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Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci

Cite this dataset

Ripolles-Garcia, Ana et al. (2023). Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci [Dataset]. Dryad. https://doi.org/10.5061/dryad.wdbrv15rj

Abstract

Canine model of RPGRIP1-cone-rod dystrophy (CRD) was originally identified as a monogenic autosomal recessive disease characterized by early-onset blindness in a research colony. However, subsequent studies in the broader canine population revealed extensive variability in disease onset among RPGRIP1 mutants. Further studies led to the identification of a genetic modifier, a MAP9 variant that gave rise to earlier disease onset among RPGRIP1 mutants. We now describe the mapping of L3, an additional modifier locus, based on phenotypic variation specific to cone photoreceptor function. A genome-wide association study and haplotype analysis mapped L3 to a 4.1-Mb locus on canine chromosome 30, and containing 49 genes, at least 38 of which were indicated in retinal expression. RNA-seq and whole genome sequencing did not find critical disease-causing genetic variant. However, filtering of moderate variants resulted in 11 missense variants as candidates for L3. We then established the natural disease history of RPGRIP1 -CRD in a purpose-bred colony of 58 dogs including 44 RPGRIP1 mutants that were grouped into four cohorts based on the modifier status of MAP9 and L3. Functional and structural retinal phenotypes were evaluated in dogs up to nearly 9 years of age using electroretinography and vision-guided navigation, ophthalmoscopy, spectral-domain optical coherence tomography, and transmission electron microscopy. RPGRIP1 mutants affected by both MAP9 and L3 modifiers exhibited the most severe disease phenotypes with rapid progression. MAP9 alone acted as an overall accelerator of rod and cone diseases, while L3 had a cone-specific effect. Ultrastructural analysis of photoreceptors revealed varying degrees of rod and cone destruction, while the connecting cilia appeared structurally preserved in all groups. We conclude that at least three loci contribute to the pathogenesis of oligogenic RPGRIP1 -CRD. While the RPGRIP1 variant is required for disease, both MAP9 and L3 modifiers exacerbate the phenotype, individually and cumulatively. The oligogenic RPGRIP1 -CRD canine model demonstrates the impact of multiple genetic modifiers on disease phenotype under a controlled environment, and thus may contribute to the identification of new targets for broad-spectrum therapies in oligogenic or polygenic forms of inherited retinal diseases.

Methods

Libraries of 300 bp insert size was prepared, llumina HiSeq2500 paired-end reads, (2 × 100 bp, one lane per sample); Casava was used for the fastq preparation (https://bioweb.pasteur.fr/packages/pack@casava@1.8.2, v 1.8.2).

Funding

Margaret Q. Landenberger Research Foundation

Foundation Fighting Blindness, Award: RC-CMM-0720-0792-UPA

Van Sloun Foundation for Canine Genetic Research

Sanford and Susan Greenberg End Blindness Outstanding Achievement Prize

NEI/NIH grant, Award: EY-006855