title: Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis.
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.
authors.affiliation: 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.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Drivas
authors.affiliation: 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.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Wojno
authors.affiliation: Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA 50309, USA.
authors.forename: Budd A
authors.initials: BA
authors.lastname: Tucker
authors.affiliation: 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, USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: 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.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004194:Disease / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins