Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation
Identifieur interne : 003682 ( PascalFrancis/Corpus ); précédent : 003681; suivant : 003683Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation
Auteurs : Guy Froyen ; Mark Corbett ; Joke Vandewalle ; Irma Jarvela ; Owen Lawrence ; Cliff Meldrum ; Marijke Bauters ; Karen Govaerts ; Lucianne Vandeleur ; Hilde Van Esch ; Jamel Chelly ; Damien Sanlaville ; Hans Van Bokhoven ; Hans-Hilger Ropers ; Frederic Laumonnier ; Enzo Ranieri ; Charles E. Schwartz ; Fatima Abidi ; Patrick S. Tarpey ; P. Andrew Futreal ; Annabel Whibley ; F. Lucy Raymond ; Michael R. Stratton ; Jean-Pierre Fryns ; Rodney Scott ; Maarit Peippo ; Marjatta Sipponen ; Michael Partington ; David Mowat ; Michael Field ; Anna Hackett ; Peter Marynen ; Gillian Turner ; Jozef GeczSource :
- American journal of human genetics [ 0002-9297 ] ; 2008.
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Abstract
Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.
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Format Inist (serveur)
| NO : | PASCAL 08-0160921 INIST |
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| ET : | Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation |
| AU : | FROYEN (Guy); CORBETT (Mark); VANDEWALLE (Joke); JARVELA (Irma); LAWRENCE (Owen); MELDRUM (Cliff); BAUTERS (Marijke); GOVAERTS (Karen); VANDELEUR (Lucianne); VAN ESCH (Hilde); CHELLY (Jamel); SANLAVILLE (Damien); VAN BOKHOVEN (Hans); ROPERS (Hans-Hilger); LAUMONNIER (Frederic); RANIERI (Enzo); SCHWARTZ (Charles E.); ABIDI (Fatima); TARPEY (Patrick S.); FUTREAL (P. Andrew); WHIBLEY (Annabel); RAYMOND (F. Lucy); STRATTON (Michael R.); FRYNS (Jean-Pierre); SCOTT (Rodney); PEIPPO (Maarit); SIPPONEN (Marjatta); PARTINGTON (Michael); MOWAT (David); FIELD (Michael); HACKETT (Anna); MARYNEN (Peter); TURNER (Gillian); GECZ (Jozef) |
| AF : | Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB/3000 Leuven/Belgique (1 aut., 3 aut., 7 aut., 8 aut., 32 aut.); Human Genome Laboratory, Department of Human Genetics, K.U.Leuven/3000 Leuven/Belgique (1 aut., 3 aut., 7 aut., 8 aut., 32 aut.); Department of Genetic Medicine, Women's and Children's Hospital/Adelaide SA 5005/Australie (2 aut., 9 aut., 16 aut., 34 aut.); Laboratory of Molecular Genetics, Helsinki University Central Hospital (Laboratory Services)/00290 Helsinki/Finlande (4 aut.); Department of Medical Genetics, University of Helsinki/00290 Helsinki/Finlande (4 aut.); Molecular Genetics Laboratory HAPS, John Hunter Hospital/Newcastle NSW 2305/Australie (5 aut., 6 aut., 25 aut.); University Hospital Leuven, Department of Human Genetics, University of Leuven/3000 Leuven/Belgique (10 aut., 24 aut.); Institut Cochin, Université Paris Descartes, CNRS (UMR 8104)/75014 Paris/France (11 aut.); Inserm, U567/75014 Paris/France (11 aut.); Genetic Department, Necker Enfants Malades Hospital/75935 Paris/France (12 aut.); Department of Human Genetics, University Medical Centre/6500 Nijmegen/Pays-Bas (13 aut.); Max-Planck Institute for Molecular Genetics/14195 Berlin/Allemagne (14 aut.); INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais/37044 Tours/France (15 aut.); Greenwood Genetic Center, JC Self Research Institute of Human Genetics/Greenwood, SC 29646/Etats-Unis (17 aut., 18 aut.); The Wellcome Trust Sanger Institute/Hinxton CB10 ISA/Royaume-Uni (19 aut., 20 aut., 23 aut.); Cambridge Institute of Medical Research/Cambridge CB2 2XY/Royaume-Uni (21 aut., 22 aut.); The Family Federation of Finland/00101 Helsinki/Finlande (26 aut., 27 aut.); The GOLD service Hunter Genetics University of Newcastle/New South Wales NSW 2308/Australie (28 aut., 30 aut., 31 aut., 33 aut.); Department of Genetics, Sydney Children's Hospital/New South Wales NSW 2308/Australie (29 aut.); Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide/Adelaide SA 5005/Australie (34 aut.) |
