Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis.
X-linked ichthyosis (XLI) is often associated with a recurrent microdeletion at Xp22.31 due to non-allelic homologous recombination between the CRI-S232 low-copy repeat regions flanking the STS gene. The clinical features of these patients may include mental retardation (MR) and the VCX-A gene has been proposed as the candidate MR gene. Analysis of DNA from four XLI patients with MR by array-comparative genomic hybridization (array-CGH) on a 150 kb resolution X chromosome-specific array revealed a 1.5 Mb interstitial microdeletion with breakpoints in the CRI-S232 repeat sequences, each of which harbors a VCX gene. We demonstrate that the recombination sites in all four cases are situated in the 1 kb repeat unit 2 region present at the 3' ends of the VCX-A and VCX-B genes thereby deleting VCX-A and VCX-B1 but not VCX-B and VCX-C. Array-CGH with DNA of an XLI patient with MR and an inherited t(X;Y)(p22.31;q11.2) showed an Xpter deletion of 8.0 Mb resulting in the deletion of all four VCX genes and duplication of both VCY homologs. These data confirm the role of VCX-A in the occurrence of MR in XLI patients. Moreover, we propose a VCX/Y teamwork-dependent mechanism for the incidence of mental impairment in XLI patients.
Van Esch
Hilde
H
Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
Hollanders
Karen
K
Badisco
Liesbeth
L
Melotte
Cindy
C
Van Hummelen
Paul
P
Vermeesch
Joris Robert
JR
Devriendt
Koen
K
Fryns
Jean-Pierre
JP
Marynen
Peter
P
Froyen
Guy
G
D041321:Chromosomes, Human, X / Q000235:genetics*; D041322:Chromosomes, Human, Y / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D016114:Ichthyosis, X-Linked / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics
D009687:Nuclear Proteins; C404411:VCX protein, human; C404412:VCY protein, human