliation>Hunter Genetics Unit, Waratah, New South Wales, Australia</mods:affiliation></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><mods:affiliation>Service de Pédiatrie Bretagne sud, Lorient, France</mods:affiliation></affiliation></author><author><name sortKey="Lienhardt, Anne" sort="Lienhardt, Anne" uniqKey="Lienhardt A" first="Anne" last="Lienhardt">Anne Lienhardt</name><affiliation><mods:affiliation>Centre 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</mods:affiliation></affiliation></author><author><name sortKey="Silve, Caroline" sort="Silve, Caroline" uniqKey="Silve C" first="Caroline" last="Silve">Caroline Silve</name><affiliation><mods:affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnès" last="Linglart">Agnès Linglart</name><affiliation><mods:affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Assistance 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</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: agnes.linglart@inserm.fr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2011-01">2011-01</date><biblScope unit="volume">48</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="55">55</biblScope></imprint><idno type="ISSN">0022-2593</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Albright osteodystrophy</term><term>Allele</term><term>Bastepe</term><term>Biochemical characteristics</term><term>Body mass index</term><term>Clin</term><term>Clin endocrinol metab</term><term>Cytosine</term><term>Defect</term><term>Deletion</term><term>Different patterns</term><term>Differentially</term><term>Differentially methylated regions</term><term>Dmrs</term><term>Endocrinol</term><term>Epigenetic</term><term>Epigenetic changes</term><term>Epigenetic defects</term><term>Euclidean distance</term><term>Genet</term><term>Gnas</term><term>Gnas locus</term><term>Gnas1</term><term>Gure</term><term>Hopital</term><term>Hormonal resistance</term><term>Imprinting</term><term>Juppner</term><term>Linglart</term><term>Locus</term><term>Metab</term><term>Methylated</term><term>Methylation</term><term>Methylation abnormalities</term><term>Methylation changes</term><term>Methylation defects</term><term>Methylation patterns</term><term>Mosaicism</term><term>Nesp</term><term>Nesp dmrs</term><term>Nesp exon</term><term>Normal range</term><term>Nucleic acids</term><term>Osteodystrophy</term><term>Parathyroid hormone</term><term>Parental imprinting</term><term>Php1</term><term>Php4</term><term>Primer</term><term>Principal component analysis</term><term>Proc natl acad</term><term>Pseudohypoparathyroidism</term><term>Pseudohypoparathyroidism type</term><term>Quantitative method</term><term>Restriction analysis</term><term>Somatic mosaicism</term><term>Sporadic pseudohypoparathyroidism type</term><term>Sporphplb</term><term>Unmethylated</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Albright osteodystrophy</term><term>Allele</term><term>Bastepe</term><term>Biochemical characteristics</term><term>Body mass index</term><term>Clin</term><term>Clin endocrinol metab</term><term>Cytosine</term><term>Defect</term><term>Deletion</term><term>Different patterns</term><term>Differentially</term><term>Differentially methylated regions</term><term>Dmrs</term><term>Endocrinol</term><term>Epigenetic</term><term>Epigenetic changes</term><term>Epigenetic defects</term><term>Euclidean distance</term><term>Genet</term><term>Gnas</term><term>Gnas locus</term><term>Gnas1</term><term>Gure</term><term>Hopital</term><term>Hormonal resistance</term><term>Imprinting</term><term>Juppner</term><term>Linglart</term><term>Locus</term><term>Metab</term><term>Methylated</term><term>Methylation</term><term>Methylation abnormalities</term><term>Methylation changes</term><term>Methylation defects</term><term>Methylation patterns</term><term>Mosaicism</term><term>Nesp</term><term>Nesp dmrs</term><term>Nesp exon</term><term>Normal range</term><term>Nucleic acids</term><term>Osteodystrophy</term><term>Parathyroid hormone</term><term>Parental imprinting</term><term>Php1</term><term>Php4</term><term>Primer</term><term>Principal component analysis</term><term>Proc natl acad</term><term>Pseudohypoparathyroidism</term><term>Pseudohypoparathyroidism type</term><term>Quantitative method</term><term>Restriction analysis</term><term>Somatic mosaicism</term><term>Sporadic pseudohypoparathyroidism type</term><term>Sporphplb</term><term>Unmethylated</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="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.</div></front></TEI><istex><corpusName>bmj</corpusName><keywords><teeft><json:string>methylation</json:string><json:string>gnas</json:string><json:string>cytosine</json:string><json:string>dmrs</json:string><json:string>deletion</json:string><json:string>nesp</json:string><json:string>methylated</json:string><json:string>imprinting</json:string><json:string>genet</json:string><json:string>pseudohypoparathyroidism</json:string><json:string>gnas locus</json:string><json:string>sporphplb</json:string><json:string>gure</json:string><json:string>clin</json:string><json:string>endocrinol</json:string><json:string>restriction analysis</json:string><json:string>allele</json:string><json:string>bastepe</json:string><json:string>metab</json:string><json:string>hopital</json:string><json:string>juppner</json:string><json:string>differentially</json:string><json:string>unmethylated</json:string><json:string>primer</json:string><json:string>php1</json:string><json:string>osteodystrophy</json:string><json:string>pseudohypoparathyroidism type</json:string><json:string>linglart</json:string><json:string>php4</json:string><json:string>mosaicism</json:string><json:string>gnas1</json:string><json:string>epigenetic</json:string><json:string>locus</json:string><json:string>somatic mosaicism</json:string><json:string>epigenetic changes</json:string><json:string>differentially methylated regions</json:string><json:string>nesp dmrs</json:string><json:string>epigenetic defects</json:string><json:string>nesp exon</json:string><json:string>proc natl acad</json:string><json:string>different patterns</json:string><json:string>euclidean distance</json:string><json:string>normal range</json:string><json:string>hormonal resistance</json:string><json:string>methylation abnormalities</json:string><json:string>albright osteodystrophy</json:string><json:string>quantitative method</json:string><json:string>body mass index</json:string><json:string>methylation patterns</json:string><json:string>methylation defects</json:string><json:string>biochemical characteristics</json:string><json:string>methylation changes</json:string><json:string>principal component analysis</json:string><json:string>parental imprinting</json:string><json:string>parathyroid hormone</json:string><json:string>clin endocrinol metab</json:string><json:string>sporadic pseudohypoparathyroidism type</json:string><json:string>nucleic acids</json:string><json:string>defect</json:string></teeft></keywords><author><json:item><name>Stéphanie Maupetit-Méhouas</name><affiliations><json:string>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</json:string></affiliations></json:item><json:item><name>Virginie Mariot</name><affiliations><json:string>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</json:string></affiliations></json:item><json:item><name>Christelle Reynès</name><affiliations><json:string>MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion, Paris, France</json:string></affiliations></json:item><json:item><name>Guylène Bertrand</name><affiliations><json:string>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</json:string></affiliations></json:item><json:item><name>Francois Feillet</name><affiliations><json:string>Centre de référence des maladies héréditaires du métabolisme, INSERM U954, CHU Brabois Enfant, Vandoeuvre les Nancy, France</json:string></affiliations></json:item><json:item><name>Jean-Claude Carel</name><affiliations><json:string>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</json:string></affiliations></json:item><json:item><name>Dominique Simon</name><affiliations><json:string>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</json:string></affiliations></json:item><json:item><name>Hélène Bihan</name><affiliations><json:string>Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes, Bobigny, France</json:string></affiliations></json:item><json:item><name>Vincent Gajdos</name><affiliations><json:string>Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère, Clamart, France</json:string></affiliations></json:item><json:item><name>Eve Devouge</name><affiliations><json:string>Service de Pédiatrie, Hôpital d'Arras, France</json:string></affiliations></json:item><json:item><name>Savitha Shenoy</name><affiliations><json:string>Leicester Royal Infirmary, Leicester, UK</json:string></affiliations></json:item><json:item><name>Placide Agbo-Kpati</name><affiliations><json:string>Service de Pédiatrie, Hôpital de Lagny, Lagny, France</json:string></affiliations></json:item><json:item><name>Anne Ronan</name><affiliations><json:string>Hunter Genetics Unit, Waratah, New South Wales, Australia</json:string></affiliations></json:item><json:item><name>Catherine Naud-Saudreau</name><affiliations><json:string>Service de Pédiatrie Bretagne sud, Lorient, France</json:string></affiliations></json:item><json:item><name>Anne Lienhardt</name><affiliations><json:string>Centre 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</json:string></affiliations></json:item><json:item><name>Caroline Silve</name><affiliations><json:string>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</json:string><json:string>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</json:string></affiliations></json:item><json:item><name>Agnès Linglart</name><affiliations><json:string>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</json:string><json:string>Assistance 