TSEN54 missense variant in Standard Schnauzers with leukodystrophy

Autoři: Theresa Störk aff001;  Jasmin Nessler aff002;  Linda Anderegg aff003;  Enrice Hünerfauth aff002;  Isabelle Schmutz aff003;  Vidhya Jagannathan aff003;  Kaisa Kyöstilä aff004;  Hannes Lohi aff004;  Wolfgang Baumgärtner aff001;  Andrea Tipold aff002;  Tosso Leeb aff003
Působiště autorů: Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany aff001;  Department for Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany aff002;  Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland aff003;  Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland aff004;  Folkhälsan Research Center, Helsinki, Finland aff005;  Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland aff006
Vyšlo v časopise: TSEN54 missense variant in Standard Schnauzers with leukodystrophy. PLoS Genet 15(10): e1008411. doi:10.1371/journal.pgen.1008411
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008411


We report a hereditary leukodystrophy in Standard Schnauzer puppies. 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. 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. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. 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. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.

Klíčová slova:

Central nervous system – Dogs – Magnetic resonance imaging – Mammalian genomics – Pets and companion animals – Variant genotypes – Veterinary medicine – Cerebrum


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