Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.
Identifieur interne : 000072 ( France/Analysis ); précédent : 000071; suivant : 000073Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.
Auteurs : Cyril Burin-Des-Roziers [France] ; Pierre-Raphael Rothschild [France] ; Valérie Layet [France] ; Jian-Min Chen [France] ; Tiffany Ghiotti [France] ; Céline Leroux [France] ; Frans P M. Cremers [Pays-Bas] ; Antoine P. Brézin [France] ; Sophie Valleix [France]Source :
- Human mutation [ 1098-1004 ] ; 2016.
Abstract
Wagner disease is a rare non-syndromic autosomal dominant vitreoretinopathy, associated with splice mutations specifically targeting VCAN exon 8. We report the extensive genetic analysis of two Wagner probands, previously found negative for disease-associated splice mutations. Next-generation sequencing, quantitative real-time PCR, and long-range PCR, identified two deletions (3.4 kb and 10.5 kb) removing at least one exon-intron boundary of exon 8, and both correlating with an imbalance of VCAN mRNA isoforms. We showed that the 10.5 kb-deletion occurred de novo, causing somatic mosaicim in the proband's mother who had an unusually mild asymetrical phenotype. Therefore, exon 8 deletions are novel VCAN genetic defects responsible for Wagner disease, and VCAN mosaic mutations may be involved in the pathogenesis of Wagner disease with attenuated phenotype. NGS is then an effective screening tool for genetic diagnosis of Wagner disease, improving the chance of identifying all disease-causative variants as well as mosaic mutations in VCAN. This article is protected by copyright. All rights reserved.
DOI: 10.1002/humu.23124
PubMed: 27667122
Affiliations:
- France, Pays-Bas
- Gueldre, Région Bretagne, Île-de-France
- Brest, Le Havre, Nimègue, Paris
- Université Paris Descartes, Université de Bretagne Occidentale
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pubmed:27667122Le document en format XML
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Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique, Université Paris Descartes, Sorbonne Paris Cité, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Rothschild, Pierre Raphael" sort="Rothschild, Pierre Raphael" uniqKey="Rothschild P" first="Pierre-Raphael" last="Rothschild">Pierre-Raphael Rothschild</name><affiliation wicri:level="4"><nlm:affiliation>Service d'ophtalmologie,Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service d'ophtalmologie,Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation wicri:level="1"><nlm:affiliation>Service de Génétique médicale, Hôpital Jacques Monod, Le Havre, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Génétique médicale, Hôpital Jacques Monod, Le Havre</wicri:regionArea><placeName><settlement type="city">Le Havre</settlement></placeName></affiliation></author><author><name sortKey="Chen, Jian Min" sort="Chen, Jian Min" uniqKey="Chen J" first="Jian-Min" last="Chen">Jian-Min Chen</name><affiliation wicri:level="4"><nlm:affiliation>Institut National de la Santé et de la Recherche Médicale (INSERM), France Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), France Etablissement Français du sang (EFS)-Bretagne, Brest, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale (INSERM), France Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), France Etablissement Français du sang (EFS)-Bretagne, Brest</wicri:regionArea><placeName><settlement type="city">Brest</settlement></placeName><orgName type="university">Université de Bretagne Occidentale</orgName><placeName><settlement type="city">Brest</settlement><region type="region" nuts="2">Région Bretagne</region></placeName></affiliation></author><author><name sortKey="Ghiotti, Tiffany" sort="Ghiotti, Tiffany" uniqKey="Ghiotti T" first="Tiffany" last="Ghiotti">Tiffany Ghiotti</name><affiliation wicri:level="1"><nlm:affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Leroux, Celine" sort="Leroux, Celine" uniqKey="Leroux C" first="Céline" last="Leroux">Céline Leroux</name><affiliation wicri:level="1"><nlm:affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Cremers, Frans P M" sort="Cremers, Frans P M" uniqKey="Cremers F" first="Frans P M" last="Cremers">Frans P M. Cremers</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Brezin, Antoine P" sort="Brezin, Antoine P" uniqKey="Brezin A" first="Antoine P" last="Brézin">Antoine P. Brézin</name><affiliation wicri:level="4"><nlm:affiliation>Service d'ophtalmologie,Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service d'ophtalmologie,Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Valleix, Sophie" sort="Valleix, Sophie" uniqKey="Valleix S" first="Sophie" last="Valleix">Sophie Valleix</name><affiliation wicri:level="4"><nlm:affiliation>Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. sophie.valleix@aphp.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique, Université Paris Descartes, Sorbonne Paris Cité, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author></analytic><series><title level="j">Human mutation</title><idno type="eISSN">1098-1004</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Wagner disease is a rare non-syndromic autosomal dominant vitreoretinopathy, associated with splice mutations specifically targeting VCAN exon 8. We report the extensive genetic analysis of two Wagner probands, previously found negative for disease-associated splice mutations. Next-generation sequencing, quantitative real-time PCR, and long-range PCR, identified two deletions (3.4 kb and 10.5 kb) removing at least one exon-intron boundary of exon 8, and both correlating with an imbalance of VCAN mRNA isoforms. We showed that the 10.5 kb-deletion occurred de novo, causing somatic mosaicim in the proband's mother who had an unusually mild asymetrical phenotype. Therefore, exon 8 deletions are novel VCAN genetic defects responsible for Wagner disease, and VCAN mosaic mutations may be involved in the pathogenesis of Wagner disease with attenuated phenotype. NGS is then an effective screening tool for genetic diagnosis of Wagner disease, improving the chance of identifying all disease-causative variants as well as mosaic mutations in VCAN. This article is protected by copyright. All rights reserved.</div></front></TEI><affiliations><list><country><li>France</li><li>Pays-Bas</li></country><region><li>Gueldre</li><li>Région Bretagne</li><li>Île-de-France</li></region><settlement><li>Brest</li><li>Le Havre</li><li>Nimègue</li><li>Paris</li></settlement><orgName><li>Université Paris Descartes</li><li>Université de Bretagne Occidentale</li></orgName></list><tree><country name="France"><noRegion><name sortKey="Burin Des Roziers, Cyril" sort="Burin Des Roziers, Cyril" uniqKey="Burin Des Roziers C" first="Cyril" last="Burin-Des-Roziers">Cyril Burin-Des-Roziers</name></noRegion><name sortKey="Brezin, Antoine P" sort="Brezin, Antoine P" uniqKey="Brezin A" first="Antoine P" last="Brézin">Antoine P. Brézin</name><name sortKey="Chen, Jian Min" sort="Chen, Jian Min" uniqKey="Chen J" first="Jian-Min" last="Chen">Jian-Min Chen</name><name sortKey="Ghiotti, Tiffany" sort="Ghiotti, Tiffany" uniqKey="Ghiotti T" first="Tiffany" last="Ghiotti">Tiffany Ghiotti</name><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><name sortKey="Leroux, Celine" sort="Leroux, Celine" uniqKey="Leroux C" first="Céline" last="Leroux">Céline Leroux</name><name sortKey="Rothschild, Pierre Raphael" sort="Rothschild, Pierre Raphael" uniqKey="Rothschild P" first="Pierre-Raphael" last="Rothschild">Pierre-Raphael Rothschild</name><name sortKey="Valleix, Sophie" sort="Valleix, Sophie" uniqKey="Valleix S" first="Sophie" last="Valleix">Sophie Valleix</name></country><country name="Pays-Bas"><region name="Gueldre"><name sortKey="Cremers, Frans P M" sort="Cremers, Frans P M" uniqKey="Cremers F" first="Frans P M" last="Cremers">Frans P M. 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