Abstract
Defects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and cone-rod dystrophy in humans. A form of canine cone-rod dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1ins/ins) as the primary disease locus while a homozygous deletion in MAP9 (MAP9del/del) was later identified as a modifier associated with the early onset form. However, we find further variability in cone electroretinograms (ERGs) ranging from normal to absent in an extended RPGRIP1ins/ins canine colony, irrespective of the MAP9 genotype. Ophthalmoscopically, cone ERGabsentRPGRIP1ins/ins eyes show discolouration of the tapetal fundus with varying onset and disease progression, while sd-OCT reveals atrophic changes. Despite marked changes in cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and cone ERGabsentRPGRIP1ins/ins littermates. Cone morphology of the dogs lacking cone ERG are truncated with shortened outer and inner segments. Immunohistochemically, cone ERGabsentRPGRIP1ins/ins retinas have extensive L/M-opsin mislocalization, lack CNGB3 labelling in the L/M-cones, and lack GC1 in all cones. Our results indicate that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to cone-specific functional and morphologic defects.
Highlights
Defects in the cilia gene retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) cause Leber congenital amaurosis and cone-rod dystrophy in humans
While the cone ERGabsent phenotype was seen among RPGRIP1ins/ins dogs of all microtubule associated protein 9 (MAP9) genotypes, notably, all the double homozygotes (RPGRIP1ins/insMAP9del/del; n = 6) fell into the cone ERGabsent phenotype (Fig. 2a2)
Among the RPGRIP1ins/ins animals in the general breed population, a MAP9del/del mutation has been identified as a modifier leading to early onset of the disease[9,10]
Summary
Defects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and cone-rod dystrophy in humans. A form of canine cone-rod dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1ins/ins) as the primary disease locus while a homozygous deletion in MAP9 (MAP9del/del) was later identified as a modifier associated with the early onset form. Despite marked changes in cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and cone ERGabsent RPGRIP1ins/ins littermates. Our results indicate that cord[1] is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to cone-specific functional and morphologic defects. Among the positional candidate genes, retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) was found to harbour a homozygous 44 bp insertion (RPGRIP1ins/ins) in exon 2 ( revised to exon 3; CanFam3.1) that segregated with cord[1] in the colony[6]. While the insertion was initially predicted to result in a frame shift and protein truncation[6], it was later shown that exon skipping occurs, allowing the main functional domain RID (RPGR-interacting domain) to remain intact[8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
