Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation

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 FutrealAnnabel 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 Gécz

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157 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)432-443
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished or Issued - 8 Feb 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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