OMIA:001432-9615 : Cone-rod dystrophy 4 in Canis lupus familiaris
Categories: Vision / eye phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 608194 (trait) , 613826 (trait) , 605446 (gene) , 610070 (gene)
Links to MONDO diseases: No links.
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".
Ripolles-Garcia et al. (2023) "report mapping of L3 as an additional modifier locus, within a 4.1-Mb locus on canine chromosome 30. We establish the natural disease history of RPGRIP1-CRD based on up to nine-year long-term functional and structural retinal data from 58 dogs including 44 RPGRIP1 mutants grouped according to the modifier status. RPGRIP1 mutants affected by both MAP9 and L3 modifiers exhibited the most severe phenotypes with rapid disease progression. MAP9 alone was found to act as an overall accelerator of rod and cone diseases, while L3 had a cone-specific effect."
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.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|ASIP||agouti signaling protein||Homo sapiens||20||NC_000020.11 (34186493..34269344)||ASIP||Homologene, Ensembl , NCBI gene|
|RPGRIP1||retinitis pigmentosa GTPase regulator interacting protein 1||Canis lupus familiaris||15||NC_051819.1 (18575495..18646528)||RPGRIP1||Homologene, Ensembl , NCBI gene|
|MAP9||microtubule-associated protein 9||Canis lupus familiaris||15||NC_051819.1 (53638052..53583032)||MAP9||Homologene, Ensembl , NCBI gene|
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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.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|943||Miniature Long-haired Dachsund||Cone-rod dystrophy 4||MAP9||deletion, gross (>20)||Naturally occurring variant||CanFam3.1||15||g.52905336_52927296del||c.75+181_1378-215del||XM_005629374.1; 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 size of the deletion based on genome build CanFam3.1 MAP9_corrected is 21,961 bp, with deletion breakpoints in intron 10 of MAP9 and MAP9."||2016||27017229|
|699||Miniature Long-haired Dachsund||Cone-rod dystrophy 4||RPGRIP1||insertion, gross (>20)||Naturally occurring variant||CanFam3.1||15||g.18332036_18332037ins[A;GGAAGCAACAGGATG]||c.142_143ins[A;GGAAGCAACAGGATG]||p.(I49Kfs*26)||NM_001313773.1; NP_001300702.1; published as a 44-bp insertion in exon 2 of the RPGRIP1 gene; comprising a poly(A) stretch flanked by a perfect 15-bp duplication: g.8228_8229insA29GGAAGCAACAGGATG||2006||16806805|
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.
|2023||Ripolles-Garcia, A., Murgiano, L., Ziolkowska, N., Marinho, F.P., Roszak, K., Iffrig, S., Aguirre, G.D., Miyadera, K. :|
|Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci. Hum Mol Genet :, 2023. Pubmed reference: 36951959 . DOI: 10.1093/hmg/ddad046.|
|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., 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.|
|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.|
|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., 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., 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.|
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