Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia

Abstract

BackgroundAchromatopsia is an autosomal recessive disease characterized by the loss of cone photoreceptor function that results in day-blindness, total colorblindness, and decreased central visual acuity. The most common causes for the disease are mutations in the CNGB3 gene, coding for the beta subunit of the cyclic nucleotide-gated channels in cones. CNGB3-achromatopsia, or cone degeneration (cd), is also known to occur in two canine breeds, the Alaskan malamute (AM) and the German shorthaired pointer.ResultsHere we report an in-depth characterization of the achromatopsia phenotype in a new canine breed, the miniature Australian shepherd (MAS). Genotyping revealed that the dog was homozygous for a complete genomic deletion of the CNGB3 gene, as has been previously observed in the AM. Identical breakpoints on chromosome 29 were identified in both the affected AM and MAS with a resulting deletion of 404,820 bp. Pooled DNA samples of unrelated purebred Australian shepherd, MAS, Siberian husky, Samoyed and Alaskan sled dogs were screened for the presence of the affected allele; one Siberian husky and three Alaskan sled dogs were identified as carriers. The affected chromosomes from the AM, MAS, and Siberian husky were genotyped for 147 SNPs in a 3.93 Mb interval within the cd locus. An identical shared affected haplotype, 0.5 Mb long, was observed in all three breeds and defined the minimal linkage disequilibrium (LD) across breeds. This supports the idea that the mutated allele was identical by descent (IBD).ConclusionWe report the occurrence of CNGB3-achromatopsia in a new canine breed, the MAS. The CNGB3-deletion allele previously described in the AM was also observed in a homozygous state in the affected MAS, as well as in a heterozygous carrier state in a Siberian husky and Alaskan sled dogs. All affected alleles were shown to be IBD, strongly suggesting an affected founder effect. Since the MAS is not known to be genetically related to the AM, other breeds may potentially carry the same cd-allele and be affected by achromatopsia.

Gene therapies for inherited retinal disorders

“…AAV-based gene replacement has proven effective for all three genes, in diverse mouse and canine models of this disease (Alexander et al, 2007 ;Chang et al, 2006 ;Yeh et al, 2013 ;Schon et al, 2013 ). Three forms of achromatopsia (also known as rod monochromacy), which is characterized by complete loss of cone function, can be caused by recessive mutations in GNAT2 , CNGB3 , and CNGA3 .…”

Hereditary retinal eye diseases in childhood and youth affecting the central retina

“…[25] Its prevalence is estimated to be about 1:30000. Clinically, complete achromatopsia and incomplete achromatopsia can be distinguished.…”

Achromatopsia in three sibling Labrador Retrievers in the UK

“…Achromatopsia in the canine due to early cone photoreceptor degeneration (CD) was first reported in Alaskan Malamutes (AM) . The disease is an autosomal recessively inherited condition in AM and is due to deletion of the CNGB3 gene . The disease has also been reported in German Shorthaired Pointers and is due to a missense mutation in exon 6 ( D262N ) of the CNGB3 gene .…”

“…[1][2][3] The disease is an autosomal recessively inherited condition in AM and is due to deletion of the CNGB3 gene. [4][5][6][7] The disease has also been reported in German Shorthaired Pointers and is due to a missense mutation in exon 6 (D262N) of the CNGB3 gene. 6 More recently, homozygous CNGB3 achromatopsia has been detected in the Miniature Australian Shepherd and heterozygous carrier states detected in Siberian Husky and Alaskan Sled Dog breeds.…”