The product of
Pde6b contributes to the heterotetrameric phosphodiesterase complex (PDE, αβγ
2),
11 12 which regulates cytoplasmic cGMP levels in rod photoreceptors in response to light. On light stimulation, PDE is activated by removal of the γ-inhibitory subunits, resulting in a decrease in cGMP levels and hyperpolarization of the rod cell.
13 In mice with the retinal degeneration 1 (
rd1) mutation elevated cGMP levels persist because of a homozygous null mutation in the
Pde6b gene.
14 15 16 17 This results in permanent opening of cGMP-gated cation channels in the membrane of the rod photoreceptors, allowing an excess of extracellular ions to enter the cell, which ultimately leads to cell death by apoptosis.
18 The phenotypic resemblance between patients with arRP due to mutations in
PDE6B and the
Pde6b rd1 mouse has made this mouse an excellent model of this condition. However, this model (
Pde6b rd1 ) presents with rapid photoreceptor degeneration that is apparent at postnatal day 8, and by 3 weeks of age, these animals have lost nearly all of their rod cells.
19 Mouse models that present with slower onset of disease would be useful tools to gain knowledge of and test therapies for this debilitating condition. As part of the MRC Harwell ENU mutagenesis program,
20 21 new models of retinal degeneration were identified. ENU-mutagenized male BALB/cAnN (BALB/c) mice were mated to C3H/HeN (C3H) females, to produce F1 progeny that were screened for eye defects.
21 Because C3H mice are homozygous for the
Pde6b rd1 allele, all the F1 mice screened were heterozygous for the recessive
Pde6b rd1 allele, which enabled Thaung et al.
21 to identify seven mutant lines that carried new recessive alleles of
Pde6b. The phenotype of four of these lines was indistinguishable from that of C3H, and these were named retinal degeneration 1, 1-4 Harwell (
Pde6b rd1 -1 -4H ). On fundus examination, the remaining three new mutant lines at 3 weeks of age appeared to have a near-normal retina compared with the degenerated retina observed in age-matched C3H mice. These lines were named atypical retinal degenerations (atrd)1-3 (
Pde6b atrd1 -3 ).