Morphologic and molecular genetic characterization of X-linked progressive retinal atrophy in the dog

Progressive retinal atrophies (PRA) in dogs comprise a group of inherited retinal degenerations which resemble retinitis pigmentosa (RP) in humans. In both species, the relatively homogenous histopathologic and clinical manifestation of these disorders (progressive photoreceptor loss), belies their complex and heterogeneous genetic causation. X-linked progressive retinal atrophy (XLPRA) causes clinically evident retinal degeneration in hemizygous males by early adulthood and progresses to complete blindness over a 2--3 year period. Retinal pathology is characterized by initial degeneration of rod outer segments, followed by progressive rod and cone death with resultant complete retinal atrophy. Carrier females display a patchy pattern of rod photoreceptor loss. which is presumably due to random X chromosome inactivation. Using available canine X chromosome markers, as well as intragenic markers developed for the purposes of this study, we established the position of the XLPRA locus on the canine X chromosome by linkage analysis. XLPRA is tightly linked to an intragenic marker within the canine RPGR gene (LOD 11.7, zero recombination), thus making it the locus homolog of one form of human X-linked RP, RP3. During the process of genetic marker development, we cloned and characterized the coding regions of two canine X-linked genes, tissue inhibitor of metalloproteinases 1 (TIMP-1) and retinitis pigmentosa GTP-ase regulator (RPGR), both of which resemble their human homologs closely. Ordering of intragenic markers during the linkage study established a broad framework map for the canine X chromosome. Of the mammalian species in which X chromosome structure has been described, the structure of the canine X chromosome most closely resembles that seen in the human.