| DT : | Publication en série; Niveau analytique |
| SO : | American journal of human genetics; ISSN 0002-9297; Coden AJHGAG; Etats-Unis; Da. 2008; Vol. 82; No. 2; Pp. 432-443; Bibl. 42 ref. |
| LA : | Anglais |
| EA : | Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too. |
| CC : | 002A04; 002A07; 002B23A; 002B18C12 |
| FD : | Arriération mentale; Duplication chromosomique; Dehydrogenase; Ubiquitine; Ligases; Association; Génétique; Homme |
| FG : | Chromosome anormal; Aberration chromosomique; Oxidoreductases; Enzyme; Déficience intellectuelle; Trouble du développement |
| ED : | Mental retardation; Chromosome duplication; Dehydrogenase; Ubiquitin; Ligases; Association; Genetics; Human |
| EG : | Abnormal chromosome; Chromosomal aberration; Oxidoreductases; Enzyme; Intellectual deficiency; Developmental disorder |
| SD : | Retraso mental; Duplicación cromosómica; Dehydrogenase; Ubiquitina; Ligases; Asociación; Genética; Hombre |
| LO : | INIST-2610.354000173625010150 |
| ID : | 08-0160921 |
Links to Exploration step
Pascal:08-0160921Le document en format XML
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Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vandeleur, Lucianne" sort="Vandeleur, Lucianne" uniqKey="Vandeleur L" first="Lucianne" last="Vandeleur">Lucianne Vandeleur</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation><inist:fA14 i1="07"><s1>University Hospital Leuven, Department of Human Genetics, University of Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>10 aut.</sZ><sZ>24 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><inist:fA14 i1="08"><s1>Institut Cochin, Université Paris Descartes, CNRS (UMR 8104)</s1><s2>75014 Paris</s2><s3>FRA</s3><sZ>11 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="09"><s1>Inserm, U567</s1><s2>75014 Paris</s2><s3>FRA</s3><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Sanlaville, Damien" sort="Sanlaville, Damien" uniqKey="Sanlaville D" first="Damien" last="Sanlaville">Damien Sanlaville</name><affiliation><inist:fA14 i1="10"><s1>Genetic Department, Necker Enfants Malades Hospital</s1><s2>75935 Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Van Bokhoven, Hans" sort="Van Bokhoven, Hans" uniqKey="Van Bokhoven H" first="Hans" last="Van Bokhoven">Hans Van Bokhoven</name><affiliation><inist:fA14 i1="11"><s1>Department of Human Genetics, University Medical Centre</s1><s2>6500 Nijmegen</s2><s3>NLD</s3><sZ>13 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><inist:fA14 i1="12"><s1>Max-Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>14 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Laumonnier, Frederic" sort="Laumonnier, Frederic" uniqKey="Laumonnier F" first="Frederic" last="Laumonnier">Frederic Laumonnier</name><affiliation><inist:fA14 i1="13"><s1>INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais</s1><s2>37044 Tours</s2><s3>FRA</s3><sZ>15 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Ranieri, Enzo" sort="Ranieri, Enzo" uniqKey="Ranieri E" first="Enzo" last="Ranieri">Enzo Ranieri</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name><affiliation><inist:fA14 i1="14"><s1>Greenwood Genetic Center, JC Self Research Institute of Human Genetics</s1><s2>Greenwood, SC 29646</s2><s3>USA</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Abidi, Fatima" sort="Abidi, Fatima" uniqKey="Abidi F" first="Fatima" last="Abidi">Fatima Abidi</name><affiliation><inist:fA14 i1="14"><s1>Greenwood Genetic Center, JC Self Research Institute of Human Genetics</s1><s2>Greenwood, SC 29646</s2><s3>USA</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S." last="Tarpey">Patrick S. Tarpey</name><affiliation><inist:fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><inist:fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Whibley, Annabel" sort="Whibley, Annabel" uniqKey="Whibley A" first="Annabel" last="Whibley">Annabel Whibley</name><affiliation><inist:fA14 i1="16"><s1>Cambridge Institute of Medical Research</s1><s2>Cambridge CB2 2XY</s2><s3>GBR</s3><sZ>21 aut.