Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males
Identifieur interne : 00A676 ( Main/Exploration ); précédent : 00A675; suivant : 00A677Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males
Auteurs : Hilde Van Esch [Allemagne] ; Marijke Bauters [Belgique] ; Jaakko Ignatius [Finlande] ; Mieke Jansen [Belgique] ; Martine Raynaud [France] ; Karen Hollanders [Belgique] ; Dorien Lugtenberg [Pays-Bas] ; Thierry Bienvenu [France] ; Lars Riff Jensen [Allemagne] ; Jozef Gecz [Australie] ; Claude Moraine [France] ; Peter Marynen [Belgique] ; Jean-Pierre Fryns [Allemagne] ; Guy Froyen [Belgique]Source :
- American journal of human genetics [ 0002-9297 ] ; 2005.
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Abstract
Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1AM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.
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Affiliations:
- Allemagne, Australie, Belgique, Finlande, France, Pays-Bas
- Berlin, Centre-Val de Loire, Gueldre, Région Centre, Île-de-France
- Berlin, Nimègue, Paris, Tours
- Université Paris-Descartes
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Scientifique, Institut Cochin</s1><s2>Paris</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">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Jensen, Lars Riff" sort="Jensen, Lars Riff" uniqKey="Jensen L" first="Lars Riff" last="Jensen">Lars Riff Jensen</name><affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Max Planck Institute for Molecular Genetics</s1><s2>Berlin</s2><s3>DEU</s3><sZ>9 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation 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first="Marijke" last="Bauters">Marijke Bauters</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Human Genome Laboratory, Centre for Human Genetics, Flanders Interuniversity Institute for Biotechnology</s1><s2>Leuven</s2><s3>BEL</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>12 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Ignatius, Jaakko" sort="Ignatius, Jaakko" uniqKey="Ignatius J" first="Jaakko" last="Ignatius">Jaakko Ignatius</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Clinical Genetics, Oulu University Hospital and Oulu University</s1><s2>Oulu</s2><s3>FIN</s3><sZ>3 aut.</sZ></inist:fA14><country>Finlande</country><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Jansen, Mieke" sort="Jansen, Mieke" uniqKey="Jansen M" first="Mieke" last="Jansen">Mieke Jansen</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Human Genome Laboratory, Centre for Human Genetics, Flanders Interuniversity Institute for Biotechnology</s1><s2>Leuven</s2><s3>BEL</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>12 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Centre Hospitalier Universitaire de Tours, Service de Génétique</s1><s2>Tours</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Centre-Val de Loire</region><region type="old region">Région Centre</region><settlement type="city">Tours</settlement></placeName></affiliation></author><author><name sortKey="Hollanders, Karen" sort="Hollanders, Karen" uniqKey="Hollanders K" first="Karen" last="Hollanders">Karen Hollanders</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Human Genome Laboratory, Centre for Human Genetics, Flanders Interuniversity Institute for Biotechnology</s1><s2>Leuven</s2><s3>BEL</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>12 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Lugtenberg, Dorien" sort="Lugtenberg, Dorien" uniqKey="Lugtenberg D" first="Dorien" last="Lugtenberg">Dorien Lugtenberg</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Department of Human Genetics, University Medical Centre</s1><s2>Nijmegen</s2><s3>NLD</s3><sZ>7 aut.</sZ></inist:fA14><country>Pays-Bas</country><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Bienvenu, Thierry" sort="Bienvenu, Thierry" uniqKey="Bienvenu T" first="Thierry" last="Bienvenu">Thierry Bienvenu</name><affiliation wicri:level="4"><inist:fA14 i1="06"><s1>Université Paris-Descartes, Faculté de Médecine, INSERM, Centre National de la Récherche Scientifique, Institut Cochin</s1><s2>Paris</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">Paris</settlement><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation></author><author><name sortKey="Jensen, Lars Riff" sort="Jensen, Lars Riff" uniqKey="Jensen L" first="Lars Riff" last="Jensen">Lars Riff Jensen</name><affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Max Planck Institute for Molecular Genetics</s1><s2>Berlin</s2><s3>DEU</s3><sZ>9 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Adelaide</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Department of