Linkage Mapping of Canine Rod Cone Dysplasia Type 2 (rcd2) to CFA7, the Canine Ortholog of Human 1q31

Abstract

Abstract: : Canine inherited progressive retinal atrophy represents a rich set of natural models for human retinitis pigmentosa (RP) and allied diseases. Rod cone dysplasia type 2 (rcd2), an early onset form of PRA, is phenotypically similar to early onset forms of RP. This autosomal recessive disease segregates naturally in the collie breed of dog. Multiple genes have been evaluated as candidates for rcd2, but all have been excluded. Purpose: To identify the locus responsible for rcd2 through linkage mapping. Methods: An experimental colony of dogs segregating the rcd2 phenotype was developed, and a set of informative pedigrees produced. The power of these pedigrees for identification of the rcd2 locus in a genome wide scan was estimated by simulation. For the best–case scenario (at theta = 0) simulations yielded a LOD score = 28.297; and at theta = 0.1, a LOD score of 14.282. A genome wide scan of these pedigrees using a set of 241 markers was undertaken (Mammalian Genotyping Service, Marshfield, WI). Genotypes were checked for Mendelian segregation using the prepare option of MultiMap. Linkage between rcd2 and each marker was determined using the MultiMap best–twopoints function. To refine the localized homology between canine and human maps, an RH map of the identified rcd2 region was built using a 3000 cR panel. Positional candidate gene strategy was then undertaken to begin to evaluate potentially causative genes. Results:The rcd2 locus was mapped to the telomeric region of CFA7. The highest linkage was observed between rcd2 and marker VIASD10 (theta = 0.07; LOD = 17.08), and the nonrecombinant region is flanked by markers FH2226 and FH3972. So far CRB1 is the only gene on human chromosome 1q31 known to cause retinal degeneration. Canine gene specific markers for CRB1 were developed and this gene was excluded as a positional candidate for rcd2. These data predict that a novel retinal degeneration gene will be identified in the course of fine mapping of canine rcd2.

Keywords: retinal degenerations: hereditary • genetics • gene mapping