Two mouse retinal degenerations caused by missense mutations in the β-subunit of rod cGMP phosphodiesterase gene

Abstract

We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

“…We began by evaluating whether overexpression of SOD2 and catalase affected cone survival in rd1 mice, an RP model with a defective phosphodiesterase β gene that results in early-onset, and rapid, degeneration (47). In rd1 mice, rods were almost all dead by 3 weeks after birth, and cone death occurred over the next 2 months ( Figure 1A).…”

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

“…The rd10 mouse is a mouse model of RP with a missense point mutation in the β-subunit of the rod cyclic guanosine monophosphate (cGMP) phosphodiesterase gene (Pde6b) (27). Point mutations of PDE6β have been detected in autosomal recessive RP patients (28).…”

“…Point mutations of PDE6β have been detected in autosomal recessive RP patients (28). In rd10 mice, rod photoreceptor cell death begins around postnatal day 18 (P18) and most of the rod photoreceptor cells disappear at P30, followed by cone photoreceptor cell death (27). For the present investigation of the downstream events of DNA oxidation during retinal degeneration, we crossed rd10 mice with Mutyh −/− mice to create rd10;Mutyh −/− mice.…”

Cone Phosphodiesterase-6 ' Restores Rod Function and Confers Distinct Physiological Properties in the Rod Phosphodiesterase-6 -Deficient rd10 Mouse

“…Rods, responsible for scotopic vision, are highly light sensitive. Cones, responsible for photopic vision, are intrinsically less sensitive, have faster response kinetics, and adapt to a wider range of light intensities (Pugh and Cobbs, 1986;Fu and Yau, 2007). One of the key unresolved questions is how the physiological differences between rods and cones can be correlated with the distinctive properties of their phototransduction proteins.…”