TSEN54 missense variant in Standard Schnauzers with leukodystrophy.

Störk, Theresa; Nessler, Jasmin; Anderegg, Linda; Hünerfauth, Enrice; Schmutz, Isabelle; Jagannathan, Vidya; Kyöstilä, Kaisa; Lohi, Hannes; Baumgärtner, Wolfgang; Tipold, Andrea; Leeb, Tosso (2019). TSEN54 missense variant in Standard Schnauzers with leukodystrophy. PLoS genetics, 15(10), e1008411. Public Library of Science 10.1371/journal.pgen.1008411

[img]
Preview
Text (uncorrected proof)
epub__journal.pgen.1008411.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (27MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Anderegg, Linda; Schmutz, Isabelle; Jagannathan, Vidya and Leeb, Tosso

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1553-7390

Publisher:

Public Library of Science

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

08 Oct 2019 10:45

Last Modified:

24 Oct 2019 14:34

Publisher DOI:

10.1371/journal.pgen.1008411

PubMed ID:

31584937

BORIS DOI:

10.7892/boris.133748

URI:

https://boris.unibe.ch/id/eprint/133748

Actions (login required)

Edit item Edit item
Provide Feedback