Human Molecular Genetics Advance Access originally published online on October 11, 2008
Human Molecular Genetics 2009 18(1):178-192; doi:10.1093/hmg/ddn327
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New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene
1 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA 2 Department of Biochemistry and Molecular Biology 3 Department of Neuroscience 4 Department of Ophthalmology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 2072886383; Fax: +1 2072886077; Email: patsy.nishina{at}jax.org
Received August 29, 2008; Accepted October 9, 2008
The heterotetrameric phosphodiesterase (PDE) 6 complex, made up of 
, β and two 
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.
Present address: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 9-1 Shirokane 5-chome, Minato-ku, Tokyo 108-8641, Japan.
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