Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation.
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.
Froyen
Guy
G
Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium. guy.froyen@med.kuleuven.be
Corbett
Mark
M
Vandewalle
Joke
J
Jarvela
Irma
I
Lawrence
Owen
O
Meldrum
Cliff
C
Bauters
Marijke
M
Govaerts
Karen
K
Vandeleur
Lucianne
L
Van Esch
Hilde
H
Chelly
Jamel
J
Sanlaville
Damien
D
van Bokhoven
Hans
H
Ropers
Hans-Hilger
HH
Laumonnier
Frederic
F
Ranieri
Enzo
E
Schwartz
Charles E
CE
Abidi
Fatima
F
Tarpey
Patrick S
PS
Futreal
P Andrew
PA
Whibley
Annabel
A
Raymond
F Lucy
FL
Stratton
Michael R
MR
Fryns
Jean-Pierre
JP
Scott
Rodney
R
Peippo
Maarit
M
Sipponen
Marjatta
M
Partington
Michael
M
Mowat
David
D
Field
Michael
M
Hackett
Anna
A
Marynen
Peter
P
Turner
Gillian
G
Gécz
Jozef
J
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*
D018076:DNA, Complementary; D025521:Tumor Suppressor Proteins; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases