An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9

[摘要] Purpose: To identify the causativemutation in a canine cone-rod dystrophy (crd3) that segregates as anadult onset disorder in the Glen of Imaal Terrier breed of dog. Methods: Glen of Imaal Terriers wereascertained for crd3 phenotype by clinical ophthalmoscopic examination,and in selected cases by electroretinography. Blood samples fromaffected cases and non-affected controls were collected and used, afterDNA extraction, to undertake a genome-wide association study usingAffymetrix Version 2 Canine single nucleotide polymorphism chips and250K Sty Assay protocol. Positional candidate gene analysis wasundertaken for genes identified within the peak-association signalregion. Retinal morphology of selected crd3-affected dogs was evaluatedby light and electron microscopy. Results: A peak association signalexceeding genome-wide significance was identified on canine chromosome16. Evaluation of genes in this region suggested A Disintegrin AndMetalloprotease domain, family member 9 (ADAM9), identifiedconcurrently elsewhere as the cause of human cone-rod dystrophy 9(CORD9), as a strong positional candidate for canine crd3. Sequenceanalysis identified a large genomic deletion (over 20 kb) that removedexons 15 and 16 from the ADAM9 transcript, introduced apremature stop, and would remove critical domains from the encodedprotein. Light and electron microscopy established that, as in ADAM9knockout mice, the primary lesion in crd3 appears to be a failure ofthe apical microvilli of the retinal pigment epithelium toappropriately invest photoreceptor outer segments. Byelectroretinography, retinal function appears normal in very youngcrd3-affected dogs, but by 15 months of age, cone dysfunction ispresent. Subsequently, both rod and cone function degenerate. Conclusions: Identification of this ADAM9deletion in crd3-affected dogs establishes this canine disease asorthologous to CORD9 in humans, and offers opportunities for furthercharacterization of the disease process, and potential for genetictherapeutic intervention.

[学科分类] 生物化学/生物物理