Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans

Abstract

Progressive rod-cone degeneration (prcd) is the most widespread hereditary retinal disease leading to blindness in dogs and phenotypically is the canine counterpart of retinitis pigmentosa (RP) in humans. In previous efforts to identify the genetic locus for prcd, the canine homologs for many of the genes causally associated with RP in humans, such as RHO, PDE6B, and RDS/peripherin, have been excluded. In parallel with a recent undertaking to establish a framework map of the canine genome, multiple prcd-informative pedigrees have been typed with a panel of more than 100 anchor loci and microsatellite-based markers. Identification of a linkage group flanking prcd ([TK1, GALK1, prcd]-[MYL4, C09.173, C09.2263]-RARA-C09.250-C09.474-NF1) localizes prcd close to the centromeric end of canine chromosome 9 (CFA9), and excludes RARA as a candidate gene. The conserved synteny of this region of CFA9 and distal human chromosome 17q establishes the potential locus homology of prcd in the dog with RP17, a human retinitis pigmentosa locus for which no gene has yet been identified. Assignment of the prcd disease locus to an identified canine autosome represents a powerful application of the developing canine linkage map in medical genetics. The usefulness of this approach is further demonstrated by identification of the correspondence of the prcd interval to homologous human and mouse chromosomal regions. The rapid progress that is now occurring in the field of canine genetics will expedite the identification of the genes underlying many of the inherited traits and diseases that make the dog a unique asset for the study of mammalian traits.

Figure 1

Pedigrees of prcd-informative three-generation families 1–6, 8, and 9, used in linkage studies. Circles represent females, squares represent males, open symbols indicate homozygous normal at prcd locus, solid symbols indicate prcd-affected, and half-filled symbols indicate prcd heterozygous. The hatched symbol in family 1 indicates a sibling for whom prcd phenotype could not be reliably ascertained. Although shown as separate pedigrees, these families together form part of a much larger prcd colony.

Figure 2

(A) Pedigree of prcd-informative family 7, with haplotype data. The order of loci is according to results of two-point linkage analyses in the present study. For the prcd locus, p indicates disease allele and + indicates wild-type allele. For MYL4, allele numbers are assigned as described in the text. For all other loci, allele numbers were assigned according to ref. . Loci 173, 2263, 474, and 250 represent microsatellite markers C09.173, C09.2263, C09.474, and C09.250, respectively. Haplotypes demonstrating recombination events are indicated (—∗), although indicated position does not always correspond to the only possible site of the recombination. (B) Pedigree of sire of F₂ litter in family 3, with haplotypes indicating that this individual received a TK1–prcd–MYL4 recombinant chromosome from his dam. Although this recombination can equally be interpreted to have taken place between TK1 and prcd, or between prcd and MYL4, the haplotypes also indicate that two different TK1 alleles are segregating in phase with prcd in this dog’s pedigree.

Figure 3

Linkage map of the prcd interval on canine chromosome 9 (CFA9). The location of prcd is shown relative to that of nine loci corresponding to type I and II markers. Loci listed on a single line indicate no recombinations observed between these markers in the present study. TK1 and GALK1/prcd are on separate lines but at a single location because, although no obligate recombinations were observed in this interval, indications of possible recombinations between TK1 and prcd were detected. Order and distances (in cM, centimorgans) shown are based on two-point linkage analyses of the data in this study.