New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene.
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.
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Kenji
K
Sakamoto
Michael
M
McCluskey
Theodore G
TG
Wensel
Jürgen K
JK
Naggert
Patsy M
PM
Nishina
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006152:Cyclic GMP / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020125:Mutation, Missense; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism
D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C498747:Pde6a protein, mouse; D006152:Cyclic GMP