</sZ><sZ>22 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F. Lucy" last="Raymond">F. Lucy Raymond</name><affiliation><inist:fA14 i1="16"><s1>Cambridge Institute of Medical Research</s1><s2>Cambridge CB2 2XY</s2><s3>GBR</s3><sZ>21 aut.</sZ><sZ>22 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><inist:fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></inist:fA14></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><inist:fA14 i1="07"><s1>University Hospital Leuven, Department of Human Genetics, University of Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>10 aut.</sZ><sZ>24 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Scott, Rodney" sort="Scott, Rodney" uniqKey="Scott R" first="Rodney" last="Scott">Rodney Scott</name><affiliation><inist:fA14 i1="06"><s1>Molecular Genetics Laboratory HAPS, John Hunter Hospital</s1><s2>Newcastle NSW 2305</s2><s3>AUS</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>25 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Peippo, Maarit" sort="Peippo, Maarit" uniqKey="Peippo M" first="Maarit" last="Peippo">Maarit Peippo</name><affiliation><inist:fA14 i1="17"><s1>The Family Federation of Finland</s1><s2>00101 Helsinki</s2><s3>FIN</s3><sZ>26 aut.</sZ><sZ>27 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Sipponen, Marjatta" sort="Sipponen, Marjatta" uniqKey="Sipponen M" first="Marjatta" last="Sipponen">Marjatta Sipponen</name><affiliation><inist:fA14 i1="17"><s1>The Family Federation of Finland</s1><s2>00101 Helsinki</s2><s3>FIN</s3><sZ>26 aut.</sZ><sZ>27 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Partington, Michael" sort="Partington, Michael" uniqKey="Partington M" first="Michael" last="Partington">Michael Partington</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Mowat, David" sort="Mowat, David" uniqKey="Mowat D" first="David" last="Mowat">David Mowat</name><affiliation><inist:fA14 i1="19"><s1>Department of Genetics, Sydney Children's Hospital</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>29 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation><inist:fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Turner, Gillian" sort="Turner, Gillian" uniqKey="Turner G" first="Gillian" last="Turner">Gillian Turner</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="20"><s1>Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>34 aut.</sZ></inist:fA14></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0160921</idno><date when="2008">2008</date><idno type="stanalyst">PASCAL 08-0160921 INIST</idno><idno type="RBID">Pascal:08-0160921</idno><idno type="wicri:Area/PascalFrancis/Corpus">003682</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation</title><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><inist:fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Corbett, Mark" sort="Corbett, Mark" uniqKey="Corbett M" first="Mark" last="Corbett">Mark Corbett</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vandewalle, Joke" sort="Vandewalle, Joke" uniqKey="Vandewalle J" first="Joke" last="Vandewalle">Joke Vandewalle</name><affiliation><inist:fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Jarvela, Irma" sort="Jarvela, Irma" uniqKey="Jarvela I" first="Irma" last="Jarvela">Irma Jarvela</name><affiliation><inist:fA14 i1="04"><s1>Laboratory of Molecular Genetics, Helsinki University Central Hospital (Laboratory Services)</s1><s2>00290 Helsinki</s2><s3>FIN</s3><sZ>4 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="05"><s1>Department of Medical Genetics, University of Helsinki</s1><s2>00290 Helsinki</s2><s3>FIN</s3><sZ>4 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Lawrence, Owen" sort="Lawrence, Owen" uniqKey="Lawrence O" first="Owen" last="Lawrence">Owen Lawrence</name><affiliation><inist:fA14 i1="06"><s1>Molecular Genetics Laboratory HAPS, John Hunter Hospital</s1><s2>Newcastle NSW 2305</s2><s3>AUS</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>25 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Meldrum, Cliff" sort="Meldrum, Cliff" uniqKey="Meldrum C" first="Cliff" last="Meldrum">Cliff Meldrum</name><affiliation><inist:fA14 i1="06"><s1>Molecular Genetics Laboratory HAPS, John Hunter Hospital</s1><s2>Newcastle NSW 2305</s2><s3>AUS</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>25 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Bauters, Marijke" sort="Bauters, Marijke" uniqKey="Bauters M" first="Marijke" last="Bauters">Marijke Bauters</name><affiliation><inist:fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Govaerts, Karen" sort="Govaerts, Karen" uniqKey="Govaerts K" first="Karen" last="Govaerts">Karen Govaerts</name><affiliation><inist:fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vandeleur, Lucianne" sort="Vandeleur, Lucianne" uniqKey="Vandeleur L" first="Lucianne" last="Vandeleur">Lucianne Vandeleur</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation><inist:fA14 i1="07"><s1>University Hospital Leuven, Department of Human Genetics, University of Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>10 aut.</sZ><sZ>24 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><inist:fA14 i1="08"><s1>Institut Cochin, Université Paris Descartes, CNRS (UMR 8104)</s1><s2>75014 Paris</s2><s3>FRA</s3><sZ>11 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="09"><s1>Inserm, U567</s1><s2>75014 Paris</s2><s3>FRA</s3><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Sanlaville, Damien" sort="Sanlaville, Damien" uniqKey="Sanlaville D" first="Damien" last="Sanlaville">Damien Sanlaville</name><affiliation><inist:fA14 i1="10"><s1>Genetic Department, Necker Enfants Malades Hospital</s1><s2>75935 Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Van Bokhoven, Hans" sort="Van Bokhoven, Hans" uniqKey="Van Bokhoven H" first="Hans" last="Van Bokhoven">Hans Van Bokhoven</name><affiliation><inist:fA14 i1="11"><s1>Department of Human Genetics, University Medical Centre</s1><s2>6500 Nijmegen</s2><s3>NLD</s3><sZ>13 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><inist:fA14 i1="12"><s1>Max-Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>14 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Laumonnier, Frederic" sort="Laumonnier, Frederic" uniqKey="Laumonnier F" first="Frederic" last="Laumonnier">Frederic Laumonnier</name><affiliation><inist:fA14 i1="13"><s1>INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais</s1><s2>37044 Tours</s2><s3>FRA</s3><sZ>15 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Ranieri, Enzo" sort="Ranieri, Enzo" uniqKey="Ranieri E" first="Enzo" last="Ranieri">Enzo Ranieri</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name><affiliation><inist:fA14 i1="14"><s1>Greenwood Genetic Center, JC Self Research Institute of Human Genetics</s1><s2>Greenwood, SC 29646</s2><s3>USA</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Abidi, Fatima" sort="Abidi, Fatima" uniqKey="Abidi F" first="Fatima" last="Abidi">Fatima Abidi</name><affiliation><inist:fA14 i1="14"><s1>Greenwood Genetic Center, JC Self Research Institute of Human Genetics</s1><s2>Greenwood, SC 29646</s2><s3>USA</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S." last="Tarpey">Patrick S. Tarpey</name><affiliation><inist:fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><inist:fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Whibley, Annabel" sort="Whibley, Annabel" uniqKey="Whibley A" first="Annabel" last="Whibley">Annabel Whibley</name><affiliation><inist:fA14 i1="16"><s1>Cambridge Institute of Medical Research</s1><s2>Cambridge CB2 2XY</s2><s3>GBR</s3><sZ>21 aut.</sZ><sZ>22 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F. Lucy" last="Raymond">F. Lucy Raymond</name><affiliation><inist:fA14 i1="16"><s1>Cambridge Institute of Medical Research</s1><s2>Cambridge CB2 2XY</s2><s3>GBR</s3><sZ>21 aut.</sZ><sZ>22 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><inist:fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></inist:fA14></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><inist:fA14 i1="07"><s1>University Hospital Leuven, Department of Human Genetics, University of Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>10 aut.</sZ><sZ>24 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Scott, Rodney" sort="Scott, Rodney" uniqKey="Scott R" first="Rodney" last="Scott">Rodney Scott</name><affiliation><inist:fA14 i1="06"><s1>Molecular Genetics Laboratory HAPS, John Hunter Hospital</s1><s2>Newcastle NSW 2305</s2><s3>AUS</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>25 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Peippo, Maarit" sort="Peippo, Maarit" uniqKey="Peippo M" first="Maarit" last="Peippo">Maarit Peippo</name><affiliation><inist:fA14 i1="17"><s1>The Family Federation of Finland</s1><s2>00101 Helsinki</s2><s3>FIN</s3><sZ>26 aut.</sZ><sZ>27 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Sipponen, Marjatta" sort="Sipponen, Marjatta" uniqKey="Sipponen M" first="Marjatta" last="Sipponen">Marjatta Sipponen</name><affiliation><inist:fA14 i1="17"><s1>The Family Federation of Finland</s1><s2>00101 Helsinki</s2><s3>FIN</s3><sZ>26 aut.</sZ><sZ>27 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Partington, Michael" sort="Partington, Michael" uniqKey="Partington M" first="Michael" last="Partington">Michael Partington</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Mowat, David" sort="Mowat, David" uniqKey="Mowat D" first="David" last="Mowat">David Mowat</name><affiliation><inist:fA14 i1="19"><s1>Department of Genetics, Sydney Children's Hospital</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>29 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation><inist:fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Turner, Gillian" sort="Turner, Gillian" uniqKey="Turner G" first="Gillian" last="Turner">Gillian Turner</name><affiliation><inist:fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><inist:fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="20"><s1>Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>34 aut.</sZ></inist:fA14></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="2008">2008</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>Association</term><term>Chromosome duplication</term><term>Dehydrogenase</term><term>Genetics</term><term>Human</term><term>Ligases</term><term>Mental retardation</term><term>Ubiquitin</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Arriération mentale</term><term>Duplication chromosomique</term><term>Dehydrogenase</term><term>Ubiquitine</term><term>Ligases</term><term>Association</term><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0002-9297</s0></fA01><fA02 i1="01"><s0>AJHGAG</s0></fA02><fA03 i2="1"><s0>Am. j. hum. genet.</s0></fA03><fA05><s2>82</s2></fA05><fA06><s2>2</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation</s1></fA08><fA11 i1="01" i2="1"><s1>FROYEN (Guy)</s1></fA11><fA11 i1="02" i2="1"><s1>CORBETT (Mark)</s1></fA11><fA11 i1="03" i2="1"><s1>VANDEWALLE (Joke)</s1></fA11><fA11 i1="04" i2="1"><s1>JARVELA (Irma)</s1></fA11><fA11 i1="05" i2="1"><s1>LAWRENCE (Owen)</s1></fA11><fA11 i1="06" i2="1"><s1>MELDRUM (Cliff)</s1></fA11><fA11 i1="07" i2="1"><s1>BAUTERS (Marijke)</s1></fA11><fA11 i1="08" i2="1"><s1>GOVAERTS (Karen)</s1></fA11><fA11 i1="09" i2="1"><s1>VANDELEUR (Lucianne)</s1></fA11><fA11 i1="10" i2="1"><s1>VAN ESCH (Hilde)</s1></fA11><fA11 i1="11" i2="1"><s1>CHELLY (Jamel)</s1></fA11><fA11 i1="12" i2="1"><s1>SANLAVILLE (Damien)</s1></fA11><fA11 i1="13" i2="1"><s1>VAN BOKHOVEN (Hans)</s1></fA11><fA11 i1="14" i2="1"><s1>ROPERS (Hans-Hilger)</s1></fA11><fA11 i1="15" i2="1"><s1>LAUMONNIER (Frederic)</s1></fA11><fA11 i1="16" i2="1"><s1>RANIERI (Enzo)</s1></fA11><fA11 i1="17" i2="1"><s1>SCHWARTZ (Charles E.)</s1></fA11><fA11 i1="18" i2="1"><s1>ABIDI (Fatima)</s1></fA11><fA11 i1="19" i2="1"><s1>TARPEY (Patrick S.)</s1></fA11><fA11 i1="20" i2="1"><s1>FUTREAL (P. Andrew)</s1></fA11><fA11 i1="21" i2="1"><s1>WHIBLEY (Annabel)</s1></fA11><fA11 i1="22" i2="1"><s1>RAYMOND (F. Lucy)</s1></fA11><fA11 i1="23" i2="1"><s1>STRATTON (Michael R.)</s1></fA11><fA11 i1="24" i2="1"><s1>FRYNS (Jean-Pierre)</s1></fA11><fA11 i1="25" i2="1"><s1>SCOTT (Rodney)</s1></fA11><fA11 i1="26" i2="1"><s1>PEIPPO (Maarit)</s1></fA11><fA11 i1="27" i2="1"><s1>SIPPONEN (Marjatta)</s1></fA11><fA11 i1="28" i2="1"><s1>PARTINGTON (Michael)</s1></fA11><fA11 i1="29" i2="1"><s1>MOWAT (David)</s1></fA11><fA11 i1="30" i2="1"><s1>FIELD (Michael)</s1></fA11><fA11 i1="31" i2="1"><s1>HACKETT (Anna)</s1></fA11><fA11 i1="32" i2="1"><s1>MARYNEN (Peter)</s1></fA11><fA11 i1="33" i2="1"><s1>TURNER (Gillian)</s1></fA11><fA11 i1="34" i2="1"><s1>GECZ (Jozef)</s1></fA11><fA14 i1="01"><s1>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></fA14><fA14 i1="02"><s1>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>32 aut.</sZ></fA14><fA14 i1="03"><s1>Department of Genetic Medicine, Women's and Children's Hospital</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>9 aut.</sZ><sZ>16 aut.</sZ><sZ>34 aut.</sZ></fA14><fA14 i1="04"><s1>Laboratory of Molecular Genetics, Helsinki University Central Hospital (Laboratory Services)</s1><s2>00290 Helsinki</s2><s3>FIN</s3><sZ>4 aut.</sZ></fA14><fA14 i1="05"><s1>Department of Medical Genetics, University of Helsinki</s1><s2>00290 Helsinki</s2><s3>FIN</s3><sZ>4 aut.</sZ></fA14><fA14 i1="06"><s1>Molecular Genetics Laboratory HAPS, John Hunter Hospital</s1><s2>Newcastle NSW 2305</s2><s3>AUS</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>25 aut.</sZ></fA14><fA14 i1="07"><s1>University Hospital Leuven, Department of Human Genetics, University of Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>10 aut.</sZ><sZ>24 aut.</sZ></fA14><fA14 i1="08"><s1>Institut Cochin, Université Paris Descartes, CNRS (UMR 8104)</s1><s2>75014 Paris</s2><s3>FRA</s3><sZ>11 aut.</sZ></fA14><fA14 i1="09"><s1>Inserm, U567</s1><s2>75014 Paris</s2><s3>FRA</s3><sZ>11 aut.</sZ></fA14><fA14 i1="10"><s1>Genetic Department, Necker Enfants Malades Hospital</s1><s2>75935 Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></fA14><fA14 i1="11"><s1>Department of Human Genetics, University Medical Centre</s1><s2>6500 Nijmegen</s2><s3>NLD</s3><sZ>13 aut.</sZ></fA14><fA14 i1="12"><s1>Max-Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>14 aut.</sZ></fA14><fA14 i1="13"><s1>INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais</s1><s2>37044 Tours</s2><s3>FRA</s3><sZ>15 aut.</sZ></fA14><fA14 i1="14"><s1>Greenwood Genetic Center, JC Self Research Institute of Human Genetics</s1><s2>Greenwood, SC 29646</s2><s3>USA</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></fA14><fA14 i1="15"><s1>The Wellcome Trust Sanger Institute</s1><s2>Hinxton CB10 ISA</s2><s3>GBR</s3><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ></fA14><fA14 i1="16"><s1>Cambridge Institute of Medical Research</s1><s2>Cambridge CB2 2XY</s2><s3>GBR</s3><sZ>21 aut.</sZ><sZ>22 aut.</sZ></fA14><fA14 i1="17"><s1>The Family Federation of Finland</s1><s2>00101 Helsinki</s2><s3>FIN</s3><sZ>26 aut.</sZ><sZ>27 aut.</sZ></fA14><fA14 i1="18"><s1>The GOLD service Hunter Genetics University of Newcastle</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>28 aut.</sZ><sZ>30 aut.</sZ><sZ>31 aut.</sZ><sZ>33 aut.</sZ></fA14><fA14 i1="19"><s1>Department of Genetics, Sydney Children's Hospital</s1><s2>New South Wales NSW 2308</s2><s3>AUS</s3><sZ>29 aut.</sZ></fA14><fA14 i1="20"><s1>Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide</s1><s2>Adelaide SA 5005</s2><s3>AUS</s3><sZ>34 aut.</sZ></fA14><fA20><s1>432-443</s1></fA20><fA21><s1>2008</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>2610</s2><s5>354000173625010150</s5></fA43><fA44><s0>0000</s0><s1>© 2008 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>42 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>08-0160921</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>American journal of human genetics</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.</s0></fC01><fC02 i1="01" i2="X"><s0>002A04</s0></fC02><fC02 i1="02" i2="X"><s0>002A07</s0></fC02><fC02 i1="03" i2="X"><s0>002B23A</s0></fC02><fC02 i1="04" i2="X"><s0>002B18C12</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Arriération mentale</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Mental retardation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Retraso mental</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Duplication chromosomique</s0><s5>09</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Chromosome duplication</s0><s5>09</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Duplicación cromosómica</s0><s5>09</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Dehydrogenase</s0><s2>FE</s2><s5>10</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Dehydrogenase</s0><s2>FE</s2><s5>10</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Dehydrogenase</s0><s2>FE</s2><s5>10</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Ubiquitine</s0><s5>11</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Ubiquitin</s0><s5>11</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Ubiquitina</s0><s5>11</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Ligases</s0><s2>FE</s2><s5>12</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Ligases</s0><s2>FE</s2><s5>12</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Ligases</s0><s2>FE</s2><s5>12</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Association</s0><s5>13</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Association</s0><s5>13</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Asociación</s0><s5>13</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Génétique</s0><s5>14</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Genetics</s0><s5>14</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Genética</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Homme</s0><s5>15</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Human</s0><s5>15</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Hombre</s0><s5>15</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Chromosome anormal</s0></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Abnormal chromosome</s0></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Cromosoma anormal</s0></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Aberration chromosomique</s0></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Chromosomal aberration</s0></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Aberración cromosómica</s0></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Oxidoreductases</s0><s2>FE</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Oxidoreductases</s0><s2>FE</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Oxidoreductases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Déficience intellectuelle</s0><s5>37</s5></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Intellectual deficiency</s0><s5>37</s5></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Deficiencia intelectual</s0><s5>37</s5></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Trouble du développement</s0><s5>38</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Developmental disorder</s0><s5>38</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Trastorno