Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis

Details

• Alternative Title:
  Sci Transl Med
• Personal Author:
  Drivas, Theodore G. ; Wojno, Adam P. ; Tucker, Budd A. ; Stone, Edwin M. ; Bennett, Jean
• Description:
  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.
• Subjects:
  Antigens, Neoplasm Article Disease Exons Genetic Pleiotropy Genetic Predisposition To Disease Humans Models, Genetic Neoplasm Proteins Phenotype
• Source:
  Sci Transl Med. 7(291):291ra97.
• Pubmed ID:
  26062849
• Pubmed Central ID:
  PMC4486480
• Document Type:
  Journal Article
• Funding:
  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
• Volume:
  7
• Issue:
  291
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:2dd89cba0123e0ffb8b4438dd7e8dca9089f6aab7f1ed45935da7524f149ed6e
• Download URL:
  https://stacks.cdc.gov/view/cdc/32806/cdc_32806_DS1.pdf
• File Type:
  [PDF - 1023.51 KB ]