CNGB3-achromatopsia is the most common form of achromatopsia in humans [9, 12]. In dogs, two different CNGB3 mutations were identified that result in the achromatopsia phenotype . One is the D262N missense mutation in German shorthaired pointers, while the other is a genomic deletion of CNGB3 found in the AM . Both of these mutations lead to the same disease phenotype with complete loss of cone function . In our study, we found that affected AMs have a 404,820 bp deletion containing three known genes, CPNE3, CNGB3, and CNBD1. Since dogs with either the D262N missense mutation or the genomic deletion of CNGB3 show very similar disease phenotype, the loss of the CPNE3 and CNBD1 genes does not appear to have phenotypic consequences. CPNE3 is part of a family of proteins known as the copines. They all share a similar structure and interact with a range of cell signaling and cytoskeletal proteins in response to increases in intracellular calcium [25, 26]. They are known to be responsible for calcium-dependent phospholipid binding [25, 26]. CNBD1 has not been fully characterized. Future studies comparing the two types of CNGB3 mutations may shed light on the function and importance of CPNE3 and CNBD1 by identifying subtle phenotypic differences.
One day-blind AM was genotyped normal for the CNGB3-deletion mutation. We do not have pedigree information or access to DNA samples from its close relatives; therefore, with these limitations we can only suggest heterogeneity for day-blindness in the AM breed, though non-genetic basis for that particular dog is not excluded. Seddon and colleagues  found genetic heterogeneity of day-blindness in AMs in Australia.
We also report the occurrence of achromatopsia in a MAS based on the identical classical clinical phenotype and genomic CNGB3 deletion that was reported in the AM. Pooled-sample screening identified other arctic breeds closely related to the AM carrying the affected allele: one Siberian husky and three Alaskan sled dogs. We are not aware of any reports about day-blindness in these arctic breeds; however, the occurrence of achromatopsia would not be surprising based on our findings.
The presence of the same large genomic CNGB3 deletion in several related and unrelated canine breeds suggests that these mutated alleles are IBD. To further confirm this idea, we expanded the locus genotyping to a 3.93 Mb interval. One hundred and forty seven SNPs were identified and confirmed an identical shared affected haplotype across the three breeds, a segment of 0.5–1.04 Mb in size. Comparing haplotypes of large segments of DNA between unrelated dogs gives the opportunity to observe historical recombination, instead of meiosis recombination within a specific pedigree. This is a powerful tool when the dogs that are chosen are the least related to each other within a breed, as well as across different breeds. The shared affected haplotype observed in the purebred affected AM was reduced from 3.53 Mb segment to 1.0–1.5 Mb when compared to affected MAS, and then further reduced to 0.5–1.04 Mb when compared to a third breed, the Siberian husky.
Linkage disequilibrium (LD) mapping has become a useful tool for genomic studies and has been previously used in studies of inherited canine retinal diseases [28–30]. As exemplified in the case study presented here, dogs which share the same ancestral mutated chromosome, also share the same haplotype within a region flanking the mutation, a region that is in LD with the disease. This is especially powerful when the same disease is observed in more than one breed [28, 31, 32]. The results in this study suggest that CNGB3 deletion is an ancestral mutation that originated from a dog that served as a common founder. Although most of the dogs carrying the achromatopsia mutation possess an arctic lineage, we have also found it in the MAS whose distinct physical characteristic, functional, and genetic background suggest a different breed origin. The MAS breed was developed in the late 1960s as smaller Australian shepherds were selectively bred in order to achieve the desired size. Contrary to the name of the breed, Australian shepherds were relatively recently developed in the western United States in the 19th and early 20th century. In contrast, the AM is thought to be among the more ancient breeds . During the time of the Klondike Gold Rush in the 19th century, the AM became valuable and was frequently crossbred with other breeds, possibly including the Australian shepherd. Achromatopsia was first observed in an inbred strain of the AM in the 1960s [15–18].
The Alaskan sled dogs are a population of dogs with a northern breed ancestry and were developed through the selection and breeding of several dog breeds based on their athletic abilities. They are mixed breed dogs comprised of several different lineages and can be separated into two clusters, sprint and distance, based on their racing style . It was found that the AM and Siberian husky contributed to enhanced endurance, the pointer and saluki contributed to enhanced speed, and the Anatolian shepherd contributed to work ethic . The presence of both AM and Siberian husky in their ancestry suggests that the mutated cd-allele in these sled dogs could have been contributed by either breed. While it is established that the AM, Siberian husky, and Alaskan sled dog are closely related and belong within the same ancestral cluster [20, 21, 33], the relation of AM to MAS is less clear. Therefore, based on breed history, it is difficult to determine when a mixture between any of these breeds occurred that introduced the mutation.
There are similar reports of the founder effect in other genetic diseases in dogs. Founder effect may be more obvious in more closely related breeds. Examples include the mutation in ADAMTS17, which causes primary lens luxation in many breeds, most of which are terriers or breeds with terrier co-ancestry , and a 7.8-kb deletion in the non-homologous end-joining factor 1 (NHEJI1) that is responsible for collie eye anomaly in several breeds, most of which fall into a cluster of collie-like dogs . Further example includes multidrug sensitivity, which is caused by a mutation in the canine multidrug resistant gene MDR1: Several collie-related breeds and two sight hounds, not expected to share collie ancestry, were found to segregate the affected allele which was determined to be IBD since it was conserved among these affected breeds . Another example is the mutation causing progressive rod-cone degeneration (prcd) in over 20 dog breeds representing all the breed groups defined by the American Kennel Club (herding, hound, working, terrier, toy, sporting and non-sporting as well as miscellaneous) . This apparent disparate association is similar to our findings of the identical CNGB3 mutation in the MAS and three arctic breeds.
Day-blindness is a rather rare finding in canines with only CNGB3-achromatopsia having been thoroughly characterized. Based on eye certification data  and our DNA testing results over the past 20 years, we suspect that CNGB3-achromatopsia has become rare or even non-existent in North American AMs, but it is still reported in Australia [27, 37]. Except for a transgenic CNGB3-knockout mouse , the dogs discussed here represent the only known animal model of CNGB3-achromatopsia, the most common form of the disease in humans [9, 12]. Naturally occurring achromatopsia based on mutations in other genes have been described in Awassi sheep (CNGA3) [39, 40] and in mice (CNGA3, GNAT2 and PDE6C) [41–43]. These animals provide valuable models for translational research, including the development of new therapies [14, 41, 44].