Generalized progressive retinal atrophy of Sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene

Abstract

We investigated the gene encoding the β subunit of cGMP phosphodiesterase (PDE6B) as a candidate for generalized progressive retinal atrophy (gPRA), an autosomal recessively transmitted eye disease in dogs. The PDE6B gene was isolated from a genomic library. Single-strand conformation polymorphism analysis revealed eight intronic variations in different subsets of the 14 dog breeds investigated. In addition, we identified an 8-bp insertion after codon 816 in certain Sloughi dogs. Analysis of PRA-affected and obligatory carrier Sloughis showed that this mutation cosegregates with disease status in a large pedigree. All other exchanges identified were not located in functionally relevant parts of the gene (e.g., in the splice signal consensus sites). In most dog breeds (Labrador retriever, Tibetan mastiff, dachshund, Tibetan terrier, miniature poodle, Australian cattle dog, cocker spaniel, collie, Saarloos wolfhound, Chesapeake Bay retriever, and Yorkshire terrier), PDE6B was excluded as a candidate gene for gPRA because heterozygous allele constellations were detected in diseased animals. Therefore, the PDE6B sequence variations did not segregate together with the mutation(s) causing gPRA. Direct and indirect DNA tests concerning gPRA can be offered now for a variety of different dog breeds.

Identification of Genetic Variants in <I>PDC, RHO, PDE6A</I> and <I>PDE6B</I> in Dogs with Progressive Retinal Atrophy

“…A single base deletion at codon 616 in the PDE6A gene is co-segregated with PRA status with zero discordance in PRA affected Cardigan Welsh Corgis 23 . A different mutation in PDE6B for rcd1a was found to be associated with PRA in the Sloughi by using a candidate gene approach 22 . A stop mutation in exon 21 of canine PDE6B gene was also identified by sequencing in Iris Setters breed 21,40,41 .…”

“…There are a number of retina-specific genes involved in the visual transduction pathway which are the candidate genes for PRA. PRA was associated with the mutation in -subunit of the cGMP-specific phosphodiesterase (PDE6B) gene in Irish setters and Sloughis 21,22 and in the -subunit of the cGMP-specific phosphodiesterase (PDE6A) gene in Cardigan Welsh Corgis 23 . A missense mutation in Phosducin (PDC) was detected in the Miniature Schnauzer 24 .…”

Genetics of eye disorders in the dog.

“…Retinal disorders can be categorized in various ways and the way in which they have been Cone-rod dystrophy CRD3 ADAM9 Glen of Imaal terrier [53,54] Primary open angle glaucoma POAG ADAMTS10 Beagle [147] Primary lens luxation PLL ADAMTS17 Multiple, mainly terrier breeds [129,132] Rod cone degeneration RCD4 C2orf71 Gordon Setter, Irish Setter, Tibetan Terrier [30] Generalised progressive retinal atrophy gPRA CCDC66 Schappendoes [28] Progressive retinal atrophy PRA CNGB1 Papillon [15,17] Cone degeneration CD CNGB3 Alaskan malamute [68] Cone degeneration CD CNGB3 German shorthaired pointer [69] Dwarfism with retinal dysplasia (oculoskeletal dysplasia) DRD2 (OSD2) COL9A2 Samoyed [90] Dwarfism with retinal dysplasia (oculoskeletal dysplasia) DRD1 (OSD1) COL9A3 Labrador retriever [90] Hereditary cataract HC, EHC HSF4 Staffordshire bull terrier, Boston terrier, French bulldog [103] Hereditary cataract HC HSF4 Australian Shepherd [107] Collie eye anomaly CEA NHEJ1 Collies [91] Cone-rod dystrophy NPHP4 Standard wirehaired dachshund [49] Photoreceptor dysplasia PD PDC Miniature schnauzer [13] Rod cone dysplasia RCD1 PDE6B Irish setter [2] Rod cone dysplasia RCD1 PDE6B Sloughi [3] Rod cone dysplasia RCD3 PDE6A Cardigan Welsh corgi [4] Progressive rod-cone degeneration PRCD PRCD Multiple breeds [23] Rod cone dysplasia RCD2 RD3 Collie [7] Autosomal dominant progressive retinal atrophy ADPRA RHO English mastiff [24] Congenital stationary night blindness CSNB RPE65 Briard [58,59] X-linked progressive retinal atrophy XLPRA2 RPGR Mixed breed dogs [18] X-linked progressive retinal atrophy XLPRA1 RPGR Siberian Husky, Samoyed [18] Cone-rod dystrophy CORD1 (CRD4) RPGRIP Dachshunds [38] Early retinal degeneration ERD STK38L Norwegian elkhound [11] Canine multifocal retinopathy CMR1…”

Analysis of PDE6D and PDE6G genes for generalised progressive retinal atrophy (gPRA) mutations in dogs

“…The DNA of 22 dog breeds including 114 gPRA-affected animals are covered in this study. For six of these breeds either the causative gPRA mutations (Irish Setter [31], and Sloughi [12]) or linked markers for the progressive rod cone degeneration (prcd) form of gPRA are already known (Australian Cattle Dog, English Cocker Spaniel, Labrador Retriever, Miniature Poodle; patented by OptiGen, USA). The PDE6G gene is located near the prcd region, but is excluded as a cause for RP 17 in man [4], the homologous gPRA form in these breeds [1].…”

“…For autosomal recessively transmitted (ar), generalised progressive retinal atrophy (gPRA), the most common hereditary form in dogs, mutations have been identified in the β subunit of the PDE (PDE6B) gene in Irish Setters and Sloughis [12,31] and in the α subunit (PDE6A) gene in Cardigan Welsh Corgis [25].…”