Paediatrics, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Adelaide</wicri:noRegion></affiliation></author><author><name sortKey="Moraine, Claude" sort="Moraine, Claude" uniqKey="Moraine C" first="Claude" last="Moraine">Claude Moraine</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Centre Hospitalier Universitaire de Tours, Service de Génétique</s1><s2>Tours</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Centre-Val de Loire</region><region type="old region">Région Centre</region><settlement type="city">Tours</settlement></placeName></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Human Genome Laboratory, Centre for Human Genetics, Flanders Interuniversity Institute for Biotechnology</s1><s2>Leuven</s2><s3>BEL</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>12 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Fryns, Jean Pierre" sort="Fryns, Jean Pierre" uniqKey="Fryns J" first="Jean-Pierre" last="Fryns">Jean-Pierre Fryns</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre for Human Genetics, University Hospital Gasthuisberg</s1><s3>DEU</s3><sZ>1 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>University Hospital Gasthuisberg</wicri:noRegion><wicri:noRegion>Centre for Human Genetics, University Hospital Gasthuisberg</wicri:noRegion></affiliation></author><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Human Genome Laboratory, Centre for Human Genetics, Flanders Interuniversity Institute for Biotechnology</s1><s2>Leuven</s2><s3>BEL</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>12 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">American journal of human genetics</title><title level="j" type="abbreviated">Am. j. hum. genet.</title><idno type="ISSN">0002-9297</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of human genetics</title><title level="j" type="abbreviated">Am. j. hum. genet.</title><idno type="ISSN">0002-9297</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Chromosome duplication</term><term>Genetics</term><term>Human</term><term>Male</term><term>Mental retardation</term><term>Nervous system</term><term>Progressive</term><term>Severe</term><term>Symptomatology</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Arriération mentale</term><term>Duplication chromosomique</term><term>Grave</term><term>Progressif</term><term>Système nerveux</term><term>Symptomatologie</term><term>Mâle</term><term>Génétique</term><term>Homme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1AM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Belgique</li><li>Finlande</li><li>France</li><li>Pays-Bas</li></country><region><li>Berlin</li><li>Centre-Val de Loire</li><li>Gueldre</li><li>Région Centre</li><li>Île-de-France</li></region><settlement><li>Berlin</li><li>Nimègue</li><li>Paris</li><li>Tours</li></settlement><orgName><li>Université Paris-Descartes</li></orgName></list><tree><country name="Allemagne"><noRegion><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name></noRegion><name sortKey="Fryns, Jean Pierre" sort="Fryns, Jean Pierre" uniqKey="Fryns J" first="Jean-Pierre" last="Fryns">Jean-Pierre Fryns</name><name sortKey="Jensen, Lars Riff" sort="Jensen, Lars Riff" uniqKey="Jensen L" first="Lars Riff" last="Jensen">Lars Riff Jensen</name></country><country name="Belgique"><noRegion><name sortKey="Bauters, Marijke" sort="Bauters, Marijke" uniqKey="Bauters M" first="Marijke" last="Bauters">Marijke Bauters</name></noRegion><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><name sortKey="Hollanders, Karen" sort="Hollanders, Karen" uniqKey="Hollanders K" first="Karen" last="Hollanders">Karen Hollanders</name><name sortKey="Jansen, Mieke" sort="Jansen, Mieke" uniqKey="Jansen M" first="Mieke" last="Jansen">Mieke Jansen</name><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name></country><country name="Finlande"><noRegion><name sortKey="Ignatius, Jaakko" sort="Ignatius, Jaakko" uniqKey="Ignatius J" first="Jaakko" last="Ignatius">Jaakko Ignatius</name></noRegion></country><country name="France"><region name="Centre-Val de Loire"><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name></region><name sortKey="Bienvenu, Thierry" sort="Bienvenu, Thierry" uniqKey="Bienvenu T" first="Thierry" last="Bienvenu">Thierry Bienvenu</name><name sortKey="Moraine, Claude" sort="Moraine, Claude" uniqKey="Moraine C" first="Claude" last="Moraine">Claude Moraine</name></country><country name="Pays-Bas"><region name="Gueldre"><name sortKey="Lugtenberg, Dorien" sort="Lugtenberg, Dorien" uniqKey="Lugtenberg D" first="Dorien" last="Lugtenberg">Dorien Lugtenberg</name></region></country><country name="Australie"><noRegion><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name></noRegion><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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