Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 291, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaa5370
Keywords
-
Categories
Funding
- Grousbeck Family Foundation
- Foundation Fighting Blindness
- Research to Prevent Blindness
- NIH [R24EY019861, 1F30AG044078-01A1, 1R24 EY019861-01A1, 8DP1EY023177, 1DP2OD007483]
- Howard Hughes Medical Institute
- Treatrush (European Union)
- Transdisciplinary Awards Program in Translational Medicine and Therapeutics (University of Pennsylvania)
- Mackall Foundation Trust
- Pennsylvania Department of Health (Penn Genome Frontiers Institute)
- F.M. Kirby Foundation
- [CEP290]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available