Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612775 (trait) , 602713 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2010

Species-specific name: Progressive retinal atrophy; PRA-crd3

Species-specific symbol: crd3

Mapping: By conducting an autozygosity-mapping analysis on 12 affected and 12 matched control Glen of Imaal Terriers, each genotyped with the Affymetrix Canine Genome 2.0 Array “Platinum Panel” (comprising "∼50.000 SNPs"), Kropatsch et al. (2010) highlighted a region on "CFA16 from 24.7 to 29.9 Mb". In an independent study published just a week after Kropatsch et al. (2010) Goldstein et al (2010) undertook a GWAS on 21 affected and 22 matched control Glen of Imaal Terriers, each genotyped with the Affymetrix Version 2 Canine SNP chip (yielding 60,245 informative SNPs for analysis), Goldstein et al. (2010), highlighting a region on chromosome CFA16 "shared by six SNPs comprising an interval of approximately 4.4 Mb".

Molecular basis: Fine mapping and subsequent sequencing enabled Kropatsch et al. (2010) to identify the causal mutation as "a deletion of exons 15 and 16 which alters the reading frame leading to a premature stop codon" in the ADAM9 gene. A week later came a report of an independent exhaustive evaluation of candidate genes (both comparative positional and positional) that eventually enabled Goldstein et al. (2010) to identify the same causal mutation, namely "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".

Clinical features: Onset of disease has been reported on average at 6 years of age (Kropatsch et al., 2010). Affected dogs develop visual problems (difficulties avoiding obstacles in dim light) and the disease gradually results in total blindness (Goldstein et al., 2010). However, ophthalmoscopical changes can be observed in dogs as young as 3 years of age and can present either as "subtle but generalized hyperreflectivity of the tapetal fundus, and retinal vascular attenuation" or "as a discrete, distinctly hyperreflective lesion, with no accompanying ophthalmoscopic evidence of generalized retinal disease" (Goldstein et al., 2010). The electroretinogram (ERG) was normal in a 12-weeks-old affected dog. ERG dysfunction was detected at 15 month of age. As the disease progresses ERG changes become more pronounced. Loss of cone function is more severe compared to loss of rod function (Goldstein et al., 2010).

Breed: Glen of Imaal Terrier (Dog) (VBO_0200609).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: