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OMIA 002179-9615 : Stargardt disease 1 in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 248200 (trait) , 601691 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Molecular basis: Mäkeläinen et al. (2019): "To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing [WGS] of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified." These same authors genotyped "eight additional clinically affected and fourteen unaffected Labrador retrievers. Out of these 22 dogs, 16 were related to the family quartet used in the WGS . . . . all eight affected individuals were homozygous for the ABCA4 insertion and the 14 unaffected individuals were either heterozygous or homozygous for the wild-type allele".

Clinical features: Mäkeläinen et al. (2019): "The affected sib-pair . . . was visually impaired under both daylight and dimlight conditions when examined at 10 years of age. Their pupils were dilated under daylight conditions and pupillary light and dazzle reflexes were abnormal, whereas menace responses were present. On indirect ophthalmoscopy, the tapetal reflectivity varied between normal to grayish hyporeflection when the indirect ophthalmoscopy lens was tilted slightly back and forth, both in the visual streak, as well as in the more peripheral parts of the tapetal fundus in both eyes of the affected dogs. The visual streak is an area of high photoreceptor cell density in the canine retina, located superior to the optic disc and extending horizontally from the nasal to the temporal region . . . . Furthermore, a mild to moderate vascular attenuation was observed, as seen in the fundus photograph, taken at the age of 10 years, of the affected male (LAB4) and compared to a fundus photograph of an unaffected, age-matched Labrador retriever dog (LAB27) . . . . These ophthalmoscopic findings were symmetrical between the eyes of the affected dogs, diffusely spread over the tapetal fundus and not strictly confined to the visual streak or area centralis."

Ekesten et al. (2022) studied "retinal appearance and morphology in Labrador retrievers (LRs) heterozygous and homozygous for an ABCA4 loss-of-function mutation. ... Abnormal appearance and morphology in the fovea equivalent are present in juvenile ABCA4InsC/InsC. In the older affected LRs, the visual streak and then the peripheral retina also develop an abnormal appearance. Vision deteriorates slowly, but some vision is retained throughout life. Older heterozygotes may show a mild retinal phenotype but no obvious visual impairment."

Breed: Labrador Retriever.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4 Canis lupus familiaris 6 NC_051810.1 (55434279..55561973) ABCA4 Homologene, Ensembl, NCBI gene

Variants

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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
1050 Labrador Retriever Stargardt disease 1 ABCA4 insertion, small (<=20) Naturally occurring variant CanFam3.1 6 g.55146556dup c.4176dup p.(F1393Lfs*3) Mäkeläinen et al. (2019): "ENSCAFT00000005367 exon28 4170dupC* V1390fs" Importantly, the same authors also explain in Table S3 that "*The insertion is found in a cytosine mononucleotide-repeat region [55,146,550–55,146,556] and it is arbitrary at what position the actual insertion occurs. In the text we have denoted the insertion as c.4176insC, p.F1393Lfs*1395)." Variant information changed to reflect HGVS nomenclature 2019 30889179
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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.
2022 Ekesten, B., Mäkeläinen, S., Ellis, S., Kjellström, U., Bergström, T.F. :
Abnormal appearance of the area centralis in Labrador Retrievers with an ABCA4 loss-of-function mutation. Transl Vis Sci Technol 11:36, 2022. Pubmed reference: 35201338. DOI: 10.1167/tvst.11.2.36.
2019 Mäkeläinen, S., Gòdia, M., Hellsand, M., Viluma, A., Hahn, D., Makdoumi, K., Zeiss, C.J., Mellersh, C., Ricketts, S.L., Narfström, K., Hallböök, F., Ekesten, B., Andersson, G., Bergström, T.F. :
An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease. PLoS Genet 15:e1007873, 2019. Pubmed reference: 30889179. DOI: 10.1371/journal.pgen.1007873.
2010 Zangerl, B., Lindauer, S.J., Acland, G.M., Aguirre, G.D. :
Identification of genetic variation and haplotype structure of the canine ABCA4 gene for retinal disease association studies. Mol Genet Genomics 284:243-50, 2010. Pubmed reference: 20661590.
2006 Lippmann, T., Pasternack, S.M., Kraczyk, B., Dudek, S.E., Dekomien, G. :
Indirect exclusion of four candidate genes for generalized progressive retinal atrophy in several breeds of dogs. J Negat Results Biomed 5:19, 2006. Pubmed reference: 17134500. DOI: 10.1186/1477-5751-5-19.
2004 Kijas, J.W., Zangerl, B., Miller, B., Nelson, J., Kirkness, E.F., Aguirre, G.D., Acland, G.M. :
Cloning of the canine ABCA4 gene and evaluation in canine cone-rod dystrophies and progressive retinal atrophies. Mol Vis 10:223-32, 2004. Pubmed reference: 15064680.

Edit History


  • Created by Frank Nicholas on 25 Mar 2019
  • Changed by Frank Nicholas on 25 Mar 2019
  • Changed by Imke Tammen2 on 11 Sep 2022