Molecular Genetics of Muscular/Neurosensory Models

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DESCRIPTION (provided by applicant): We have recently identified a spontaneous mouse mutant, veils (vis), that has retinal vasculopathy, hearing loss and progressive muscle wasting, phenotypes reported for many human diseases, such as Coat's disease, syndromic and non-syndromic congenital hearing loss, and muscular dystrophy, respectively. We have mapped veils to a 0.19+/-0.13 cM interval on mouse Chr. 8 in a 1,072 meiotic recombinant cross and established the physical contig of the critical region. Portions of human Chrs. 2, 4q, 8, 13, 17, 18, l9p and 22 map to this region, the breakpoints of which have yet to be refined. Interestingly, veils has many, if not all of the phenotypes reported for the disease fascioscapulohumeral muscular dystrophy la (FSHD), the third most prevalent muscular dystrophy that affects 1/20,000 and maps to human Chr. 4q35. Also, a neuromyopathy associated with a highly variable age-of-onset maps to Chr. l9pl3. Veils is a potential genetic and/or phenotypic model for these diseases. The veils mouse is also unique in that it shows retinal lamination abnormalities, a phenotype that has not previously been reported in the literature. In order to understand the biological mechanisms that underlie the disease processes and identify the biochemical pathways that are affected in different tissues, we will: (a) positionally clone the veils gene and identify the mutation in the second allele myd and test the hypothesis that the phenotypic differences between v/s and myd are explained by allelic heterogeneity; (b) begin to identify genes in the genetic background that can significantly alter the disease phenotypes of vis/vis mice; and (c) test the hypothesis that the observed phenotypes are the result of developmental defects rather than degenerative processes. Identification of disease causing genes and animal models is extremely important. Many diseases in humans, especially those involving the eye, if identified early enough, can be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights to new treatment regimens and the models can then be used to test those therapeutics. Finally, knowledge of the disease causing genes may lead to an understanding of pathways that are critical in maintaining normal function and physiology of the organism and perhaps, may identify therapeutic targets for prevention of muscle wasting, and vision or hearing loss.