Journal article
Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis
Science translational medicine, Vol.7(291), pp.291ra97-291ra97
06/10/2015
DOI: 10.1126/scitranslmed.aaa5370
PMCID: PMC4486480
PMID: 26062849
Abstract
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.
Details
- Title: Subtitle
- Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis
- Creators
- Theodore G Drivas - Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAdam P Wojno - Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USABudd A Tucker - Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA 50309, USAEdwin M Stone - Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA 50309, USA. Howard Hughes Medical Institute, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, IA 50309, USAJean Bennett - Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. jebennet@mail.med.upenn.edu
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.7(291), pp.291ra97-291ra97
- DOI
- 10.1126/scitranslmed.aaa5370
- PMID
- 26062849
- PMCID
- PMC4486480
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6242
- eISSN
- 1946-6242
- Publisher
- United States
- Grant note
- 1R24 EY019861-01A1 / NEI NIH HHS DP1 OD008267 / NIH HHS DP2 OD007483 / NIH HHS Howard Hughes Medical Institute DP1 EY023177 / NEI NIH HHS P30 EY001583 / NEI NIH HHS R24EY019861 / NEI NIH HHS 1F30AG044078-01A1 / NIA NIH HHS R24 EY019861 / NEI NIH HHS F30 AG044078 / NIA NIH HHS 8DP1EY023177 / NCCDPHP CDC HHS 1DP2OD007483 / NIH HHS
- Language
- English
- Date published
- 06/10/2015
- Academic Unit
- Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979979702771
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