期刊
HUMAN MOLECULAR GENETICS
卷 18, 期 1, 页码 178-192出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn327
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资金
- National Institutes of Health [EY016501, NS41215]
- Foundation for Fighting Blindness
- [CA34196]
- NATIONAL CANCER INSTITUTE [P30CA034196] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R01EY016501] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U01NS041215] Funding Source: NIH RePORTER
The heterotetrameric phosphodiesterase (PDE) 6 complex, made up of alpha, beta and two gamma subunits, regulates intracellular cGMP levels by hydrolyzing cGMP in response to light activation of G protein coupled receptors in cones and rods, making it an essential component of the visual phototransduction cascade [Zhang, X. and Cote, R.H. (2005) cGMP signaling in vertebrate retinal photoreceptor cells. Front. Biosci., 10, 1191-1204.]. Using a genetic positional candidate cloning strategy, we have identified missense mutations within the catalytic domain of the Pde6a gene in two mouse models from an ethyl nitrosourea chemical mutagenesis screen. In these first small rodent models of PDE6A, significantly different biochemical outcomes and rates of degeneration of murine photoreceptor cells were observed, indicating allelic variation and previously unrecognized structure-function relationships. In addition, these new models reveal that the mutations not only affect the function of the PDE6A protein itself, but also the level of PDE6B within the retina. Finally, we show that the variation of the disease phenotype by background modifier genes may be dependent upon the particular disease allele present.
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