Dataset Information

A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations.

ABSTRACT: Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (p(raw)?=?1.94×10(-10), p(genome)?=?1.0×10(-5)), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans.

SUBMITTER: Downs LM

PROVIDER: S-EPMC3124514 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations.

Downs Louise M LM Wallin-Håkansson Berit B Boursnell Mike M Marklund Stefan S Hedhammar Åke Å Truvé Katarina K Hübinette Louise L Lindblad-Toh Kerstin K Bergström Tomas T Mellersh Cathryn S CS

PloS one 20110627 6

Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasi ...[more]

PMID: 21738669

Similar Datasets

Project description:BACKGROUND:Generalized progressive retinal atrophy (PRA) is a group of inherited eye diseases characterised by progressive retinal degeneration that ultimately leads to blindness in dogs. To date, more than 20 different mutations causing canine-PRA have been described and several breeds including the Golden Retriever are affected by more than one form of PRA. Genetically distinct forms of PRA may have different clinical characteristics such as rate of progression and age of onset. However, in many instances the phenotype of different forms of PRA cannot be distinguished at the basic clinical level achieved during routine ophthalmoscopic examination. Mutations in two distinct genes have been reported to cause PRA in Golden Retrievers (prcd-PRA and GR_PRA1), but for approximately 39% of cases in this breed the causal mutation remains unknown. RESULTS:A genome-wide association study of 10 PRA cases and 16 controls identified an association on chromosome 8 not previously associated with PRA (praw?=?1.30×10(-6) and corrected with 100,000 permutations, pgenome?=?0.148). Using haplotype analysis we defined a 737 kb critical region containing 6 genes. Two of the genes (TTC8 and SPATA7) have been associated with Retinitis Pigmentosa (RP) in humans. Using targeted next generation sequencing a single nucleotide deletion was identified in exon 8 of the TTC8 gene of affected Golden Retrievers. The frame shift mutation was predicted to cause a premature termination codon. In a larger cohort, this mutation, TTC8 c.669delA, segregates correctly in 22 out of 29 cases tested (75.9%). Of the PRA controls none are homozygous for the mutation, only 3.5% carry the mutation and 96.5% are homozygous wildtype. CONCLUSIONS:Our results show that PRA is genetically heterogeneous in one of the world's numerically largest breeds, the Golden Retriever, and is caused by multiple, distinct mutations. Here we discuss the mutation that causes a form of PRA, that we have termed PRA2, that accounts for approximately 30% of PRA cases in the breed. The genetic explanation for approximately 9% of cases remains to be identified. PRA2 is a naturally occurring animal model for Retinitis Pigmentosa, and potentially Bardet-Biedl Syndrome.

Project description:Inherited retinal degenerations, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), represent leading causes of incurable blindness in humans. This is also true in dogs, where the term progressive retinal atrophy (PRA) is used to describe inherited photoreceptor degeneration resulting in progressive vision loss. Because of the similarities in ocular anatomy, including the presence of a cone photoreceptor-rich central retinal region, and the close genotype-phenotype correlation, canine models contribute significantly to the understanding of retinal disease mechanisms and the development of new therapies. The screening of the pure-bred dog population for new forms of PRA represents an important strategy to establish new large animal models. By examining 324 dogs of the Swedish vallhund breed in seven countries and across three continents, we were able to describe a new and unique form of PRA characterized by the multifocal appearance of red and brown discoloration of the tapetal fundus followed over time by thinning of the retina. We propose three stages of the disease based on the appearance of the ocular fundus and associated visual deficits. Electroretinography revealed a gradual loss of both rod and cone photoreceptor-mediated function in Stages 2 and 3 of the disease. In the few dogs that suffered from pronounced vision loss, night-blindness occurred first in late Stage 2, followed by decreased day-vision in Stage 3. Histologic examinations confirmed the loss of photoreceptor cells at Stage 3, which was associated with the accumulation of autofluorescent material in the adjacent retinal pigment epithelium. Pedigree analysis was suggestive of an autosomal-recessive mode of inheritance. Mutations in six known canine retinal degeneration genes as well as hypovitaminosis E were excluded as causes of the disease. The observed variability in the age of disease onset and rate of progression suggest the presence of genetic and/or environmental disease modifiers.

Project description:Background:Dogs have human-directed social skills that allow them to communicate and cooperate with humans. We have previously identified two loci on chromosome 26 associated with human contact-seeking behaviors during an unsolvable problem task in laboratory beagles (Persson et al., 2016). The aim of the present study was to verify the single nucleotide polymorphisms (SNPs) in additional dog breeds. We also studied how the allele frequencies have changed during domestication and recent selection. Methods:Dogs of two breeds, 61 golden retrievers and 100 Labrador retrievers, were phenotyped and genotyped, and 19 wolves were genotyped. The Labrador retrievers were divided into common and field type by pedigree data to make it possible to study the effects of recent selection. All dogs were tested in an unsolvable problem task where human-directed social behaviors were scored. DNA from dogs (buccal swabs) and wolves (blood or brain tissue) was analyzed for genotype on two of the previously identified SNP markers, BICF2G630798942 (SNP1) and BICF2S23712114 (SNP2), by pyrosequencing. Results:There was genetic variation for SNP1 in both dog breeds whereas the wolves were fixed for this polymorphism, and for SNP2 there was variation in both dogs and wolves. For both SNPs, Labrador retriever types differed significantly in allele frequencies. We found associations between SNPs and human-directed social behavior in both dog breeds. In golden retrievers, SNP1 was associated with physical contact variables, for example, with the duration of physical contact with the owner (F 2,56 = 4.389, p = 0.017). SNP2 was associated with several behavioral variables in both breeds, among others owner gazing frequency in both golden retrievers (F 2,55 = 6.330, p = 0.003) and Labradors (F 1,93 = 5.209, p = 0.025). Discussion:Our results verify the association between the previously identified SNPs and human-directed social behavior scored in an unsolvable problem task. Differences in allele frequencies suggest that these loci have been affected by selection. The results indicate that these genomic regions are involved in human-directed social behavior in not only beagles but in other dog breeds as well. We hypothesize that they may have been important during dog domestication.

Dataset Information

A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations.

Publications

A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets