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

Goldstein O, Mezey JG, Boyko AR, Gao C, Wang W, Bustamante CD, Anguish LJ, Jordan JA, Pearce-Kelling SE, Aguirre GD, Acland GM - Mol. Vis. (2010)

Bottom Line: By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present.Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14853-6401, USA.

ABSTRACT

Purpose: To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.

Methods: Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.

Results: A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.

Conclusions: Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

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Related in: MedlinePlus

Light- and electron-microscopic retinal morphology in normal and canine cone-rod dystrophy 3 (crd3) affected dogs. In the retina of a 27-weeks-old non-affected dog (A), the outer nuclear layer (ONL) comprises approximately 10 rows of rod nuclei and a single distal row of cone nuclei. The inner and outer segments of the photoreceptors (IS, OS) are of consistent proportions, tightly aligned, and parallel, and the distal OS tips are in close proximity to the apical membrane of the retinal pigment epithelium (RPE). In retinas of 4.7- and 13.4-weeks-old crd3-affected dogs (B, C), rod and cone IS and OS lack the tightly packed highly parallel organization of a normal photoreceptor layer, and the distal OS tips appear to be more distant from the RPE apical membrane than in normal dogs. In the retina of an 18-weeks-old crd3-affected dog (D), IS and OS are disarrayed and disorganized, and a distinct gap is observed between the RPE and the OS (arrows). The retinas of 26-weeks- and 5 years-old crd3-affected dogs (E, F) exhibit continued photoreceptor degeneration as evidenced by loss of cone and rod IS, OS, and nuclei. Electron micrograph of the retina of a 27-weeks-old nonaffected dog (G) shows that the microvilli from the RPE apical membrane extend to invest the photoreceptor OS. Electron micrographs of the retina of a 13.4-weeks-old crd3-affected dog (H, I) show that the RPE apical microvilli form a tangled flattened mat that does not extend to invest the photoreceptor OS (arrows).
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f2: Light- and electron-microscopic retinal morphology in normal and canine cone-rod dystrophy 3 (crd3) affected dogs. In the retina of a 27-weeks-old non-affected dog (A), the outer nuclear layer (ONL) comprises approximately 10 rows of rod nuclei and a single distal row of cone nuclei. The inner and outer segments of the photoreceptors (IS, OS) are of consistent proportions, tightly aligned, and parallel, and the distal OS tips are in close proximity to the apical membrane of the retinal pigment epithelium (RPE). In retinas of 4.7- and 13.4-weeks-old crd3-affected dogs (B, C), rod and cone IS and OS lack the tightly packed highly parallel organization of a normal photoreceptor layer, and the distal OS tips appear to be more distant from the RPE apical membrane than in normal dogs. In the retina of an 18-weeks-old crd3-affected dog (D), IS and OS are disarrayed and disorganized, and a distinct gap is observed between the RPE and the OS (arrows). The retinas of 26-weeks- and 5 years-old crd3-affected dogs (E, F) exhibit continued photoreceptor degeneration as evidenced by loss of cone and rod IS, OS, and nuclei. Electron micrograph of the retina of a 27-weeks-old nonaffected dog (G) shows that the microvilli from the RPE apical membrane extend to invest the photoreceptor OS. Electron micrographs of the retina of a 13.4-weeks-old crd3-affected dog (H, I) show that the RPE apical microvilli form a tangled flattened mat that does not extend to invest the photoreceptor OS (arrows).

Mentions: By light microscopy, at 4.7 weeks of age, the rod and cone inner (IS) and outer segments (OS) of the crd3-affected retina lacked the tightly packed, highly parallel organization of a normal photoreceptor layer (Figure 2). At 4.7, 13.4, and 18 weeks of age (Figure 2B,C,D), an apparent gap was consistently observed between the distal ends of the photoreceptor OS and the retinal pigment epithelium (RPE; Figure 2D, arrows); IS and OS appeared disarrayed and disorganized; and structural abnormalities of cone IS and OS were at least as or more severe than those of rods. At later ages, distinct thinning and reduction of cell numbers in the ONL was observed (Figure 2 E,F). At 5 years of age (Figure 2F), cones and rods were severely reduced in number, with only a few nuclei remaining in the ONL, most of which appeared rod-like.


