OMIA 001432-9615 : Cone-rod dystrophy 4 in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 608194 , 613826

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Cross-species summary: This disorder has been renamed in OMIA on the basis of the review by Miyadera et al. (2012)

Species-specific name: Early-onset cone-rod dystrophy

Species-specific symbol: cord1; crd4

Mapping: By conducting a GWAS on 31 affected and 49 control Miniature longhaired dachshunds, each genotyped with the Canine SNP20 SNP chip, Miyadera et al. (2012) highlighted a region on chromosome CFA15.

Molecular basis: In miniature longhaired dachshunds with this disorder, Mellersh et al. (2006) discovered a 44-bp insertion in exon 2 of the RPGRIP1 gene that encodes retinitis pigmentosa GTPase regulator-interacting protein 1. The insertion results in a frameshift, which in turn creates a premature stop codon. At the time, this appeared to be the causative mutation, and was so listed in OMIA. However, subsequent studies (Miyadera et al., 2009; Busse et al., 2011; Miyadera et al., 2012; Mammalian Genome 23: 212-223) raised some doubts about this conclusion. These doubts were confirmed by Kuznetsova et al. (2012). This disorder was, therefore, re-categorised in OMIA as being without a known causative mutation.

The PlosONE paper by Miyadera et al. (2012) has caused the above decision to be reversed! These authors commenced by noting that RGRIP1 is the key gene for the homologous human disorder and that there is no other possible candidate gene in canine mapped region. Tellingly, they provide substantial evidence for "leakiness" of the causal insertion in RGRIP1 attributable to "transcriptional or translational frameshifting in RPGRIP1 expression" which occurs at levels "unprecedented in eukaryotic cellular genes". They conclude that "The frameshifting observed here can contribute to leakiness of the RPGRIP1−/− mutation in vivo in cord1 dogs, accounting for the survival of vision in some affected animals until late in life". These authors also suspect that the extent of "leakiness" is affected by alleles at a modifier locus first reported by Miyadera et al. (2012; Mammalian Genome 23: 212-223). On the strength of these conclusions, RGRIP1 has been reinstated as an important key gene for this disorder!

Forman et al. (2016) reported progress in identifying the modifier locus reported by Miyadera et al. (2012; Mammalian Genome 23: 212-223), namely an approximately 22kb deletion "approximately 30 Mb upstream of RPGRIP1 . . . The deletion breakpoints were identified in MAP9 intron 10 and in a downstream partial MAP9 pseudogene. The fusion of these two genes, which we have called MAP9 EORD (microtubule-associated protein, early onset retinal degeneration), is in frame and is expressed at the RNA level, with the 3' region containing several predicted deleterious variants. We speculate that MAP9 associates with α-tubulin in the basal body of the cilium. RPGRIP1 is also known to locate to the cilium, where it is closely associated with RPGR. RPGRIP1 mutations also cause redistribution of α-tubulin away from the ciliary region in photoreceptors. Hence, a MAP9 partial deficit is a particularly attractive candidate to synergise with a partial RPGRIP1 deficit to cause a more serious disease."

Upon finding that the combination of the RPGRIP1 and MAP9 variants was not sufficient to explain all cases, Das et al. (2107) concluded "that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to cone-specific functional and morphologic defects".

Clinical features: "The earliest ophthalmoscopic signs, which include changes in the granular appearance of the tapetal fundus followed by generalized tapetal hyperreflectivity and retinal vascular attenuation, are detectable at approximately 6 months of age. The electroretinogram of affected dogs is typically normal in waveform and latency at 10 weeks of age but markedly reduced in amplitude or even virtually extinguished by 9 months." (Mellersh et al., 2006)

Pathology: "Significant histological changes are visible at 10.5 weeks of age, including thinning of the outer nuclear layer, irregularity and attenuation of the rod photoreceptor outer segments, and early disorganization of the rod outer segment disc lamellae, and by 25 weeks the photoreceptors are grossly degenerate." (Mellersh et al., 2006)

Breed: Miniature Long-haired Dachsund.

Associated genes:

Symbol Description Species Chr Location OMIA gene details page Other Links
RPGRIP1 retinitis pigmentosa GTPase regulator interacting protein 1 Canis lupus familiaris 15 NC_006597.3 (18316887..18388724) RPGRIP1 Homologene, Ensembl, NCBI gene
MAP9 microtubule-associated protein 9 Canis lupus familiaris 15 NC_006597.3 (52930275..52895062) MAP9 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Miniature Long-haired Dachsund Cone-rod dystrophy 4 MAP9 deletion, gross (>20) An approximately 22kb deletion "approximately 30 Mb upstream of RPGRIP1 . . . The deletion breakpoints were identified in MAP9 intron 10 and in a downstream partial MAP9 pseudogene." 2016 27017229
Miniature Long-haired Dachsund Cone-rod dystrophy 4 RPGRIP1 insertion, gross (>20) a 44-bp insertion in exon 2 of the RPGRIP1 gene 2006 16806805

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2018 Das, R.G., Marinho, F.P., Iwabe, S., Santana, E., McDaid, K.S., Aguirre, G.D., Miyadera, K. :
Author Correction: Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology. Sci Rep 8:13058, 2018. Pubmed reference: 30139995. DOI: 10.1038/s41598-018-31337-1.
2017 Das, R.G., Marinho, F.P., Iwabe, S., Santana, E., McDaid, K.S., Aguirre, G.D., Miyadera, K. :
Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology. Sci Rep 7:12823, 2017. Pubmed reference: 28993665. DOI: 10.1038/s41598-017-13112-w.
2016 Forman, O.P., Hitti, R.J., Boursnell, M., Miyadera, K., Sargan, D., Mellersh, C. :
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 27:237-45, 2016. Pubmed reference: 27017229. DOI: 10.1007/s00335-016-9627-x.
2014 Lhériteau, E., Petit, L., Weber, M., Le Meur, G., Deschamps, J.Y., Libeau, L., Mendes-Madeira, A., Guihal, C., François, A., Guyon, R., Provost, N., Lemoine, F., Papal, S., El-Amraoui, A., Colle, M.A., Moullier, P., Rolling, F. :
Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. Mol Ther 22:265-277, 2014. Pubmed reference: 24091916. DOI: 10.1038/mt.2013.232.
2012 Kuznetsova, T., Iwabe, S., Boesze-Battaglia, K., Pearce-Kelling, S., Chang-Min, Y., McDaid, K., Miyadera, K., Komaromy, A., Aguirre, G.D. :
Exclusion of RPGRIP1 ins44 from Primary Causal Association with Early-Onset Cone-Rod Dystrophy in Dogs. Invest Ophthalmol Vis Sci 53:5486-501, 2012. Pubmed reference: 22807295. DOI: 10.1167/iovs.12-10178.
Kuznetsova, T., Zangerl, B., Aguirre, G.D. :
RPGRIP1 and Cone-Rod Dystrophy in Dogs. Adv Exp Med Biol 723:321-8, 2012. Pubmed reference: 22183349. DOI: 10.1007/978-1-4614-0631-0_42.
Miyadera, K., Acland, G.M., Aguirre, G.D. :
Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23:40-61, 2012. Pubmed reference: 22065099. DOI: 10.1007/s00335-011-9361-3.
Miyadera, K., Brierley, I., Aguirre-Hernández, J., Mellersh, C.S., Sargan, D.R. :
Multiple mechanisms contribute to leakiness of a frameshift mutation in canine cone-rod dystrophy. PLoS One 7:e51598, 2012. Pubmed reference: 23251588. DOI: 10.1371/journal.pone.0051598.
Miyadera, K., Kato, K., Boursnell, M., Mellersh, C.S., Sargan, D.R. :
Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mamm Genome 23:212-23, 2012. Pubmed reference: 22193413. DOI: 10.1007/s00335-011-9384-9.
2011 Busse, C., Barnett, K.C., Mellersh, C.S., Adams, V.J. :
Ophthalmic and cone derived electrodiagnostic findings in outbred Miniature Long-haired Dachshunds homozygous for a RPGRIP1 mutation. Vet Ophthalmol 14:146-52, 2011. Pubmed reference: 21521437. DOI: 10.1111/j.1463-5224.2010.00848.x.
Kuznetsova, T., Zangerl, B., Goldstein, O., Acland, G.M., Aguirre, G.D. :
Structural organization and expression pattern of the canine RPGRIP1 isoforms in retinal tissue. Invest Ophthalmol Vis Sci 52:2989-98, 2011. Pubmed reference: 21282582. DOI: 10.1167/iovs.10-6094.
2009 Lhériteau, E., Libeau, L., Stieger, K., Deschamps, J.Y., Mendes-Madeira, A., Provost, N., Lemoine, F., Mellersh, C., Ellinwood, N.M., Cherel, Y., Moullier, P., Rolling, F. :
The RPGRIP1-deficient dog, a promising canine model for gene therapy. Mol Vis 15:349-61, 2009. Pubmed reference: 19223988.
Miyadera, K., Kato, K., Aguirre-Hernández, J., Tokuriki, T., Morimoto, K., Busse, C., Barnett, K., Holmes, N., Ogawa, H., Sasaki, N., Mellersh, C.S., Sargan, D.R. :
Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis 15:2287-305, 2009. Pubmed reference: 19936303.
2007 Turney, C., Chong, N.H., Alexander, R.A., Hogg, C.R., Fleming, L., Flack, D., Barnett, K.C., Bird, A.C., Holder, G.E., Luthert, P.J. :
Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund. Invest Ophthalmol Vis Sci 48:4240-9, 2007. Pubmed reference: 17724213. DOI: 10.1167/iovs.04-0737.
2006 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 88:293-301, 2006. Pubmed reference: 16806805. DOI: 10.1016/j.ygeno.2006.05.004.
1993 Curtis, R., Barnett, K.C. :
Progressive Retinal Atrophy in Miniature Longhaired Dachshund Dogs British Veterinary Journal 149:71-85, 1993. Pubmed reference: 8439801. DOI: 10.1016/S0007-1935(05)80211-8.
1965 Barnett, K.C. :
Canine retinopathies–III. The other breeds. Journal of Small Animal Practice 6:185-196, 1965.

Edit History


  • Created by Frank Nicholas on 25 Aug 2006
  • Changed by Frank Nicholas on 26 Sep 2011
  • Changed by Frank Nicholas on 06 Dec 2011
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  • Changed by Frank Nicholas on 20 Jan 2018