Journal Article

New mouse models for recessive retinitis pigmentosa caused by mutations in the <i>Pde6a</i> gene

Kenji Sakamoto, Michael McCluskey, Theodore G. Wensel, Jürgen K. Naggert and Patsy M. Nishina

in Human Molecular Genetics

Volume 18, issue 1, pages 178-192
Published in print January 2009 | ISSN: 0964-6906
Published online October 2008 | e-ISSN: 1460-2083 | DOI:
New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene

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The heterotetrameric phosphodiesterase (PDE) 6 complex, made up of α, β and two γ 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.

Journal Article.  8853 words.  Illustrated.

Subjects: Genetics and Genomics

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