Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608194 (trait) , 613826 (trait) , 605446 (gene) , 610070 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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, RPGRIP1-CRD

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."
Donner and Mellersh (2024) genotyped the RPGRIP1 (omia.variant:699) and MAP9 (omia.variant:943) in at least 50 dogs of 132 diverse breeds and identified that both variants were present in multipel breeds. The authors concluded: "data indicate that both variants are likely to be ancient and predate the development and genetic isolation of modern dog breeds. That both variants are present individually at high frequency in multiple breeds is consistent with the hypothesis that homozygosity of either variant alone is not associated with a clinically relevant phenotype, whereas the negative correlation between the two variants is consistent with the application of selective pressure, from dog breeders, against homozygosity at both loci, probably due to the more severe phenotype associated with homozygosity at both loci."

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: Dachshund, Miniature Long-Haired (Dog) (VBO_0200409).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated genes: