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Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

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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.

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The authors are grateful to all patients and their families. We would like to thank T. Nagase for the hKIAA1202 cDNA, M. Pagano for the hFBXO4 cDNA, A. Munnich for providing incontinentia pigmenti fibroblasts, N. Tang for screening Chinese controls, E. Flori for karyotyping patient B, A. Tzschach for collecting clinical information and S. Haas for computational support. U. Fischer, B. Moser, H. Madle, S. Freier and S. Pannetier rendered reliable technical assistance. This study was financed by the Fondation Jérome Lejeune, the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Université Louis Pasteur, the Hôpital Universitaire de Strasbourg, the South Carolina Department of Disabilities and Special Needs, the German Human Genome Program (01KW99087), the National Genome Research Network (01GR0105) and the 5th EU Framework (QLG3-CT-2002-01810). The Wilhelm Johannsen Centre for Functional Genome Research is established by the Danish National Research Foundation. A. D. was supported by a fellowship from the Ministère pour la Recherche et Technologie and C. E. S. by a grant from NICHD (HD26202)

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Correspondence to Vera Kalscheuer.

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O. Hagens and A. Dubos contributed equally to this work.

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Hagens, O., Dubos, A., Abidi, F. et al. Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation. Hum Genet 118, 578–590 (2006).

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