Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.
Identifieur interne : 000012 ( PubMed/Corpus ); précédent : 000011; suivant : 000013Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.
Auteurs : Cyril Burin-Des-Roziers ; Pierre-Raphael Rothschild ; Valérie Layet ; Jian-Min Chen ; Tiffany Ghiotti ; Céline Leroux ; Frans P M. Cremers ; Antoine P. Brézin ; Sophie ValleixSource :
- 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
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.</title><author><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><affiliation><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.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation><nlm:affiliation>Service de Génétique médicale, Hôpital Jacques Monod, Le Havre, France.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Ghiotti, Tiffany" sort="Ghiotti, Tiffany" uniqKey="Ghiotti T" first="Tiffany" last="Ghiotti">Tiffany Ghiotti</name><affiliation><nlm:affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Leroux, Celine" sort="Leroux, Celine" uniqKey="Leroux C" first="Céline" last="Leroux">Céline Leroux</name><affiliation><nlm:affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</nlm:affiliation></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><nlm:affiliation>Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Valleix, Sophie" sort="Valleix, Sophie" uniqKey="Valleix S" first="Sophie" last="Valleix">Sophie Valleix</name><affiliation><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></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27667122</idno><idno type="pmid">27667122</idno><idno type="doi">10.1002/humu.23124</idno><idno type="wicri:Area/PubMed/Corpus">000012</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.</title><author><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><affiliation><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.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation><nlm:affiliation>Service de Génétique médicale, Hôpital Jacques Monod, Le Havre, France.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Ghiotti, Tiffany" sort="Ghiotti, Tiffany" uniqKey="Ghiotti T" first="Tiffany" last="Ghiotti">Tiffany Ghiotti</name><affiliation><nlm:affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Leroux, Celine" sort="Leroux, Celine" uniqKey="Leroux C" first="Céline" last="Leroux">Céline Leroux</name><affiliation><nlm:affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</nlm:affiliation></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><nlm:affiliation>Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Valleix, Sophie" sort="Valleix, Sophie" uniqKey="Valleix S" first="Sophie" last="Valleix">Sophie Valleix</name><affiliation><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></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><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">27667122</PMID><DateCreated><Year>2016</Year><Month>9</Month><Day>26</Day></DateCreated><DateRevised><Year>2016</Year><Month>9</Month><Day>26</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1098-1004</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2016</Year><Month>Sep</Month><Day>26</Day></PubDate></JournalIssue><Title>Human mutation</Title><ISOAbbreviation>Hum. Mutat.</ISOAbbreviation></Journal><ArticleTitle>Deletions Overlapping VCAN Exon 8 are New Molecular Defects for Wagner Disease.</ArticleTitle><ELocationID EIdType="doi" ValidYN="Y">10.1002/humu.23124</ELocationID><Abstract><AbstractText NlmCategory="UNASSIGNED">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.</AbstractText><CopyrightInformation>This article is protected by copyright. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Burin-des-Roziers</LastName><ForeName>Cyril</ForeName><Initials>C</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rothschild</LastName><ForeName>Pierre-Raphael</ForeName><Initials>PR</Initials><AffiliationInfo><Affiliation>Service d'ophtalmologie,Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Layet</LastName><ForeName>Valérie</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Service de Génétique médicale, Hôpital Jacques Monod, Le Havre, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Jian-Min</ForeName><Initials>JM</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ghiotti</LastName><ForeName>Tiffany</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leroux</LastName><ForeName>Céline</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cremers</LastName><ForeName>Frans P M</ForeName><Initials>FP</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brézin</LastName><ForeName>Antoine P</ForeName><Initials>AP</Initials><AffiliationInfo><Affiliation>Service d'ophtalmologie,Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Valleix</LastName><ForeName>Sophie</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Laboratoire de Génétique moléculaire, Service de Génétique, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. sophie.valleix@aphp.fr.</Affiliation></AffiliationInfo></Author></AuthorList><Language>ENG</Language><PublicationTypeList><PublicationType UI="">JOURNAL ARTICLE</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>Sep</Month><Day>26</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Hum Mutat</MedlineTA><NlmUniqueID>9215429</NlmUniqueID><ISSNLinking>1059-7794</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">VCAN</Keyword><Keyword MajorTopicYN="N">Wagner disease</Keyword><Keyword MajorTopicYN="N">deletion</Keyword><Keyword MajorTopicYN="N">next generation sequencing</Keyword><Keyword MajorTopicYN="N">somatic mosaicism</Keyword><Keyword MajorTopicYN="N">vitreoretinopathy</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>4</Month><Day>22</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2016</Year><Month>8</Month><Day>31</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>9</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>9</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>9</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>9</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27667122</ArticleId><ArticleId 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