Cone-Rod Degeneration Research In The Miniature Longhaired Dachshund Summary – March 2011

Cathryn Mellersh, PhD

An association between a mutation in the gene RPGRIP1 and cone-rod degeneration (CORD1) in miniature longhaired dachshunds was published in the peer-reviewed scientific journal Genomics in 2006 [1].

The original research that established this association was undertaken with a very

inbred colony of dogs that all descended from a small number of animals. In the original colony of dogs there was absolute correlation between genotype and CORD1 phenotype. Following the original publication it became apparent that there was considerable variation in the age of onset of disease in dogs that carried two copies of the mutation, indicating (an) additional modifying gene(s) might be involved in determining the age of onset of the condition. The authors of the original publication have acknowledged this variation from the onset and have continued to work, in cooperation with dachshund owners and breeders worldwide, to fully understand the genetic basis of CORD1 in this breed. Studies have been undertaken to measure the behavioral abnormalities, responses to menace and light, fundoscopy, and electroretinography (ERG) of dogs with the CORD1 mutation, and these studies have demonstrated, unequivocally, that the cone photoreceptors in the retinas of dogs with two copies of the CORD1 mutation do not function normally, even although their retinas might appear normal upon ophthalmoscopic examination [2, 3]. This means that even though the eyes of a dog with two copies of the CORD1 mutation may appear normal when examined by an ophthalmologist the dog is unlikely to be seeing colour as it should or have normal visual accuity. Recent studies have provided firm evidence of a second, modifying gene that influences the effects of the RPGRIP1 mutation.

These results have yet to be published but have been reported at various scientific

conferences and at the Dachshund Breed Conference in Warwickshire, UK in 2009 by Keiko Miyadera, so are

quite familiar to those who have followed the research closely. Keiko Miyadera has recently successfully defended her PhD thesis entitled ‘Phenotypic and genetic heterogeneties in a canine retinal degeneration’ which describes her studies over the last three years investigating CORD1 in the dachshund. The overwhelming conclusion from these intensive studies is that the previously reported RPGRIP1 mutation, upon which the widely used DNA test is based, causes cone photoreceptors to malfunction and together with an additional mutation in a modifying gene causes early onset cone-rod degeneration. The CORD1 mutation is recessive, meaning no dog need be removed from the breeding population and every dog can be safely bred from, regardless of their genotype at the RPGRIP1 gene. The author would like to thank all the dachshund owners and breeders who have contributed to these studies over the years and who have contributed constructively to discussions about cone-rod degeneration in this breed.

Below are the publications that detail the findings to date.

1.

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.

2.

Busse C, Barnett KC, Mellersh CS, Adams V. Ophthalmic and cone derived electrodiagnostic

findings in outbred Miniature Long-haired Dachshunds homozygous for a RPGRIP1 mutation . . Veterinary Ophthalmology in press.

3.

Miyadera K, Kato K, Aguirre-Hernandez J, Tokuriki T, Morimoto K, Busse C, Barnett K,

Holmes N, Ogawa H, Sasaki N, Mellersh CS, Sargan DR. Phenotypic variation and genotypephenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis 2009; 15: 2287-2305.