Abstract:
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Welander distal myopathy (WDM) is a late onset autosomal dominant disease characterized by slow progression of distal muscle weakness. Usually hands are first affected with weakness of the finger extensor muscles. A few much more severely affected patients proved to be homozygotes. The WDM locus was mapped to chromosome 2p13 by Åhlberg et al already in 1999. Further genotyping during 2004-2007, using additional new microsatellite markers narrowed down the linked region to <980 Kb, with a core region of >530 kb.. All known coding sequences in the linked region, including their putative promotor regions, as well as known hypotetical genes, have been sequenced. Several linked SNP polymorphisms have been identified, but the disease causing mutation is still pending. Large deletions and duplications in the area were excluded by screening with a 250K SNP microarray linkage chip. Analyses of cDNA of all linked genes syntesized from mRNA isolated from muscle biopsies, is being finalized in search of potential splicing mutations. Studies of expression levels with RT-PCR (Taqman) of four linked genes has been performed, and the expression levels of the rest of the genes are being analysed. No abnormal results have so far been obtained and the gene is still unidentified. Total sequencing of the linked genomic area, including all introns and regions between genes, has been started using high throughput segencing in microfabricated high-density picolitre reactors. With all these extended methods we hope to identify the underlying genetic defect causing WDM.
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