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 RDS͞peripherin, have been excluded. In parallel with a recent undertaking to establish a framework map of the canine genome, multiple prcdinformative pedigrees have been typed with a panel of more than 100 anchor loci and microsatellite-based markers. Identification of a linkage group f lanking 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.

Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa

“…For this reason, availability of a good animal model, allowing experimental testing of candidate chemical chaperones for clinical efficacy for RP17, would be highly desirable. Examining the CA4 gene in dogs affected with canine progressive rod-cone degeneration, which maps to the syntenic region of the dog genome (35), is a logical first step in searching for such an animal model.…”

“…Biosynthesis was studied in COS cells transfected with WT and mutant CA4 cDNAs by prelabeling with 35 S-translabel for 15-120 min and examining the radiolabeled newly synthesized CA IV after immunoprecipitation and SDS͞ PAGE. The results in Fig.…”

Finding cardiovascular disease genes in the dog

“…Recent studies have brought advances in understanding the genetics of breed development 15 and the availability of ever higher resolution maps [16][17][18][19][20][21] . These have led to the mapping of disease loci for a variety of diseases including metabolic disorders 22,23 , blindness [24][25][26][27][28] , cancer 29,30 neurologic disorders 31,32 , hip dysplasia 33 epilepsy 34 , as well as several morphologic traits 35,36 . In addition, the advancement of a framework for how to study complex canine traits 37 has led to deepening of our knowledge about the organization of the canine genome 38,39 and how it relates to morphological variation between breeds.…”

Chromosome-Specific Single-Locus FISH Probes Allow Anchorage of an 1800-Marker Integrated Radiation-Hybrid/Linkage Map of the Domestic Dog Genome to All Chromosomes

“…Indeed, extensive canine pedigrees, coupled with an enormous diversity in morphology and behavior, provides a valuable mechanism for understanding the genetic regulation of mammalian growth and development. In addition, the mating of closely related individuals in order to maximize segregation of desirable traits has led to the propagation of autosomal recessive diseases in the modern dog, many of which are similar or, in some cases, identical to human diseases (e.g., Dodds 1989;Menon et al 1992;Sharp et al 1992;Stolzfus et al 1992;Henthorn et al 1994;Zheng et al 1994;Acland et al 1998Acland et al , 1999Lin et al 1999;Veske et al 1999). To date, ∼360 genetic diseases have been identified in the dog, representing the largest number reported for any nonhuman mammal (Patterson 2000(Patterson , 2001.…”