title: Rhodopsin gene expression determines rod outer segment size and rod cell resistance to a dominant-negative neurodegeneration mutant.
abstract: Two outstanding unknowns in the biology of photoreceptors are the molecular determinants of cell size, which is remarkably uniform among mammalian species, and the mechanisms of rod cell death associated with inherited neurodegenerative blinding diseases such as retinitis pigmentosa. We have addressed both questions by performing an in vivo titration with rhodopsin gene copies in genetically engineered mice that express only normal rhodopsin or an autosomal dominant allele, encoding rhodopsin with a disease-causing P23H substitution. The results reveal that the volume of the rod outer segment is proportional to rhodopsin gene expression; that P23H-rhodopsin, the most common rhodopsin gene disease allele, causes cell death via a dominant-negative mechanism; and that long term survival of rod cells carrying P23H-rhodopsin can be achieved by increasing the levels of wild type rhodopsin. These results point to promising directions in gene therapy for autosomal dominant neurodegenerative diseases caused by dominant-negative mutations.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Brandee A
authors.initials: BA
authors.lastname: Price
authors.forename: Ivette M
authors.initials: IM
authors.lastname: Sandoval
authors.forename: Fung
authors.initials: F
authors.lastname: Chan
authors.forename: Ralph
authors.initials: R
authors.lastname: Nichols
authors.forename: Ramon
authors.initials: R
authors.lastname: Roman-Sanchez
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Wensel
authors.forename: John H
authors.initials: JH
authors.lastname: Wilson
mesh_terms: D000483:Alleles; D000818:Animals; D015870:Gene Expression; D005799:Genes, Dominant; D015316:Genetic Therapy; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000503:physiopathology; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism; D012374:Rod Cell Outer Segment / Q000378:metabolism / Q000502:physiology
chemical_list: D012243:Rhodopsin