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408288.0 [No comment] 05.03.2009 11:01 Released

ID: 408288.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Submicroscopic duplications of th hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation
Authors: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; Gécz, Jozef
Date of Publication (YYYY-MM-DD):2008-01-24
Title of Journal:The American Journal of Human Genetics,
Journal Abbrev.:Am J Hum Genet
Issue / Number:2
Start Page:432
End Page:443
Copyright:2008 The American Society of Human Genetics. All rights reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1. Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium;
2. Human Genome Laboratory, Department of Human Genetics, K.U.Leuven, B-3000 Leuven, Belgium;
3. Department of Genetic Medicine, Women's and Children's Hospital, Adelaide SA 5005, Australia;
4. Laboratory of Molecular Genetics, Helsinki University Central Hospital (Laboratory Services), 00290 Helsinki, Finland;
5. Department of Medical Genetics, University of Helsinki, 00290 Helsinki, Finland;
6. Molecular Genetics Laboratory HAPS, John Hunter Hospital, Newcastle NSW 2305, Australia;
7. University Hospital Leuven, Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium;
8. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), F-75014 Paris, France;
9. Inserm, U567, F-75014 Paris, France;
10. Genetic Department, Necker Enfants Malades Hospital, F-75935 Paris, France;
11. Department of Human Genetics, University Medical Centre, NL-6500 Nijmegen, The Netherlands;
12. INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais, F-37044 Tours, France;
13. Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC 29646, USA;
14. The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK;
15. Cambridge Institute of Medical Research, Cambridge CB2 2XY, UK;
16. The Family Federation of Finland, 00101 Helsinki, Finland;
17 The GOLD service Hunter Genetics University of Newcastle, New South Wales NSW 2308, Australia;
18 Department of Genetics, Sydney Children's Hospital, New South Wales NSW 2308, Australia;
19. Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide, Adelaide SA 5005, Australia.
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