A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund

Abstract

Cone-rod dystrophy is a retinal degenerative disorder occurring naturally in man and dog. Here we identify a novel gene for early-onset cone-rod dystrophy in the wire-haired dachshund. For the first time, we use genome-wide association-based Sibling Transmission Disequilibrium Test (sibTDT) analysis of only 13 discordant sib-pairs to identify a single significantly associated 6.5-Mb region (PrawTDT = 4.8 × 10−5, PgenomeTDT = 6 × 10−4) on canine chromosome 5, containing more than 70 genes. Segregation studies using microsatellites in the candidate region including additional meiosis supported the sibTDT analysis but could not further reduce the area. Candidate gene resequencing identified a 180-bp deletion in exon/intron 5 of NPHP4 (nephronophthisis 4, also known as nephroretinin). RT-PCR analysis of NPHP4 in cases and controls showed exon skipping of exon 5, resulting in a truncated protein that retains the binding domain interacting with nephronophthisis 1 (also known as nephrocystin-1) in the kidney but lacks the domain interacting with RPGRIP1 in retina. We suggest that this deletion in the canine NPHP4 gene is the cause of cone-rod dystrophy in the standard wire-haired dachshund. In humans, mutations in NPHP4 have been associated with simultaneous eye and kidney disease. Here we describe the first naturally occurring mutation in NPHP4 without additional kidney disease. Further studies will permit elucidation of the complex molecular mechanism of this retinopathy and the development of potential therapies.

The role of primary cilia in the development and disease of the retina

“…221 Mutations in NPHP1 cause the ciliopathies NPHP, 222 JBTS 223 and SLS, 224 all of which include retinal degeneration in some patients. NPHP4 localizes to the base of the connecting cilium, proximal to SDCCAG8, RPGRIP1 and RPGR 200 and when mutated leads to CORD in dogs, 225 NPHP, SLS and CORS in humans. 204,226,227 Similar to Nphp1 mutant mice, mice with mutations in Nphp4 exhibit mislocalization of OS proteins (rhodopsin and ROM1) to the IS and inner nuclear layer.…”

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…”

Le chien dans la pathologie et la génétique comparée: exemples de maladies et de gènes partagés entre l'homme et le chien

“…Concernant les maladies à composantes génétiques « simples » ou supposées simples, de nombreux travaux font actuellement état de l'identification de gènes responsables d'affections partagées entre l'homme et le chien, comme, par exemple, des rétinopa-thies (Wilk et al 2008), la sclérose amyothrophique latérale (Awano et al 2009), des maladies cardiaques (Meurs et al 2010), les lipofuscinoses neuronales canines (Abitbol et al 2010 ;Katz et al 2011), les épilepsies (Lohi et al 2005 ;Sepalla et al 2011), des maladies dermatologiques telle que l'ichtyose (Grall et al 2012), ou encore des anomalies comme le phénotype sans poil des chiens nus (Drogemuller et al, 2008).…”