TSEN54 missense variant in Standard Schnauzers with leukodystrophy

• DOI: 10.1371/journal.pgen.1008411
• Publication Date: 2019-10-04T17:31:50Z
• Authors: Theresa Störk; Jasmin Nessler; Linda Anderegg; Enrice Hünerfauth; Isabelle Schmutz; Vidhya Jagannathan; Kaisa Kyöstilä; Hannes Lohi; Wolfgang Baumgärtner; Andrea Tipold; Tosso Leeb
• Keywords: Disease gene identification

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 ventral strabismus consistent with diffuse intracranial lesion. Magnetic resonance imaging revealed white matter disease without mass effect. Macroscopically, the cerebral showed gelatinous texture centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, severe multifocal reduction myelin formation moderate edema inflammation detected leading to diagnosis leukodystrophy. Combined linkage analysis homozygosity mapping two related families delineated critical intervals approximately 29 Mb. The comparison whole genome sequence data one affected 221 control genomes single private homozygous protein changing variant intervals, TSEN54:c.371G>A p.(Gly124Asp). TSEN54 encodes tRNA splicing endonuclease subunit 54. In humans, several variants were reported cause different types pontocerebellar hypoplasia. genotypes c.371G>A perfectly associated phenotype 12 Schnauzers almost 1000 dogs from breeds. These results suggest that causes identification candidate causative enables genetic testing so unintentional breeding can be avoided future. Our findings extend known genotype-phenotype correlation for variants.