In other species: black-footed cat

Categories: Vision / eye phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 609237 (gene) , 609254 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: This disorder has been named in OMIA on the basis of the review by Miyadera et al. (2012)

Species-specific symbol: crd2

History: This disorder was first reported and given the symbol crd2 by Kijas et al. (2004), in a family of Pit Bull Terriers.

Mapping: By conducting a GWAS on 15 affected and 13 control dogs from a colony of Pit Bull Terriers segregating the disorder, each genotyped for approximately 127,000 SNPs on the Affymetrix canine SNP chip v2 (yielding 60,245 informative SNPs), Goldstein et al. (2013) mapped crd2 to a "a 4.4 Mb interval on CFA33 (22,690,750-27,122,415)". Homozygosity mapping identified a 2.3 Mb candidate block, namely "CFA33: 27,065,615-29,382,529".

Molecular basis: Sequencing of a likely candidate gene (IQCB1) in the candidate block (see Mapping section) enabled Goldstein et al. (2013) to identify the causal mutation to be "3 cytosines compared to 2 in the wild-type allele (CFA33: 28,120,686-28,120,687 . . . . This insertion, c.952-953insC, causes a frameshift that results in a change of 12 amino acids (amino acids 319-330) and introduction of a premature stop codon (p.S319IfsX12). This would yield a predicted 330 amino acid protein, in which only 318 are identical to normal".

Clinical features: As reported by Kijas et al. (2004): "early, severe, and rapidly progressive loss of cone function accompanied by progressive rod loss that is only relatively slower". Very similar clinical signs were reported by Kijas et al. (2004) in a family of American Staffordshire Terriers, but these authors showed that the two disorders are not allelic, and consequently named the other disorder crd1 (see OMIA 001674-9615)

Pathology: As reported by Goldstein et al. (2013): "By 12 weeks of age, . . . the ONL [outer nuclear layer] of the crd2-affected retina comprised only 5-7 layers; cone and rod inner and outer segments were present but distinctly abnormal, disorganized, and reduced in size and number compared to age-matched normal retina . . . . At 20 months of age, no IS [inner segments] and OS [outer segments] were present in the crd2-affected retina, and the ONL was thinned to nowhere more than 2 cell layers"

Control: Aguirre et al. (2021): "show that adeno-associated virus (AAV)-mediated NPHP5 [IQCB1] gene augmentation of mutant canine retinas at the time of active degeneration and peak cell death stably restores photoreceptor structure, function, and vision with either the canine or human NPHP5 [IQCB1] transgenes."

Breed: American Pit Bull Terrier.

Associated gene: