Canine RD3 mutation establishes rod-cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3

Abstract

Rod cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed, and to fine map rcd2 to a 230 kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2, and is predicted to alter the last 61 codons of the normal open reading frame and further extend the ORF. Thus combined meiotic linkage and LD mapping within a single canine breed can yield critical reduction of the disease interval when appropriate advantage is taken of within breed population structure. This should permit a similar approach to tackle other hereditary traits that segregate in single closed populations.

Assessment of Rod, Cone, and Intrinsically Photosensitive Retinal Ganglion Cell Contributions to the Canine Chromatic Pupillary Response

“…Diseases included CNGB1 -progressive retinal atrophy (PRA), CNGB3 achromatopsia (ACHM), PDE6B rod/cone dysplasia 1 (rcd1), RD3 rod/cone dysplasia 2 (rcd2), PDE6A rod/cone dysplasia 3 (rcd3), RPE65 Leber congenital amaurosis (LCA), PRCD progressive rod/cone degeneration (prcd), IQCB1 cone/rod dystrophy 2 (crd2), RPGR -X-linked progressive retinal atrophy 2 (XLPRA2), STK38L early retinal degeneration (erd), and NEHJ1 Collie eye anomaly (CEA). 16–39 Dogs were grouped and tested based on 4 previously reported retinal and optic nerve disease phenotypes, as follows: (1) Group 1 consisted of primary loss of rod function in dogs with CNGB1 -PRA and young (<1 year of age) dogs with PDE6A -rcd3 and PDE6B -rcd1; (2) group 2 included primary loss of cone function in dogs with CNGB3 -ACHM; (3) group 3 contained various severities of combined loss of rod and cone function in older dogs affected with PDE6B -rcd1, RD3 -rcd2, and PDE6A -rcd3, and dogs affected with RPE65 -LCA, PRCD -prcd, IQCB1 -crd2, STK38L -erd, and RPGR -XLPRA2; (4) and group 4 included primary loss of optic nerve function in 1 dog with severe optic nerve head coloboma due to NEHJ1 -CEA, which was also affected by RD3 -rcd2. We also assessed pupillary responses to differential blue and red light intensities in 2 additional WT and 2 CNGB3 -mutant dogs.…”

Mutations inRD3Are Associated with an Extremely Rare and Severe Form of Early Onset Retinal Dystrophy

“…28 The gene underlying the mouse model RD3 was identified in 2006 10 and its involvement in RCD2 has been shown very recently. 30 Identification of the mouse model RD3 gene directly let to the identification of sequence changes in the human RD3 gene as the underlying cause in an Indian family with LCA. 10 The patients presented with poor vision from birth, nystagmus, and atrophic lesions in the macular area.…”

RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells

“…A homozygous c.319C→T substitution in exon 3 of the Rd3 gene (formally the C1orf36 gene) results in an unstable truncated protein lacking the C-terminal 89 amino acids. A mutation in the human RD3 gene that also causes premature protein truncation is responsible for Leber congenital amaurosis type 12 (LCA12), and a frameshift mutation in canine RD3 resulting in an altered Cterminal protein sequence is associated with rod-cone dysplasia type 2 (rcd2) in collie dogs (10,12). These previous studies underscore the importance of RD3 in photoreceptor cell survival, but do not provide insight into the function of RD3 in photoreceptor cells or the mechanism through which mutations in RD3 cause photoreceptor degeneration.…”