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O. Goldstein, G.D. Aguirre, G.M. Acland; Candidate Gene Analyses in 3 Canine Cone–rod Dystrophies . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3191.
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© ARVO (1962-2015); The Authors (2016-present)
Cone–rod dystrophies are severe hereditary retinal diseases characterized by degeneration of cone photoreceptors preceding that of rods. Autosomal dominant, autosomal recessive and X–linked inheritance is observed in humans. At least 15 mapped human loci are recognized, including at least 9 identified causative genes. Informative pedigrees have been developed that segregate 3 different canine cone–rod dystrophies (CRD1, CRD2 and CRD3); CRD1 and CRD2 are autosomal recessive, while the mode of inheritance of CRD3 is currently under investigation. Purpose: To identify Single Nucleotide Polymorphisms (SNPs) within candidate genes to determine the role of these genes in three canine cone–rod dystrophies. Methods: Canine genomic sequence for 3 candidate genes, RPGRIP1, HRG4 and RDS, was retrieved from the UCSC database. Primers were designed to amplify all coding regions and selected noncoding genomic regions within each gene. RT–PCR on normal canine retina was used to validate expression and characterize transcripts. To search for SNPs, genomic regions within each gene were amplified and sequenced from DNA samples representing several different breeds of dog. Following SNP discovery, affected animals from each cone–rod dystrophy pedigree were genotyped at SNP loci by either direct sequencing or restriction digestion testing. Results: RT–PCR confirmed expression of RPGRIP1, HRG4 and RDS transcripts in canine retina. Three SNPs were found within the RPGRIP1 gene. SNP heterozygosity in CRD1– and CRD2–affected dogs exclude RPGRIP1 as the causative locus for these 2 diseases. Two CRD3–affected animals had 4 different RPGRIP1 SNP haplotypes between them, excluding RPGRIP1 in CRD3, regardless of the proposed mode of inheritance. Four SNPs in the RDS gene create three different haplotypes. Heterozygosity in affected animals excluded RDS as the cause of the disease in all three canine cone–rod dystrophies, assuming autosomal recessive inheritance. Six SNPs were found in HRG4. CRD2–affected animals were heterozygous for one of these SNPs, and CRD3–affected animals exhibited all 3 genotypes (AA, AG, GG) indicating that HRG4 has no role in these diseases. All six HRG4 SNPs were uninformative in available CRD1 pedigrees. Conclusions: RPGRIP1 and RDS are excluded in CRD1, CRD2 and CRD3; and HRG4 in CRD2 and CRD3. Further CRD1 animals are currently being tested to better evaluate the role of HRG4; and 10 further candidate genes are now being evaluated in all three diseases using intragenic microsatellite markers.
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