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

Goldstein O, Mezey JG, Boyko AR, Gao C, Wang W, Bustamante CD, Anguish LJ, Jordan JA, Pearce-Kelling SE, Aguirre GD, Acland GM - Mol. Vis. (2010)

Light- and electron-microscopic retinal morphology in normal and canine cone-rod dystrophy 3 (crd3) affected dogs. In the retina of a 27-weeks-old non-affected dog (A), the outer nuclear layer (ONL) comprises approximately 10 rows of rod nuclei and a single distal row of cone nuclei. The inner and outer segments of the photoreceptors (IS, OS) are of consistent proportions, tightly aligned, and parallel, and the distal OS tips are in close proximity to the apical membrane of the retinal pigment epithelium (RPE). In retinas of 4.7- and 13.4-weeks-old crd3-affected dogs (B, C), rod and cone IS and OS lack the tightly packed highly parallel organization of a normal photoreceptor layer, and the distal OS tips appear to be more distant from the RPE apical membrane than in normal dogs. In the retina of an 18-weeks-old crd3-affected dog (D), IS and OS are disarrayed and disorganized, and a distinct gap is observed between the RPE and the OS (arrows). The retinas of 26-weeks- and 5 years-old crd3-affected dogs (E, F) exhibit continued photoreceptor degeneration as evidenced by loss of cone and rod IS, OS, and nuclei. Electron micrograph of the retina of a 27-weeks-old nonaffected dog (G) shows that the microvilli from the RPE apical membrane extend to invest the photoreceptor OS. Electron micrographs of the retina of a 13.4-weeks-old crd3-affected dog (H, I) show that the RPE apical microvilli form a tangled flattened mat that does not extend to invest the photoreceptor OS (arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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f2: Light- and electron-microscopic retinal morphology in normal and canine cone-rod dystrophy 3 (crd3) affected dogs. In the retina of a 27-weeks-old non-affected dog (A), the outer nuclear layer (ONL) comprises approximately 10 rows of rod nuclei and a single distal row of cone nuclei. The inner and outer segments of the photoreceptors (IS, OS) are of consistent proportions, tightly aligned, and parallel, and the distal OS tips are in close proximity to the apical membrane of the retinal pigment epithelium (RPE). In retinas of 4.7- and 13.4-weeks-old crd3-affected dogs (B, C), rod and cone IS and OS lack the tightly packed highly parallel organization of a normal photoreceptor layer, and the distal OS tips appear to be more distant from the RPE apical membrane than in normal dogs. In the retina of an 18-weeks-old crd3-affected dog (D), IS and OS are disarrayed and disorganized, and a distinct gap is observed between the RPE and the OS (arrows). The retinas of 26-weeks- and 5 years-old crd3-affected dogs (E, F) exhibit continued photoreceptor degeneration as evidenced by loss of cone and rod IS, OS, and nuclei. Electron micrograph of the retina of a 27-weeks-old nonaffected dog (G) shows that the microvilli from the RPE apical membrane extend to invest the photoreceptor OS. Electron micrographs of the retina of a 13.4-weeks-old crd3-affected dog (H, I) show that the RPE apical microvilli form a tangled flattened mat that does not extend to invest the photoreceptor OS (arrows).
Mentions: By light microscopy, at 4.7 weeks of age, the rod and cone inner (IS) and outer segments (OS) of the crd3-affected retina lacked the tightly packed, highly parallel organization of a normal photoreceptor layer (Figure 2). At 4.7, 13.4, and 18 weeks of age (Figure 2B,C,D), an apparent gap was consistently observed between the distal ends of the photoreceptor OS and the retinal pigment epithelium (RPE; Figure 2D, arrows); IS and OS appeared disarrayed and disorganized; and structural abnormalities of cone IS and OS were at least as or more severe than those of rods. At later ages, distinct thinning and reduction of cell numbers in the ONL was observed (Figure 2 E,F). At 5 years of age (Figure 2F), cones and rods were severely reduced in number, with only a few nuclei remaining in the ONL, most of which appeared rod-like.

Bottom Line: By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present.Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14853-6401, USA.

ABSTRACT

Purpose: To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.

Methods: Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.

Results: A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.

Conclusions: Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

Show MeSH
Related in: MedlinePlus