Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3)

X-linked progressive retinal atrophy (XLPRA) in the Siberian husky dog is a naturally occurring X-linked retinopathy closely resembling X-linked retin itis pigmentosa (XLRP) in humans, In affected males, initial degeneration o f rods is followed by cone degeneration and complete retinal atrophy; carri er females have random patches of rod degeneration consistent with random X chromosome inactivation. By typing the XLPRA pedigree with five intragenic markers [dystrophin, retinitis pigmentosa GTPase regulator (RPGR), tissue inhibitor of metalloproteinases I, androgen receptor and factor IX], we est ablished a linkage map of the canine X chromosome, and confirmed that the o rder of these five genes is identical to that on the human X, XLPRA was tig htly linked to an intragenic RPGR polymorphism (LOD 11.7, zero recombinatio n), thus confirming locus homology with RP3, We cloned the full-length cani ne RPGR cDNA and three additional splice variants. No disease-causing mutat ion was found in the RPGR-coding sequence of the four splice variants chara cterized, a finding similar to similar to 80% of human XLRP patients whose disease maps to the RP3 locus. In addition, there were no significant diffe rences in the proportional expression of each splice variant in normal and pre-degenerate XLPRA-affected retina. Expression of all RPGR splice variant s increased later in the disease, when retinas were undergoing active degen eration. The results provide further evidence of cross-species retention of a complex splicing pattern in the 3' portion of RPGR, the functional signi ficance of which is unknown. In addition, the possibility of another diseas e locus in the RP3 region is supported.