Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.

We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combi...

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Autores principales:	Matthias Christen, Sandra Högler, Miriam Kleiter, Michael Leschnik, Corinna Weber, Denise Thaller, Vidhya Jagannathan, Tosso Leeb
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/a4433329618249db880debd806cd5ddf
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spelling	oai:doaj.org-article:a4433329618249db880debd806cd5ddf2021-12-02T20:02:53ZDeletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.1553-73901553-740410.1371/journal.pgen.1009716https://doaj.org/article/a4433329618249db880debd806cd5ddf2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009716https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, Chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of SELENOP and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping >600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. Selenop-/- knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the SELENOP gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.Matthias ChristenSandra HöglerMiriam KleiterMichael LeschnikCorinna WeberDenise ThallerVidhya JagannathanTosso LeebPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 8, p e1009716 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Matthias Christen Sandra Högler Miriam Kleiter Michael Leschnik Corinna Weber Denise Thaller Vidhya Jagannathan Tosso Leeb Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.
description	We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, Chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of SELENOP and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping >600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. Selenop-/- knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the SELENOP gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.
format	article
author	Matthias Christen Sandra Högler Miriam Kleiter Michael Leschnik Corinna Weber Denise Thaller Vidhya Jagannathan Tosso Leeb
author_facet	Matthias Christen Sandra Högler Miriam Kleiter Michael Leschnik Corinna Weber Denise Thaller Vidhya Jagannathan Tosso Leeb
author_sort	Matthias Christen
title	Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.
title_short	Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.
title_full	Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.
title_fullStr	Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.
title_full_unstemmed	Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.
title_sort	deletion of the selenop gene leads to cns atrophy with cerebellar ataxia in dogs.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a4433329618249db880debd806cd5ddf
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Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.

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