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.

Shroom4 (Kiaa1202) is an actin‐associated protein implicated in cytoskeletal organization

“…Most adult tissues examined express Shrm4. This agrees with previous data showing that Shrm4 mRNA is present in many adult and embryonic tissues [Hagens et al, 2005]. In brain, our Shrm4-specific antibodies reproducibly detect a protein with an apparent molecular mass of 90 kDa (Fig.…”

“…This paper describes the characterization of Shrm4, a member of the Shroom-family of genes and the mouse ortholog of human SHRM4, a gene implicated in Xlinked mental retardation in humans [Hagens et al, 2005]. As would be expected, the predicted mShrm4 protein is highly similar to hShrm4, exhibiting approximately 80% overall sequence identity, although this percentage is significantly higher in the PDZ and ASD2 motifs.…”

“…Although no known developmental function has been assigned to Shrm2, it has recently been shown that mutations in SHRM4 can lead to X-linked mental retardation in humans by a yet unknown mechanism [Hagens et al, 2005]. Shrm3 is also conserved in some invertebrates, as orthologs can be found in sea urchin and Ciona.…”

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…A missense exchange of SHROOM4 was reported to segregate with Stocco dos Santos XLMR syndrome (OMIM 300434) in a large fourgeneration pedigree. 21 The affected males in the reported family presented with severe MR, delayed or no speech, seizures and hyperactivity. Our patient with null SHROOM4 showed only moderate MR, suggesting that the missense exchange detected in Stocco dos Santos XLMR syndrome contributes to the pathogenesis of MR together with other phenotypes in a gain-of-function manner.…”

“…Information from the UCSC genome browser revealed that the deleted region contains SHROOM4 (OMIM 300579), reported to be a causative gene for XLMR. 21 Sample of his mother (II-4) was not available. The highdensity oligonucleotide aCGH revealed that the deletion at Xp11.22 in family MR67H was also flanked distally by a sequence gap and proximally by a complex repeat-rich locus containing SSX families (SSX7 and SSX2), melanoma antigen (MAGE) families and X-antigen (XAGE) families (Figure 4).…”