TSEN54 missense variant in Standard Schnauzers with leukodystrophy

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http://hdl.handle.net/10138/309167

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Störk , T , Nessler , J , Anderegg , L , Huenerfauth , E , Schmutz , I , Jagannathan , V , Kyöstilä , K , Lohi , H , Baumgaertner , W , Tipold , A & Leeb , T 2019 , ' TSEN54 missense variant in Standard Schnauzers with leukodystrophy ' , PLoS Genetics , vol. 15 , no. 10 , 1008411 . https://doi.org/10.1371/journal.pgen.1008411

Title: TSEN54 missense variant in Standard Schnauzers with leukodystrophy
Author: Störk, Theresa; Nessler, Jasmin; Anderegg, Linda; Huenerfauth, Enrice; Schmutz, Isabelle; Jagannathan, Vidhya; Kyöstilä, Kaisa; Lohi, Hannes; Baumgaertner, Wolfgang; Tipold, Andrea; Leeb, Tosso
Contributor: University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Helsinki One Health (HOH)
Date: 2019-10
Language: eng
Number of pages: 21
Belongs to series: PLoS Genetics
ISSN: 1553-7404
URI: http://hdl.handle.net/10138/309167
Abstract: 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.
Subject: FATAL INFANTILE ENCEPHALOPATHY
GLOBOID-CELL LEUKODYSTROPHY
CENTRAL-NERVOUS-SYSTEM
OLIVOPONTOCEREBELLAR HYPOPLASIA
AXONAL DAMAGE
GENE
ABNORMALITIES
MUTATIONS
GENOME
DEMYELINATION
1184 Genetics, developmental biology, physiology
413 Veterinary science
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