OMIA:002215-9615 : Leukodystrophy, TSEN54-related in Canis lupus familiaris
Categories: Nervous system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 610204 (trait) , 277470 (trait) , 225753 (trait) , 608755 (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: 2019
Inheritance: Störk et al. (2019): "The occurrence of leukodystrophy in multiple consecutive litters from related parents suggested an inherited disease. Pedigree analysis of the four affected puppies no. 1–4 revealed several inbreeding loops and was suggestive for a monogenic autosomal recessive inheritance".
Mapping: Linkage and homozygosity mapping of four affecteds, five normal littermates, and four parents of affecteds, each genotyped with an llumina CanineHD BeadChip, yielding 88,546 informative markers, enabled Störk et al. (2019) to identify "Eight [candidate] genomic segments on six different chromosomes with a total of 29,237,328 bp or roughly 1.2% of the 2.4 Gb dog genome".
Markers: Störk et al. (2019): "The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds."
Molecular basis: Comparison of private homozygous protein-changing variants in whole-genome sequence data from one affected dog with "control genome sequences from 8 wolves and 213 dogs" enabled Störk et al. (2019) to identify the likely causal variant as "a missense variant affecting exon 5 of the TSEN54 gene", namely "Chr9:5,015,506C>T (CanFam 3.1 assembly) . . . XM_540434.6:c.371G>A . . . XP_540434.3:p.(Gly124Asp)".
Clinical features: Störk et al. (2019): "Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect."
Pathology: Störk et al. (2019): "Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy." In humans, TSEN54 variants cause a phenotype termed pontocerebellar hypoplasia, which is quite distinct from the phenotype seen in dogs. In dogs, the lesions predominantly concern the white matter of the cerebrum (Störk et al., 2019).
Breed: Standard Schnauzer.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|TSEN54||TSEN54 tRNA splicing endonuclease subunit||Canis lupus familiaris||9||NC_051813.1 (5686738..5679689)||TSEN54||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|
|1130||Standard Schnauzer||Leukodystrophy, TSEN54-related||TSEN54||missense||Naturally occurring variant||CanFam3.1||9||g.5015506C>T||c.371G>A||p.(G124D)||XM_540434.6; XP_540434.3||2019||31584937|
|2019||Störk, T., Nessler, J., Anderegg, L., Hünerfauth, E., Schmutz, I., Jagannathan, V., Kyöstilä, K., Lohi, H., Baumgärtner, W., Tipold, A., Leeb, T. :|
|TSEN54 missense variant in Standard Schnauzers with leukodystrophy. PLoS Genet 15:e1008411, 2019. Pubmed reference: 31584937 . DOI: 10.1371/journal.pgen.1008411.|
- Changed by Frank Nicholas on 22 Oct 2019
- Created by Frank Nicholas on 22 Oct 2019
- Changed by Tosso Leeb on 23 Oct 2019
- Changed by Frank Nicholas on 23 Oct 2019