@article{f4613f5d45bf420b83562b68de695d20,
title = "Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia",
abstract = "Background: Achromatopsia 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.Results: Here 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).Conclusion: We 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.",
keywords = "Achromatopsia, Alaskan malamute, Alaskan sled dog, Australian shepherd, CNGB3, Cone degeneration, Day-blindness, Identical by descent, Siberian husky",
author = "Yeh, {Connie Y.} and Orly Goldstein and Kukekova, {Anna V.} and Debbie Holley and Knollinger, {Amy M.} and Huson, {Heather J.} and Pearce-Kelling, {Susan E.} and Acland, {Gregory M.} and Kom{\'a}romy, {Andr{\'a}s M.}",
note = "Funding Information: DNA was extracted from blood of a normal and an AM-colony cd-affected dog using QIAmp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA), following manufacturer protocol. This research colony is maintained at the Retinal Disease Studies Facility of the University of Pennsylvania (Kennett Square, PA, USA) and supported by the National Eye Institute, NIH (R01-EY006855) and a Foundation Fighting Blindness (FFB) Center grant (see review on the establishment of the colony by Sidjanin and colleagues [13]). All procedures involving animals were done in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the University of Pennsylvania IACUC. Primers were designed to amplify genomic fragments within the predicted region where the deletion had taken place, based on the CanFam 2 assembly (http://genome. ucsc.edu/cgi-bin/hgGateway; Table S1 in Additional file 1). Products were evaluated for presence/absence and size by comparing the two samples. Targeted sequences were initially chosen within the CNGB3 gene neighboring sequences and subsequently narrowed down to pinpoint the breakpoints. PCR products were sequenced using the Applied Biosystems Automated 3730 DNA analyzer (Applied Biosystems, Foster City, CA, USA), and analyzed using Sequencher 4.2.2 software (Gene Codes Corporation, Ann Arbor, MI, USA). Funding Information: This study was supported by NIH grants R01-EY019304, R01-EY006855, P30-EY001583, T32-RR007063 and the Foundation Fighting Blindness (FFB). We thank the team (Nicole MacLaren and Justin Dees) at Eye Care for Animals in Salt Lake City, UT (USA) for allowing us to use their facility. Furthermore, we thank the staff at the Retinal Disease Studies Facility (University of Pennsylvania) for technical support, Lydia Melnyk (University of Pennsylvania) for research coordination, Mary Leonard (University of Pennsylvania) for illustrations, and all the dog owners and breeders for donating samples.",
year = "2013",
month = apr,
day = "20",
doi = "10.1186/1471-2156-14-27",
language = "English (US)",
volume = "14",
journal = "BMC genetics",
issn = "1471-2156",
publisher = "BioMed Central",
}