ausblenden:
Schlagwörter:
Animals; Cell Line; Cell Line, Tumor; Consanguinity; Exons; Female; Genes, Recessive/*genetics; Genetic Linkage/genetics; Homozygote; Humans; Intellectual Disability/*genetics; Male; Mice; Mutation/genetics; NIH 3T3 Cells; Pedigree; Polymorphism, Single Nucleotide/genetics; Proteins/*genetics
Zusammenfassung:
High-throughput sequencing has greatly facilitated the elucidation of genetic disorders, but compared with X-linked and autosomal dominant diseases, the search for genetic defects underlying autosomal recessive diseases still lags behind. In a large consanguineous family with autosomal recessive intellectual disability (ARID), we have combined homozygosity mapping, targeted exon enrichment and high-throughput sequencing to identify the underlying gene defect. After appropriate single-nucleotide polymorphism filtering, only two molecular changes remained, including a non-synonymous sequence change in the SWIP [Strumpellin and WASH (Wiskott-Aldrich syndrome protein and scar homolog)-interacting protein] gene, a member of the recently discovered WASH complex, which is involved in actin polymerization and multiple endosomal transport processes. Based on high pathogenicity and evolutionary conservation scores as well as functional considerations, this gene defect was considered as causative for ID in this family. In line with this assumption, we could show that this mutation leads to significantly reduced SWIP levels and to destabilization of the entire WASH complex. Thus, our findings suggest that SWIP is a novel gene for ARID.
