Post date: Jul 27, 2016 6:47:4 PM
From Dr. Cathryn Mellersh, AHT (27th July 2016)
Background
An association between a mutation in the gene RPGRIP1 and cone-rod dystrophy (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 were undertaken to measure the behavioral abnormalities, responses to menace and light, fundoscopy, and electroretinography (ERG) of dogs with the RPGRIP1 mutation, and these studies have demonstrated consistently that the cone photoreceptors in the retinas of dogs with two copies of the RPGRIP1 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 RPGRIP1 mutation may appear normal when examined by an ophthalmologist the dog might not be seeing colour as it should or have normal visual acuity.
Additional studies provided firm evidence of a second, modifying gene that influences the effects of the RPGRIP1 mutation. These results were also accepted for publication in a peer-reviewed scientific journal in 2012 [4]. The overwhelming conclusion from these intensive studies was 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 dystrophy.
Identification of the additional mutation has been the subject of intense research over the last few years and earlier this year reached a successful conclusion with the identification of a mutation in a second gene, called MAP9, which acts as an age of onset modifier of the RPGRIP1 mutation. Details of this modifier mutation have recently been published [5].
Summary
Our current understanding of cone-rod dystrophy (CORD1) in MLHDs is as follows:
dogs that that are homozygous (have two copies) of both the RPGRIP1 and MAP9 mutations will develop CORD1 within the first two or so years of life. Their disease will be progressive and they will probably lose their sight early in life.
Dogs that are homozygous for the RPGRIP1 mutation but not the MAP9 mutation will have cone photoreceptors that do not function normally. Their retinas are likely to appear normal upon ophthalmoscopic examination. They might not see colour as they should or have normal visual acuity but their vision is likely to be sufficient for them to lead a normal life. They are unlikely to develop clinical signs of CORD1 until middle or old age (usually more than four years old) and some dogs may retain vision during most of their lives. The MAP9 mutation is not as common as the RPGRIP1 mutation so the great majority of dogs that are homozygous for the RPGRIP1 mutation will not be homozygous for the MAP9 mutation.
Currently we do not know as much about dogs that are homozygous for the MAP9 mutation but not the RPGRIP1 mutation. Our research shows these dogs will be rare, and suggests that they will not develop clinical signs of CORD1; but additional research will be required to confirm this.
DNA Testing
The CORD1 DNA test that is offered by the AHT measures the number of copies of the RPGRIP1 mutation that a dog has and does not currently provide any information about the number of copies of the MAP9 mutation a dog has. Our research has shown that two copies of the RPGRIP1 mutation are necessary for dogs to develop early onset CORD1 so we recommend breeders continue to DNA test their dogs for this mutation and avoid breeding dogs that could be homozygous.
By the end of 2016 the AHT hopes to modify the CORD1 DNA test to take into account our new understanding of CORD1 in Dachshunds. As soon as the new test is available full information will appear on our website .
The Animal Health Trust 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 dystrophy in this breed.
Below are the publications that detail the findings to date.
1. Mellersh, C.S., M.E. Boursnell, L. Pettitt, E.J. Ryder, N.G. Holmes, D. Grafham, . . . M. Vaudin, Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 2006; 88(3): p. 293-301.
2. Miyadera, K., K. Kato, J. Aguirre-Hernandez, T. Tokuriki, K. Morimoto, C. Busse, . . . D.R. Sargan, Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis 2009; 15: p. 2287-305.
3. Busse, C., K.C. Barnett, C.S. Mellersh, and V.J. Adams, Ophthalmic and cone derived electrodiagnostic findings in outbred Miniature Long-haired Dachshunds homozygous for a RPGRIP1 mutation. Veterinary Ophthalmology 2011; 14(3): p. 146-52.
4. Miyadera, K., K. Kato, M. Boursnell, C.S. Mellersh, and D.R. Sargan, Genome-wide association study in RPGRIP1 (-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mammalian Genome 2012; 23(1-2): p. 212-23.
5. Forman, O.P., R.J. Hitti, M. Boursnell, K. Miyadera, D. Sargan, and C. Mellersh, Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration. Mamm Genome 2016.