Retinal dystrophy of Swedish briard briard-beagle dogs is due to a 4-bp deletion in RPE65

The RPE65 gene encodes a 65-kDa microsomal protein expressed exclusively in retinal pigment epithelium (RPE). Mutations in the human RPE65 gene have r ecently been identified in patients with autosomal recessive, severe, child hood-onset retinal dystrophy. Here we report the characterization of a 2.4- kb canine Rpe65 cDNA. The longest open reading frame predicts a 533-amino-a cid protein with a calculated molecular mass of about 61 kDa prior to prote in modification. Sequence comparison shows that RPE65 is highly conserved t hroughout mammalian evolution. We have identified a homozygous 4-bp deletio n (485delAAGA) in putative exon 5 of the canine Rpe65 gene in affected anim als of a highly inbred kinship of Swedish briard/briard-beagle dogs, in whi ch an autosomal recessive, early-onset, and progressive retinal dystrophy s egregates. The deletion results in a frameshift and leads to a premature st op codon after inclusion of 52 canine RPE65-unrelated amino acids from resi due 153 onward. More than two-thirds of the wildtype polypeptide chain will be missing, and the mutant protein is most likely nonfunctional (null alle le), Clinical features of the canine disease are quite similar to those des cribed in human. Therefore this form of canine retinal dystrophy provides a n attractive animal model of the corresponding human disorder with immediat e significance for various therapeutic approaches, including RPE transplant ation. (C) 1999 Academic Press.