Cloning of the canine ABCA4 gene and evaluation in caninecone-rod dystrophies and progressive retinal atrophies

[摘要] Purpose: To characterize a novel early onset canine retinal disease,and evaluate the ATP-binding cassette transporter gene ABCA4 as apotential candidate gene in this and other canine retinaldegenerations.Methods: Retinal disease was characterized ophthalmoscopically andelectroretinographically in two pit bull terrier dogs and theirpurpose-bred descendants. All 50 exons of the canine ABCA4 gene wereamplified, cloned and sequenced from retinal mRNA of a normal, a carrierand an affected animal, and polymorphisms identified. The latter wereused to search for association between ABCA4 and retinal diseaseboth within the study pedigrees and in additional canine breedssegregating retinal degenerations.Results: The disease derived from either founder is distinguished byearly, severe, and rapidly progressive loss of cone function accompaniedby progressive rod loss that is only relatively slower. Cloning andcomparative sequencing of ABCA4 identified six point mutations, noneof which were obviously pathogenic. Crossbreeding studies revealed thatthe diseases in the two founders, although similar, are nonallelic.Pedigree analysis of segregating polymorphisms revealed dissociationbetween ABCA4 and both retinal phenotypes.Conclusions: The early, severe cone dysfunction in these diseasesdistinguish them from other forms of canine Progressive Retinal Atrophy.The development of a research population segregating these diseasespresents two large animal models for the heterogenous human diseasestermed cone-rod dystrophies. Analysis of the canine ABCA4 homologgene documented its sequence and identified a set of point mutationsthat were used to exclude this gene as causal to these canine cone-roddystrophies.

[学科分类] 生物化学/生物物理