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RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia

Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping...

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Autores principales: Christen, Matthias, Zdora, Isabel, Leschnik, Michael, Jagannathan, Vidhya, Puff, Christina, Hünerfauth, Enrice, Volk, Holger A., Baumgärtner, Wolfgang, Koch, Tessa C., Schäfer, Wencke, Kleiter, Miriam, Leeb, Tosso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454311/
https://www.ncbi.nlm.nih.gov/pubmed/37628572
http://dx.doi.org/10.3390/genes14081520
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author Christen, Matthias
Zdora, Isabel
Leschnik, Michael
Jagannathan, Vidhya
Puff, Christina
Hünerfauth, Enrice
Volk, Holger A.
Baumgärtner, Wolfgang
Koch, Tessa C.
Schäfer, Wencke
Kleiter, Miriam
Leeb, Tosso
author_facet Christen, Matthias
Zdora, Isabel
Leschnik, Michael
Jagannathan, Vidhya
Puff, Christina
Hünerfauth, Enrice
Volk, Holger A.
Baumgärtner, Wolfgang
Koch, Tessa C.
Schäfer, Wencke
Kleiter, Miriam
Leeb, Tosso
author_sort Christen, Matthias
collection PubMed
description Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype–phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.
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spelling pubmed-104543112023-08-26 RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia Christen, Matthias Zdora, Isabel Leschnik, Michael Jagannathan, Vidhya Puff, Christina Hünerfauth, Enrice Volk, Holger A. Baumgärtner, Wolfgang Koch, Tessa C. Schäfer, Wencke Kleiter, Miriam Leeb, Tosso Genes (Basel) Article Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype–phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs. MDPI 2023-07-25 /pmc/articles/PMC10454311/ /pubmed/37628572 http://dx.doi.org/10.3390/genes14081520 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Christen, Matthias
Zdora, Isabel
Leschnik, Michael
Jagannathan, Vidhya
Puff, Christina
Hünerfauth, Enrice
Volk, Holger A.
Baumgärtner, Wolfgang
Koch, Tessa C.
Schäfer, Wencke
Kleiter, Miriam
Leeb, Tosso
RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia
title RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia
title_full RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia
title_fullStr RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia
title_full_unstemmed RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia
title_short RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia
title_sort ralgapa1 deletion in belgian shepherd dogs with cerebellar ataxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454311/
https://www.ncbi.nlm.nih.gov/pubmed/37628572
http://dx.doi.org/10.3390/genes14081520
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