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Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation

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dc.contributor.authorFroyen, G.
dc.contributor.authorCorbett, M.
dc.contributor.authorVandewalle, J.
dc.contributor.authorJarvela, I.
dc.contributor.authorLawrence, O.
dc.contributor.authorMeldrum, C.
dc.contributor.authorBauters, M.
dc.contributor.authorGovaerts, K.
dc.contributor.authorVandeleur, L.
dc.contributor.authorVan Esch, H.
dc.contributor.authorChelly, J.
dc.contributor.authorSanlaville, D.
dc.contributor.authorvan Bokhoven, H.
dc.contributor.authorRopers, H.
dc.contributor.authorLaumonnier, F.
dc.contributor.authorRanieri, E.
dc.contributor.authorSchwartz, C.
dc.contributor.authorAbidi, F.
dc.contributor.authorTarpey, P.
dc.contributor.authorFutreal, P.
dc.contributor.authoret al.
dc.date.issued2008
dc.description.abstractSubmicroscopic 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.
dc.description.statementofresponsibilityGuy Froyen...Jozef Gécz... et al.
dc.identifier.citationAmerican Journal of Human Genetics, 2008; 82(2):432-443
dc.identifier.doi10.1016/j.ajhg.2007.11.002
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.orcidCorbett, M. [0000-0001-9298-3072]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/50845
dc.language.isoen
dc.publisherUniv Chicago Press
dc.source.urihttps://doi.org/10.1016/j.ajhg.2007.11.002
dc.subjectChromosomes, Human, X
dc.subjectHumans
dc.subjectUbiquitin-Protein Ligases
dc.subject3-Hydroxyacyl CoA Dehydrogenases
dc.subjectTumor Suppressor Proteins
dc.subjectDNA, Complementary
dc.subjectBlotting, Western
dc.subjectMicroarray Analysis
dc.subjectIn Situ Hybridization, Fluorescence
dc.subjectPedigree
dc.subjectDNA Mutational Analysis
dc.subjectGene Duplication
dc.subjectBase Sequence
dc.subjectGene Dosage
dc.subjectMutation
dc.subjectMolecular Sequence Data
dc.subjectX-Linked Intellectual Disability
dc.titleSubmicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation
dc.typeJournal article
pubs.publication-statusPublished

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