title: Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation.
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.
authors.affiliation: Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium. guy.froyen@med.kuleuven.be
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
authors.forename: Mark
authors.initials: M
authors.lastname: Corbett
authors.forename: Joke
authors.initials: J
authors.lastname: Vandewalle
authors.forename: Irma
authors.initials: I
authors.lastname: Jarvela
authors.forename: Owen
authors.initials: O
authors.lastname: Lawrence
authors.forename: Cliff
authors.initials: C
authors.lastname: Meldrum
authors.forename: Marijke
authors.initials: M
authors.lastname: Bauters
authors.forename: Karen
authors.initials: K
authors.lastname: Govaerts
authors.forename: Lucianne
authors.initials: L
authors.lastname: Vandeleur
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Frederic
authors.initials: F
authors.lastname: Laumonnier
authors.forename: Enzo
authors.initials: E
authors.lastname: Ranieri
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Fatima
authors.initials: F
authors.lastname: Abidi
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Annabel
authors.initials: A
authors.lastname: Whibley
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Rodney
authors.initials: R
authors.lastname: Scott
authors.forename: Maarit
authors.initials: M
authors.lastname: Peippo
authors.forename: Marjatta
authors.initials: M
authors.lastname: Sipponen
authors.forename: Michael
authors.initials: M
authors.lastname: Partington
authors.forename: David
authors.initials: D
authors.lastname: Mowat
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Jozef
authors.initials: J
authors.lastname: Gécz
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D041321:Chromosomes, Human, X / Q000235:genetics*; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D025521:Tumor Suppressor Proteins; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases