title: Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation.
abstract: The extensive heterogeneity underlying the genetic component of mental retardation (MR) is the main cause for our limited understanding of the aetiology of this highly prevalent condition. Hence we set out to identify genes involved in MR. We investigated the breakpoints of two balanced X;autosome translocations in two unrelated female patients with mild/moderate MR and found that the Xp11.2 breakpoints disrupt the novel human KIAA1202 (hKIAA1202) gene in both cases. We also identified a missense exchange in this gene, segregating with the Stocco dos Santos XLMR syndrome in a large four-generation pedigree but absent in >1,000 control X-chromosomes. Among other phenotypic characteristics, the affected males in this family present with severe MR, delayed or no speech, seizures and hyperactivity. Molecular studies of hKIAA1202 determined its genomic organisation, its expression throughout the brain and the regulation of expression of its mouse homologue during development. Transient expression of the wild-type KIAA1202 protein in HeLa cells showed partial colocalisation with the F-actin based cytoskeleton. On the basis of its domain structure, we argue that hKIAA1202 is a new member of the APX/Shroom protein family. Members of this family contain a PDZ and two ASD domains of unknown function and have been shown to localise at the cytoskeleton, and play a role in neurulation, cellular architecture, actin remodelling and ion channel function. Our results suggest that hKIAA1202 may be important in cognitive function and/or development.
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195, Berlin, Germany.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hagens
authors.forename: Aline
authors.initials: A
authors.lastname: Dubos
authors.forename: Fatima
authors.initials: F
authors.lastname: Abidi
authors.forename: Gotthold
authors.initials: G
authors.lastname: Barbi
authors.forename: Laura
authors.initials: L
authors.lastname: Van Zutven
authors.forename: Maria
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.forename: Claude
authors.initials: C
authors.lastname: Moraine
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Jozef
authors.initials: J
authors.lastname: Gécz
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Rita
authors.initials: R
authors.lastname: de Cassia Stocco Dos Santos
authors.forename: Vera
authors.initials: V
authors.lastname: Kalscheuer
authors.forename: André
authors.initials: A
authors.lastname: Hanauer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D041321:Chromosomes, Human, X; D003001:Cloning, Molecular; D004247:DNA; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013347:Subcellular Fractions / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D004247:DNA