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Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis
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    Genetic pleiotropy, the phenomenon by which mutations in the same gene result in markedly different disease phenotypes, has proven difficult to explain with traditional models of disease pathogenesis. We have developed a model of pleiotropic disease that explains, through the process of basal exon skipping, how different mutations in the same gene can differentially affect protein production, with the total amount of protein produced correlating with disease severity. Mutations in the centrosomal protein of 290 kDa (CEP290) gene are associated with a spectrum of phenotypically distinct human diseases (the ciliopathies). Molecular biologic examination of CEP290 transcript and protein expression in cells from patients carrying CEP290 mutations, measured by quantitative polymerase chain reaction and Western blotting, correlated with disease severity and corroborated our model. We show that basal exon skipping may be the mechanism underlying the disease pleiotropy caused by CEP290 mutations. Applying our model to a different disease gene, CC2D2A (coiled-coil and C2 domains-containing protein 2A), we found that the same correlations held true. Our model explains the phenotypic diversity of two different inherited ciliopathies and may establish a new model for the pathogenesis of other pleiotropic human diseases.

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    1DP2OD007483/OD/NIH HHS/United States
    1F30AG044078-01A1/AG/NIA NIH HHS/United States
    1R24 EY019861-01A1/EY/NEI NIH HHS/United States
    8DP1EY023177/DP/NCCDPHP CDC HHS/United States
    DP1 EY023177/EY/NEI NIH HHS/United States
    DP1 OD008267/OD/NIH HHS/United States
    R24EY019861/EY/NEI NIH HHS/United States
    Howard Hughes Medical Institute/United States
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