desarrollo</s0><s5>38</s5></fC07><fN21><s1>098</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard><server><NO>PASCAL 08-0160921 INIST</NO><ET>Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation</ET><AU>FROYEN (Guy); CORBETT (Mark); VANDEWALLE (Joke); JARVELA (Irma); LAWRENCE (Owen); MELDRUM (Cliff); BAUTERS (Marijke); GOVAERTS (Karen); VANDELEUR (Lucianne); VAN ESCH (Hilde); CHELLY (Jamel); SANLAVILLE (Damien); VAN BOKHOVEN (Hans); ROPERS (Hans-Hilger); LAUMONNIER (Frederic); RANIERI (Enzo); SCHWARTZ (Charles E.); ABIDI (Fatima); TARPEY (Patrick S.); FUTREAL (P. Andrew); WHIBLEY (Annabel); RAYMOND (F. Lucy); STRATTON (Michael R.); FRYNS (Jean-Pierre); SCOTT (Rodney); PEIPPO (Maarit); SIPPONEN (Marjatta); PARTINGTON (Michael); MOWAT (David); FIELD (Michael); HACKETT (Anna); MARYNEN (Peter); TURNER (Gillian); GECZ (Jozef)</AU><AF>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB/3000 Leuven/Belgique (1 aut., 3 aut., 7 aut., 8 aut., 32 aut.); Human Genome Laboratory, Department of Human Genetics, K.U.Leuven/3000 Leuven/Belgique (1 aut., 3 aut., 7 aut., 8 aut., 32 aut.); Department of Genetic Medicine, Women's and Children's Hospital/Adelaide SA 5005/Australie (2 aut., 9 aut., 16 aut., 34 aut.); Laboratory of Molecular Genetics, Helsinki University Central Hospital (Laboratory Services)/00290 Helsinki/Finlande (4 aut.); Department of Medical Genetics, University of Helsinki/00290 Helsinki/Finlande (4 aut.); Molecular Genetics Laboratory HAPS, John Hunter Hospital/Newcastle NSW 2305/Australie (5 aut., 6 aut., 25 aut.); University Hospital Leuven, Department of Human Genetics, University of Leuven/3000 Leuven/Belgique (10 aut., 24 aut.); Institut Cochin, Université Paris Descartes, CNRS (UMR 8104)/75014 Paris/France (11 aut.); Inserm, U567/75014 Paris/France (11 aut.); Genetic Department, Necker Enfants Malades Hospital/75935 Paris/France (12 aut.); Department of Human Genetics, University Medical Centre/6500 Nijmegen/Pays-Bas (13 aut.); Max-Planck Institute for Molecular Genetics/14195 Berlin/Allemagne (14 aut.); INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais/37044 Tours/France (15 aut.); Greenwood Genetic Center, JC Self Research Institute of Human Genetics/Greenwood, SC 29646/Etats-Unis (17 aut., 18 aut.); The Wellcome Trust Sanger Institute/Hinxton CB10 ISA/Royaume-Uni (19 aut., 20 aut., 23 aut.); Cambridge Institute of Medical Research/Cambridge CB2 2XY/Royaume-Uni (21 aut., 22 aut.); The Family Federation of Finland/00101 Helsinki/Finlande (26 aut., 27 aut.); The GOLD service Hunter Genetics University of Newcastle/New South Wales NSW 2308/Australie (28 aut., 30 aut., 31 aut., 33 aut.); Department of Genetics, Sydney Children's Hospital/New South Wales NSW 2308/Australie (29 aut.); Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide/Adelaide SA 5005/Australie (34 aut.)</AF><DT>Publication en série; Niveau analytique</DT><SO>American journal of human genetics; ISSN 0002-9297; Coden AJHGAG; Etats-Unis; Da. 2008; Vol. 82; No. 2; Pp. 432-443; Bibl. 42 ref.</SO><LA>Anglais</LA><EA>Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.</EA><CC>002A04; 002A07; 002B23A; 002B18C12</CC><FD>Arriération mentale; Duplication chromosomique; Dehydrogenase; Ubiquitine; Ligases; Association; Génétique; Homme</FD><FG>Chromosome anormal; Aberration chromosomique; Oxidoreductases; Enzyme; Déficience intellectuelle; Trouble du développement</FG><ED>Mental retardation; Chromosome duplication; Dehydrogenase; Ubiquitin; Ligases; Association; Genetics; Human</ED><EG>Abnormal chromosome; Chromosomal aberration; Oxidoreductases; Enzyme; Intellectual deficiency; Developmental disorder</EG><SD>Retraso mental; Duplicación cromosómica; Dehydrogenase; Ubiquitina; Ligases; Asociación; Genética; Hombre</SD><LO>INIST-2610.354000173625010150</LO><ID>08-0160921</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
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