Variable cone dysfunction and progressive ophthalmoscopic changes in a canine model of RPGRIP1 and MAP9 multigenic cone-rod dystrophy

Abstract

Purpose : A canine multigenic model of cone-rod dystrophy (cord1) has been associated with mutations in RPGRIP1 and MAP9, but prediction of the disease course has remained challenging. None of the RPGRIP1^ins/ins animals in the current research colony has developed clinical blindness, but some show defective cone ERG response. To understand the phenotypic spectrum of cord1, we studied in vivo retinal function and structure in genotype-ascertained animals.

Methods : Sixty-four dogs from a purpose-bred research colony, genotyped for the known RPGRIP1 and MAP9 mutations, underwent periodic ophthalmic examinations and full-field ERGs. Visually-guided behavior was tested using an obstacle course under different illuminations. To assess individual L/M- and S-cone functions, light-adapted chromatic ERGs were done using color flashes of increasing intensity on different color background light. Fundus was imaged in vivo using confocal scanning laser ophthalmoscope/spectral-domain optical coherence tomography (OCT).

Results : Cone-derived ERG responses ranged from absent, reduced, to normal across RPGRIP1^ins/ins animals of all MAP9 genotypes. Both L/M- and S-cones were equally affected in the animals tested, and rod-derived ERGs were normal in all animals. Visually-guided behavior in RPGRIP1^ins/insMAP9^+/del littermates that showed normal- or absent-cone ERG function revealed comparable performance at all light conditions. These functional phenotypes remained stable for up to 5 years. The RPGRIP1^ins/ins progeny in the current colony showed normal retinas in the early years of life, but, with age, some developed coalescing dark discoloration that extended from the periphery. As well, OCT was normal in younger animals, but progressive ONL thinning was observed among some older absent-cone ERG mutants. Significant variation in ophthalmoscopic and OCT imaging was observed and the double homozygotes tended to show earlier onset and faster progression.

Conclusions : RPGRIP1^ins/ins animals show a broad clinical spectrum independent of the MAP9 status. While the two homozygous gene mutations have been associated with cord1, neither mutation by itself leads to any specific phenotype, and involvement of other genetic factors are indicated.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.