Cord1-PRA, degenerative diseases of the retina

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). The mutation seems to be important also for Curly Coated Retriever breed.
• Genetics of cord-PRA in pit bull terriers has not been explained yet (Kijas et al. 2004).
• Clinical expression of cord2-PRA in standard 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).

Disease Cord1-PRA is caused by insertion of 44 bases (g. 8228_8229 insA29GGAAGCAACAGGATG) in exon 2 of RPGRIP1 gene (retinitis pigmentosa GTPase regulator-interacting Protein 1). This mutation was identified in miniature longhaired dachshund and the same mutation was found also in english springer spaniels. In humans, mutations in the gene RPGRIP cause disease X-linked retinitis pigmenosa-3 (RP3) and severe progressive and degenerative retinal dystrophy, which can lead to blindness.

In 2012, Miyadera et. al published new study, which partially changed position of mutation 8228_8229 g insA29GGAAGCAACAGGATG as causal for Cord1 disease. In the study, there were found several dogs with mutations in both alleles (mutated homozygote) that have no clinical symptoms of the disease. It seems that the mechanism of Cord1 disease is more complex than was originally meant. Further research continues to explore mechanism of RPGRIP1 gene transcription. Possible presence of other mutations cannot be excluded.

The first clinical symptoms of cord1-PRA in miniature longhaired dachshunds noticed in the ERG test ware found around the sixth month of dog´s age. First, degeneration of cones and subsequently degeneration of rods is registered. In the 40th week of age, no photoreceptors function was recorded by ERG in animal suffering CORD1 (Turney et al. 2007).

In all affected miniature longhaired dachshunds with clinical manifestations of CORD1 the mutation described above was found. This mutation has been identified as causal for phenotype CORD1. Melleresh et. al. 2006 found out a different average age of clinical diagnosis in case of two unrelated groups of affected animals: the first group of 6 months, the second 4.82 year. In one mutated homozygous individual no clinical symptoms were observed at age of 10.34 years (Mellersh et. Al 2006). Different ages, when the first CORD1 clinical symptoms develop, do not eliminate the possibility of existence modifying genes. These genes could affect the penetrance and expressivity of CORD1 disease (or mutation RPGRIP1). This hypothesis is currently not clearly confirmed.

Cord1-PRA is meant to be an autosomal recessive disorder. Individuals with N / N result (negative / negative) do not carry the mutation. Individuals with N / P (positive / negative) are carriers of the mutation. In individuals with two mutated alleles (P / P, positive / positive) the Cord1 disease does not necessarily have to develop. The exact mechanism of Cord1 disease is unknown. Influence of other mutations or modifications at the level of transcription cannot be excluded.

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References:

Mellersh CS, Boursnell ME, Pettitt L, Ryder EJ, Holmes NG, Grafham D, Forman OP, Sampson J, Barnett KC, Blanton S, Binns MM, Vaudin M. Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics. 2006;88:293-301.

J.W. Kijas, et al., Cloning of the canine ABCA4 gene and evaluation in canine cone-rod dystrophies and progressive retinal atrophies, Mol. Vision 10 (2004) 223-232.

Wiik AC, Wade C, Biagi T, Ropstad EO, Bjerkas E, Lindblad-Toh K, Lingaas F. A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund. Genome Res. 2008;18:1415-21.
C. Turney, et al. (2007) Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund. Invest. Ophthalmol. Visual Sci. 2007;48:4240-4249.

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.

Keiko Miyadera, Ian Brierley, Jesu´s Aguirre-Hernández, Cathryn S. Mellersh, David R. Sargan: Multiple Mechanisms Contribute to Leakiness of a Frameshift Mutation in Canine Cone-Rod Dystrophy; PLOS ONE, December 2012, Volume 7, Issue 12, e51598