Novel Retinal Gene (PRCD) Causes Progressive Rod–Cone Degeneration in Canines and Humans

Abstract

Purpose: : Progressive rod–cone degeneration (prcd) is a late–onset, autosomal recessive photoreceptor degeneration of unknown molecular etiology, representing one of the most studied animal models and a homolog for human RP. Previously, the disease relevant interval was reduced to an 83kb region on canine chromosome 9 (CFA9), which showed a common affected haplotype shared by 13 different dog breeds. Novel candidate genes were identified within this region utilizing a canine retinal EST library, and investigated for causative correlation with disease in dog and man.

Methods: : Partial cDNA for a novel retinal expressed gene was obtained from a canine retinal EST library. The gene was extended using different RT–PCR approaches to contain a complete ORF; orthologous transcripts were cloned in human and mouse. Comparison of the coding sequence between a normal and prcd affected animal revealed a single nucleotide change. This sequence was subsequently evaluated in large sets of dogs by restriction enzyme test or pyrosequencing. Exons one and three of the human ortholog were screened for variations in 1,710 patients diagnosed with RP, cone/rod dystrophy, or LCA, using SSCP. Expression studies were obtained through northern blots and TaqMan qRT–PCR.

Results: : We cloned and characterized a novel retinal expressed gene, now referred to as PRCD, in dog, human, and mouse. A homozygous mutation (TGC to TAC change of the second codon) shows complete correlation with the clinical occurrence of disease in different affected dog breeds. The same homozygous mutation was identified in a human patient from Bangladesh with ARRP. Expression studies support the predominant expression of this gene in the retina.

Conclusions: : This report provides strong evidence that a mutation in the novel gene, PRCD, is a cause for recessive retinal degeneration in both dogs and humans. Functional studies to further characterize this gene are underway.

Keywords: mutations • candidate gene analysis • retinal degenerations: hereditary