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A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia

Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance...

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Autores principales: Letko, Anna, Dietschi, Elisabeth, Nieburg, Marco, Jagannathan, Vidhya, Gurtner, Corinne, Oevermann, Anna, Drögemüller, Cord
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562999/
https://www.ncbi.nlm.nih.gov/pubmed/31083464
http://dx.doi.org/10.3390/genes10050362
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author Letko, Anna
Dietschi, Elisabeth
Nieburg, Marco
Jagannathan, Vidhya
Gurtner, Corinne
Oevermann, Anna
Drögemüller, Cord
author_facet Letko, Anna
Dietschi, Elisabeth
Nieburg, Marco
Jagannathan, Vidhya
Gurtner, Corinne
Oevermann, Anna
Drögemüller, Cord
author_sort Letko, Anna
collection PubMed
description Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance in Alpine Dachsbracke dogs. We investigated two related litters in which four cases were reported. Neuropathology of two dogs revealed spongy degeneration associated with axonal degeneration. Combined genetic linkage and autozygosity analyses in four cases and eight related controls showed one critical disease-associated interval on chromosomes 27. Private whole-genome sequence variants of one ataxia case against 600 unrelated controls revealed one protein-changing variant within the critical interval in the SCN8A gene (c.4898G>T; p.Gly1633Val). Perfect segregation with the phenotype was confirmed by genotyping >200 Alpine Dachsbracke dogs. SCN8A encodes a voltage-gated sodium channel and the missense variant was predicted deleterious by three different in silico prediction tools. Pathogenic variants in SCN8A were previously reported in humans with ataxia, pancerebellar atrophy, and cognitive disability. Furthermore, cerebellar ataxia syndrome in the ‘jolting’ mutant mice is caused by a missense variant in Scn8a. Therefore, we considered the SCN8A:c.4898G>T variant to be the most likely cause for recessively inherited spinocerebellar ataxia in Alpine Dachsbracke dogs.
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spelling pubmed-65629992019-06-17 A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia Letko, Anna Dietschi, Elisabeth Nieburg, Marco Jagannathan, Vidhya Gurtner, Corinne Oevermann, Anna Drögemüller, Cord Genes (Basel) Article Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance in Alpine Dachsbracke dogs. We investigated two related litters in which four cases were reported. Neuropathology of two dogs revealed spongy degeneration associated with axonal degeneration. Combined genetic linkage and autozygosity analyses in four cases and eight related controls showed one critical disease-associated interval on chromosomes 27. Private whole-genome sequence variants of one ataxia case against 600 unrelated controls revealed one protein-changing variant within the critical interval in the SCN8A gene (c.4898G>T; p.Gly1633Val). Perfect segregation with the phenotype was confirmed by genotyping >200 Alpine Dachsbracke dogs. SCN8A encodes a voltage-gated sodium channel and the missense variant was predicted deleterious by three different in silico prediction tools. Pathogenic variants in SCN8A were previously reported in humans with ataxia, pancerebellar atrophy, and cognitive disability. Furthermore, cerebellar ataxia syndrome in the ‘jolting’ mutant mice is caused by a missense variant in Scn8a. Therefore, we considered the SCN8A:c.4898G>T variant to be the most likely cause for recessively inherited spinocerebellar ataxia in Alpine Dachsbracke dogs. MDPI 2019-05-10 /pmc/articles/PMC6562999/ /pubmed/31083464 http://dx.doi.org/10.3390/genes10050362 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Letko, Anna
Dietschi, Elisabeth
Nieburg, Marco
Jagannathan, Vidhya
Gurtner, Corinne
Oevermann, Anna
Drögemüller, Cord
A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
title A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
title_full A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
title_fullStr A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
title_full_unstemmed A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
title_short A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
title_sort missense variant in scn8a in alpine dachsbracke dogs affected by spinocerebellar ataxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562999/
https://www.ncbi.nlm.nih.gov/pubmed/31083464
http://dx.doi.org/10.3390/genes10050362
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