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</json:string><json:string>E-mail: agnes.linglart@inserm.fr</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Pseudohypoparathyroidism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>quantitative methylation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>subtypes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>somatic mosaicism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>endocrinology</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>molecular genetics</value></json:item></subject><articleId><json:string>jmedgenet81356</json:string></articleId><arkIstex>ark:/67375/NVC-4F44R0BW-P</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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.</abstract><qualityIndicators><score>9.988</score><pdfWordCount>6324</pdfWordCount><pdfCharCount>41739</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>249</abstractWordCount><abstractCharCount>1717</abstractCharCount><keywordCount>6</keywordCount></qualityIndicators><title>Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</title><pmid><json:string>20972248</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Journal of Medical Genetics</title><language><json:string>unknown</json:string></language><issn><json:string>0022-2593</json:string></issn><eissn><json:string>1468-6244</json:string></eissn><publisherId><json:string>jmg</json:string></publisherId><volume>48</volume><issue>1</issue><pages><first>55</first></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2010-10-23</json:string></date><geogName></geogName><orgName><json:string>Paris Descartes University</json:string><json:string>Team R.D.C</json:string><json:string>INSERM</json:string></orgName><orgName_funder><json:string>INSERM</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Anne Lienhardt</json:string><json:string>Helene Bihan</json:string><json:string>Pierre-Francois Bougneres</json:string><json:string>Agnes Linglart</json:string><json:string>Gilles Grange</json:string><json:string>Dominique Simon</json:string><json:string>Caroline Silve</json:string><json:string>Helene Brion</json:string><json:string>Ib</json:string><json:string>Christelle Reynes</json:string><json:string>Vincent de Paul</json:string><json:string>Paris Diderot</json:string><json:string>Catherine Naud-Saudreau</json:string><json:string>Virginie Mariot</json:string><json:string>Thomassin</json:string><json:string>Paris Descartes</json:string><json:string>Anne Ronan</json:string><json:string>CHU Brabois</json:string><json:string>Jean-Claude Carel</json:string><json:string>Francois Feillet</json:string><json:string>Vincent Gajdos</json:string><json:string>Eve Devouge</json:string><json:string>Bernard Grandchamp</json:string><json:string>Disease</json:string><json:string>Placide Agbo-Kpati</json:string></persName><placeName><json:string>Paris</json:string><json:string>Nancy</json:string><json:string>Australia</json:string><json:string>UK</json:string><json:string>Arras</json:string><json:string>Wales</json:string><json:string>Saint Vincent</json:string><json:string>France</json:string><json:string>Limoges</json:string><json:string>Lorient</json:string><json:string>Leicester</json:string></placeName><ref_url><json:string>http://jmg.bmj</json:string></ref_url><ref_bibl><json:string>Mantovani et al</json:string><json:string>Bliek et al</json:string><json:string>Thomassin et al.</json:string><json:string>Liu et al</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/NVC-4F44R0BW-P</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - genetics & heredity</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - genetics & heredity</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Genetics(clinical)</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Genetics</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2011</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1136/jmg.2010.081356</json:string></doi><id>04167EA3EC5F03CA000338C4FC82163CCE831147</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/04167EA3EC5F03CA000338C4FC82163CCE831147/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/04167EA3EC5F03CA000338C4FC82163CCE831147/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/04167EA3EC5F03CA000338C4FC82163CCE831147/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">BMJ Publishing Group Ltd</publisher><availability><licence><p>© 2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-7M42M2QJ-2">bmj</p></availability><date>2010-10-23</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</title><author xml:id="author-0000"><persName><forename type="first">Stéphanie</forename><surname>Maupetit-Méhouas</surname></persName><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Virginie</forename><surname>Mariot</surname></persName><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Christelle</forename><surname>Reynès</surname></persName><affiliation>MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion, Paris, France</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Guylène</forename><surname>Bertrand</surname></persName><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Francois</forename><surname>Feillet</surname></persName><affiliation>Centre de référence des maladies héréditaires du métabolisme, INSERM U954, CHU Brabois Enfant, Vandoeuvre les Nancy, France</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Jean-Claude</forename><surname>Carel</surname></persName><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Dominique</forename><surname>Simon</surname></persName><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Hélène</forename><surname>Bihan</surname></persName><affiliation>Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes, Bobigny, France</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Vincent</forename><surname>Gajdos</surname></persName><affiliation>Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère, Clamart, France</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Eve</forename><surname>Devouge</surname></persName><affiliation>Service de Pédiatrie, Hôpital d'Arras, France</affiliation></author><author xml:id="author-0010"><persName><forename type="first">Savitha</forename><surname>Shenoy</surname></persName><affiliation>Leicester Royal Infirmary, Leicester, UK</affiliation></author><author xml:id="author-0011"><persName><forename type="first">Placide</forename><surname>Agbo-Kpati</surname></persName><affiliation>Service de Pédiatrie, Hôpital de Lagny, Lagny, France</affiliation></author><author xml:id="author-0012"><persName><forename type="first">Anne</forename><surname>Ronan</surname></persName><affiliation>Hunter Genetics Unit, Waratah, New South Wales, Australia</affiliation></author><author xml:id="author-0013"><persName><forename type="first">Catherine</forename><surname>Naud-Saudreau</surname></persName><affiliation>Service de Pédiatrie Bretagne sud, Lorient, France</affiliation></author><author xml:id="author-0014"><persName><forename type="first">Anne</forename><surname>Lienhardt</surname></persName><affiliation>Centre 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</affiliation></author><author xml:id="author-0015"><persName><forename type="first">Caroline</forename><surname>Silve</surname></persName><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</affiliation></author><author xml:id="author-0016" corresp="yes"><persName><forename type="first">Agnès</forename><surname>Linglart</surname></persName><email>agnes.linglart@inserm.fr</email><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation><affiliation>Assistance 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</affiliation></author><idno type="istex">04167EA3EC5F03CA000338C4FC82163CCE831147</idno><idno type="ark">ark:/67375/NVC-4F44R0BW-P</idno><idno type="DOI">10.1136/jmg.2010.081356</idno><idno type="href">jmedgenet-48-55.pdf</idno><idno type="article-id">jmedgenet81356</idno><idno type="PMID">20972248</idno><idno type="local">jmedgenet;48/1/55</idno></analytic><monogr><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="pISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><idno type="publisher-id">jmg</idno><idno type="PublisherID-hwp">jmedgenet</idno><idno type="PublisherID-nlm-ta">J Med Genet</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2011-01"></date><biblScope unit="volume">48</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="55">55</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-10-23</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>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.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Pseudohypoparathyroidism</term></item><item><term>quantitative methylation</term></item><item><term>subtypes</term></item><item><term>somatic mosaicism</term></item><item><term>endocrinology</term></item><item><term>molecular genetics</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-10-23">Created</change><change when="2011-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/04167EA3EC5F03CA000338C4FC82163CCE831147/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType 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pub-id-type="other">jmedgenet;jmg.2010.081356</article-id><article-id pub-id-type="pmid">20972248</article-id><article-id pub-id-type="other">55</article-id><article-id pub-id-type="other">jmg.2010.081356</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original article</subject></subj-group></article-categories><title-group><article-title>Quantification of the methylation at the <italic>GNAS</italic> locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Maupetit-Méhouas</surname><given-names>Stéphanie</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mariot</surname><given-names>Virginie</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Reynès</surname><given-names>Christelle</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bertrand</surname><given-names>Guylène</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Feillet</surname><given-names>Francois</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Carel</surname><given-names>Jean-Claude</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Simon</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Bihan</surname><given-names>Hélène</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gajdos</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Devouge</surname><given-names>Eve</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Shenoy</surname><given-names>Savitha</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Agbo-Kpati</surname><given-names>Placide</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Ronan</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Naud-Saudreau</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Lienhardt</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Silve</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Linglart</surname><given-names>Agnès</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff14">14</xref></contrib></contrib-group><aff id="aff1"><label>1</label>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</aff><aff id="aff2"><label>2</label>MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion, Paris, France</aff><aff id="aff3"><label>3</label>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</aff><aff id="aff4"><label>4</label>Centre de référence des maladies héréditaires du métabolisme, INSERM U954, CHU Brabois Enfant, Vandoeuvre les Nancy, France</aff><aff id="aff5"><label>5</label>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</aff><aff id="aff6"><label>6</label>Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes, Bobigny, France</aff><aff id="aff7"><label>7</label>Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère, Clamart, France</aff><aff id="aff8"><label>8</label>Service de Pédiatrie, Hôpital d'Arras, France</aff><aff id="aff9"><label>9</label>Leicester Royal Infirmary, Leicester, UK</aff><aff id="aff10"><label>10</label>Service de Pédiatrie, Hôpital de Lagny, Lagny, France</aff><aff id="aff11"><label>11</label>Hunter Genetics Unit, Waratah, New South Wales, Australia</aff><aff id="aff12"><label>12</label>Service de Pédiatrie Bretagne sud, Lorient, France</aff><aff id="aff13"><label>13</label>Centre 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</aff><aff id="aff14"><label>14</label>Assistance 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</aff><author-notes><corresp><label>Correspondence to</label> Agnès Linglart, INSERM U986, Hôpital Saint Vincent de Paul, 82 avenue Denfert-Rochereau, 75014 Paris, France; <email>agnes.linglart@inserm.fr</email></corresp></author-notes><pub-date pub-type="epub-original"><day>23</day><month>10</month><year>2010</year></pub-date><pub-date pub-type="ppub"><month>1</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>23</day><month>10</month><year>2010</year></pub-date><volume>48</volume><volume-id pub-id-type="other">48</volume-id><volume-id pub-id-type="other">48</volume-id><issue>1</issue><issue-id pub-id-type="other">jmedgenet;48/1</issue-id><issue-id pub-id-type="other">1</issue-id><issue-id pub-id-type="other">48/1</issue-id><fpage>55</fpage><history><date date-type="received"><day>20</day><month>5</month><year>2010</year></date><date date-type="rev-recd"><day>29</day><month>7</month><year>2010</year></date><date date-type="accepted"><day>18</day><month>8</month><year>2010</year></date></history><permissions><copyright-statement>© 2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</copyright-statement><copyright-year>2011</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jmedgenet-48-55.pdf"></self-uri><abstract><sec><title>Background</title><p>Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted <italic>GNAS</italic> 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.</p></sec><sec><title>Objective</title><p>To investigate if quantitative measurement of the methylation at the <italic>GNAS</italic> DMRs identifies subtypes of PHP-Ib.</p></sec><sec><title>Design and methods</title><p>In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four <italic>GNAS</italic> DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA.</p></sec><sec><title>Results</title><p>A principal component analysis using the per cent of methylation at seven cytosines of the <italic>GNAS</italic> 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 <italic>GNAS</italic> 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec></abstract><kwd-group><kwd>Pseudohypoparathyroidism</kwd><kwd>quantitative methylation</kwd><kwd>subtypes</kwd><kwd>somatic mosaicism</kwd><kwd>endocrinology</kwd><kwd>molecular genetics</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib</title></titleInfo><name type="personal"><namePart type="given">Stéphanie</namePart><namePart type="family">Maupetit-Méhouas</namePart><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Virginie</namePart><namePart type="family">Mariot</namePart><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christelle</namePart><namePart type="family">Reynès</namePart><affiliation>MTi-Université Paris Diderot, INSERM U973, Rue Hélène Brion, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Guylène</namePart><namePart type="family">Bertrand</namePart><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Francois</namePart><namePart type="family">Feillet</namePart><affiliation>Centre de référence des maladies héréditaires du métabolisme, INSERM U954, CHU Brabois Enfant, Vandoeuvre les Nancy, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean-Claude</namePart><namePart type="family">Carel</namePart><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dominique</namePart><namePart type="family">Simon</namePart><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Department of pediatric endocrinology and diabetology, Robert Debré Hospital, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hélène</namePart><namePart type="family">Bihan</namePart><affiliation>Assistance Publique-Hôpitaux de Paris, Endocrinologie Diabétologie et maladies métaboliques, Hôpital Avicennes, Bobigny, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vincent</namePart><namePart type="family">Gajdos</namePart><affiliation>Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Beclère, Clamart, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eve</namePart><namePart type="family">Devouge</namePart><affiliation>Service de Pédiatrie, Hôpital d'Arras, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Savitha</namePart><namePart type="family">Shenoy</namePart><affiliation>Leicester Royal Infirmary, Leicester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Placide</namePart><namePart type="family">Agbo-Kpati</namePart><affiliation>Service de Pédiatrie, Hôpital de Lagny, Lagny, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anne</namePart><namePart type="family">Ronan</namePart><affiliation>Hunter Genetics Unit, Waratah, New South Wales, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Catherine</namePart><namePart type="family">Naud-Saudreau</namePart><affiliation>Service de Pédiatrie Bretagne sud, Lorient, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anne</namePart><namePart type="family">Lienhardt</namePart><affiliation>Centre 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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Caroline</namePart><namePart type="family">Silve</namePart><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation><affiliation>Assistance Publique-Hôpitaux de Paris, Université Paris 7, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Agnès</namePart><namePart type="family">Linglart</namePart><affiliation>INSERM, Université Paris Descartes, U986, Hôpital Saint Vincent de Paul, Paris, France</affiliation><affiliation>Assistance 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</affiliation><affiliation>E-mail: agnes.linglart@inserm.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2011-01</dateIssued><dateCreated encoding="w3cdtf">2010-10-23</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><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.</abstract><subject><genre>keywords</genre><topic>Pseudohypoparathyroidism</topic><topic>quantitative methylation</topic><topic>subtypes</topic><topic>somatic mosaicism</topic><topic>endocrinology</topic><topic>molecular genetics</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Medical Genetics</title></titleInfo><titleInfo type="abbreviated"><title>J Med Genet</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-2593</identifier><identifier type="eISSN">1468-6244</identifier><identifier type="PublisherID">jmg</identifier><identifier type="PublisherID-hwp">jmedgenet</identifier><identifier type="PublisherID-nlm-ta">J Med Genet</identifier><part><date>2011</date><detail type="volume"><caption>vol.</caption><number>48</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>55</start></extent></part></relatedItem><identifier type="istex">04167EA3EC5F03CA000338C4FC82163CCE831147</identifier><identifier type="ark">ark:/67375/NVC-4F44R0BW-P</identifier><identifier type="DOI">10.1136/jmg.2010.081356</identifier><identifier type="href">jmedgenet-48-55.pdf</identifier><identifier type="ArticleID">jmedgenet81356</identifier><identifier type="PMID">20972248</identifier><identifier type="local">jmedgenet;48/1/55</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2011, Published by the BMJ Publishing Group Limited. 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