Indirect exclusion of four candidate genes for generalized progressive retinal atrophy in several breeds of dogs

Abstract

BackgroundGeneralized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina (ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs.ResultsMutation screening was performed initially by PCR and single strand conformation polymorphism (SSCP) analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4, CX36, MERTK and RDH12 in 71 affected dogs of 29 breeds. Yet 30 new sequence variations were identified, both, in the coding regions and intronic sequences. Many of the sequence variations were in heterozygous state in affected dogs.ConclusionBased on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK (for all 29 breeds) and RDH12 (for 9 breeds).

Mechanistic insight into the progressive retinal atrophy disease in dogs via pathway-based genome-wide association analysis

“…The ABCA4 gene encodes ATP-binding cassette, subfamily A, member 4, protein which was described to be an essential protein for human retinal degeneration disease. Moreover, this gene was found as an causal gene associated to generalized PRA disease in different breeds of dogs [36]. Besides, ATP1A, gene comes under Na + /K + transporting ATPase alpha 1 family, has been a causative gene for autosomal recessive cone-rod dystrophy (CORD8) disease [37].…”

An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease

“…The canine eye is also comparable in size to the human eye, and dog models have successfully been used for experimental gene therapy for retinal degenerative diseases, such as LCA, RP, and rod-cone dysplasia type 1 (rcd1) [ 12 , 14 , 16 , 62 ]. For over a decade there has been interest in finding a canine model for ABCA4 -mediated diseases [ 23 , 63 , 64 ]. The loss-of-function mutation identified here can be used to develop a large animal model for human STGD.…”

Identification of genetic variation and haplotype structure of the canine ABCA4 gene for retinal disease association studies

“…In recent years, these elaborate methods are being replaced by time and cost-effective screening methods. A study investigating ABCA4 in 25 dog breeds affected with PRA identified 18 sequence variants, including a single aa change, by SSCP (Lippmann et al 2006). ABCA4 was excluded as causative gene for PRA in 17 breeds, but could not be assessed in the remainder.…”

“…The large size of the ABCA4 coding region and the population structure of the dog that is segregated into genetically isolated breeds (Quignon et al 2007) pose significant limitations for the identification of variations that are potentially important in only a few breeds. Thus, a study excluding ABCA4 from association with various forms of progressive retinal atrophy (PRA), the canine RP homologous group of diseases, in 17 breeds was based on identification of only 18 polymorphisms by SSCP (Lippmann et al 2006). While association studies would be more appropriate for studies of ABCA4 in the dog, these rely on identification and availability of representative markers.…”