Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation by 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, G├ęcz Jozef in American journal of human genetics (2008).

[PMID: 18252223] PubMed


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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