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Title: Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation
Authors: Froyen, Guido ×
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 #
Issue Date: Feb-2008
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:82 issue:2 pages:432-443
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.
URI: 
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Clinical Genetics Section (-)
Human Genome Laboratory
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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