Cord2-PRA in standard wire-haired dachshund

Mutation causing eye defect cord2-PRA (also known as crd2-PRA) in standard wire-haired dachshunds, was first published in July 2008.

Cord-PRA (cone-rod dystrophy - PRA) is a form of progressive retinal atrophy disease. Cord-PRA is a degenerative retinal disease occurring in humans and dogs.
Standard wire-haired dachshunds, miniature long-haired dachshunds, english springer spaniels and pit bull terriers are the only known breeds with occurrence of cord-PRA disease (Kijas et al. 2004; Mellersh et al. 2006; Ropstad et al. 2007):

• Cord1-PRA causal mutation in miniature dachshunds and english springer spaniels was found in RPGRIP1 gene (Mellersh et al. 2006).
• Genetics of cord-PRA in pit bull terriers has not been explained yet (Kijas et al. 2004).
• Clinical expression of cord2-PRA in standard and miniature wire-haired dachshund (retina diseases without renal affection - details below) was described by Ropstad et al. 2007 b. In 2008, a team of Norwegian scientists discovered a gene mutation causing early onset retinal dystrophy in standard wire-haired dachshunds (Wiik et. al. 2008).

Causal mutation was identified as 180 bp deletion in exon / intron 5 of NPHP4 gene (nephronophthisis 4, also known as nephroretinin). The frequency of mutated gene in standard wire-haired dachshund population is about 9,5 %. Protein nephroretinin, which is created by transcription of mutated gene, is shorter than the normal protein nephroretinin. Mutated nephroretinin still preserves a binding domain interacting with nephrocystin-1 in kidneys, but lacks a domain interacting with RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein) in retina. Therefore, due to 180 bp deletion in NPHN4 gene, standard wire-haired dachshunds suffer only from retina disorder not kidney disease. On the contrary, humans, due to this deletion in NPHP4 gene, are affected both retina and kidney diseases.

The first clinical symptoms of cord2-PRA in standard wire-haired dachshunds appear between 10 months and 3 years. Total retinal atrophy occurs around the 6th year of life (Ropstad et al. 2007a), when cord2-PRA is manifested as daily blindness. Cord2-PRA affected animals showed cone-derived responses in clinical examination (ERG) already at 5 weeks.

Cord2-PRA is an autosomal recessive disorder. The disease affects dogs with P/P (positive / positive) genotype only. Dogs with P/N (positive /negative) genotype are clinically without any symptoms. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.

Note: NPHP gene is named after nephronophthisis, which is a group of autosomal recessive kidney diseases. Nephronophthisis represents the most frequent genetic cause of kidney failure in children and young people. The only treatment is often kidney transplantation.

References:

Wiik, A.C., Ropstad, E.O., Bjerkas, E., and Lingaas, F. 2008. A study of candidate genes for day blindness in the standard wire haired dachshund. BMC. Vet. Res. 4: 23. doi:10.1186/1746-6148-4-23

Kijas, J.W., Zangerl, B., Miller, B., Nelson, J., Kirkness, E.F., Aguirre, G.D., and Acland, G.M. 2004. Cloning of the canine ABCA4 gene and evaluation in canine cone-rod dystrophies and progressive retinal atrophies. Mol. Vis. 10: 223-232

Mellersh, C.S., Boursnell, M.E., Pettitt, L., Ryder, E.J., Holmes, N.G., Grafham, D., Forman, O.P., Sampson, J., Barnett, K.C., Blanton, S., et al. 2006. Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 88: 293-301

Ropstad, E.O., Bjerkas, E., and Narfstrom, K. 2007a. Electroretinographic findings in the Standard Wire Haired Dachshund with inherited early onset cone-rod dystrophy. Doc. Ophthalmol. 114: 27-36.

Ropstad, E.O., Bjerkas, E., and Narfstrom, K. 2007b. Clinical findings in early onset cone-rod dystrophy in the Standard Wire-haired Dachshund. Vet. Ophthalmol. 10: 69-75

Palánová, A., Schröffelová, D., Přibáňová, M., Dvořáková, V., Stratil, A.: Analysis of a deletion in the nephronophthisis 4 gene in different dog breeds. Vet Ophthalmol 17:76-8, 2014.