A New Mouse Model for Recessive Retinitis Pigmentosa Caused by a Mutation in the Pde6a Gene

Abstract

Purpose:: The alpha subunit of phosphodiesterase 6 (PDE6A) is a component of the rod phototransduction cascade. Mutations in the PDE6A gene have been reported in patients with autosomal recessive retinitis pigmentosa. With the exception of the Cardigan Welsh corgi dog, there is no small rodent model that carries the Pde6a mutation. Here, we report the identification of a mutation in the Pde6a gene that leads to a rapid degeneration of photoreceptor cells in the murine retina.

Methods:: The mutant was identified from an ethyl nitrosourea mutagenesis screen. A point mutation, G2159A (V685M), in the Pde6a gene was identified by direct sequencing. Homozygous Pde6a and Pde6b mutants were mated to generate compound heterozygous mice. Pathological changes were assessed by indirect ophthalmoscopy and light microscopy. Cyclic GMP levels in the retina of mutant mice and controls were measured by radioimmunoassay.

Results:: At 12 weeks of the age, the retina of A.B6-Tyr+-Pde6a/Pde6a mutant mice had a grainy appearance, and severe outer retinal degeneration was observed by light microscopy. The outer retinal degeneration was noticeable around P12. Although the thickness of outer nuclear layer of the mutant mice at P10 is the same as that in the heterozygous control, the level of cGMP in the light-adapted mutant mouse retina was clearly different than control mice at P10. Compound Pde6a +/-; Pde6b +/- were unaffected with normal ERG and retinal morphology.

Conclusions:: We show for the first time that the mutation in Pde6a gene causes rapid photoreceptor degeneration in the murine retina. Because the mutation is located in the catalytic domain of the PDE6A molecule, the change in the activity of cGMP degradation is predicted. The age at which the degeneration starts in the A.B6-Tyr+-Pde6a/Pde6a mutants is almost same as that observed in rd1 mice, which carry a mutation in the Pde6b gene, encoding the beta subunit of phosphodiesterase 6. Although further analysis is needed, this mouse mutant may be a new good model for the study of recessive retinitis pigmentosa caused by PDE6A gene mutations.

Keywords: retinal degenerations: hereditary • genetics