Kijas James W, Zangerl Barbara, Miller Brian, Nelson Jacque, Kirkness Ewen F, Aguirre Gustavo D, Acland Gregory M
James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Mol Vis. 2004 Mar 29;10:223-32.
To characterize a novel early onset canine retinal disease, and evaluate the ATP-binding cassette transporter gene ABCA4 as a potential candidate gene in this and other canine retinal degenerations.
Retinal disease was characterized ophthalmoscopically and electroretinographically in two pit bull terrier dogs and their purpose-bred descendants. All 50 exons of the canine ABCA4 gene were amplified, cloned and sequenced from retinal mRNA of a normal, a carrier and an affected animal, and polymorphisms identified. The latter were used to search for association between ABCA4 and retinal disease both within the study pedigrees and in additional canine breeds segregating retinal degenerations.
The disease derived from either founder is distinguished by early, severe, and rapidly progressive loss of cone function accompanied by progressive rod loss that is only relatively slower. Cloning and comparative sequencing of ABCA4 identified six point mutations, none of which were obviously pathogenic. Crossbreeding studies revealed that the diseases in the two founders, although similar, are nonallelic. Pedigree analysis of segregating polymorphisms revealed dissociation between ABCA4 and both retinal phenotypes.
The early, severe cone dysfunction in these diseases distinguish them from other forms of canine Progressive Retinal Atrophy. The development of a research population segregating these diseases presents two large animal models for the heterogenous human diseases termed cone-rod dystrophies. Analysis of the canine ABCA4 homolog gene documented its sequence and identified a set of point mutations that were used to exclude this gene as causal to these canine cone-rod dystrophies.
鉴定一种新型早发性犬视网膜疾病，并评估ATP结合盒转运蛋白基因ABCA4作为该疾病及其他犬视网膜变性潜在候选基因的可能性。
通过检眼镜检查和视网膜电图检查对两只斗牛梗犬及其定向培育的后代的视网膜疾病进行特征描述。从一只正常、一只携带者和一只患病动物的视网膜mRNA中扩增、克隆并测序犬ABCA4基因的所有50个外显子，鉴定多态性。后者用于在研究家系内以及在其他患有视网膜变性的犬种中寻找ABCA4与视网膜疾病之间的关联。
源自任何一个奠基者的疾病特征为早期、严重且快速进展的视锥细胞功能丧失，伴有进展相对较慢的视杆细胞丧失。ABCA4的克隆和比较测序鉴定出六个点突变，均无明显致病性。杂交研究表明，两位奠基者的疾病虽然相似，但并非等位基因。对分离多态性的家系分析显示ABCA4与两种视网膜表型之间均无关联。
这些疾病中早期、严重的视锥细胞功能障碍使其有别于其他形式的犬进行性视网膜萎缩。分离这些疾病的研究群体的建立为称为视锥-视杆营养不良的异质性人类疾病提供了两种大型动物模型。对犬ABCA4同源基因的分析记录了其序列，并鉴定出一组点突变，这些突变被用于排除该基因是这些犬视锥-视杆营养不良的病因。
