<i>RALGAPA1</i> 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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MDPI AG
2023-07-01
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| Online Access: | https://www.mdpi.com/2073-4425/14/8/1520 |
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| author | Matthias Christen Isabel Zdora Michael Leschnik Vidhya Jagannathan Christina Puff Enrice Hünerfauth Holger A. Volk Wolfgang Baumgärtner Tessa C. Koch Wencke Schäfer Miriam Kleiter Tosso Leeb |
| author_facet | Matthias Christen Isabel Zdora Michael Leschnik Vidhya Jagannathan Christina Puff Enrice Hünerfauth Holger A. Volk Wolfgang Baumgärtner Tessa C. Koch Wencke Schäfer Miriam Kleiter Tosso Leeb |
| author_sort | Matthias Christen |
| collection | DOAJ |
| 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 <i>RALGAPA1</i> 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 <i>RALGAPA1</i> develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about <i>RALGAPA1</i> variants and their functional impact in other species, suggest the <i>RALGAPA1</i> deletion is the likely causative defect for the observed phenotype in the affected dogs. |
| first_indexed | 2024-03-10T23:55:18Z |
| format | Article |
| id | doaj.art-62b6e350404948e7ae7c682e607c40b5 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T23:55:18Z |
| publishDate | 2023-07-01 |
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| series | Genes |
| spelling | doaj.art-62b6e350404948e7ae7c682e607c40b52023-11-19T01:14:21ZengMDPI AGGenes2073-44252023-07-01148152010.3390/genes14081520<i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar AtaxiaMatthias Christen0Isabel Zdora1Michael Leschnik2Vidhya Jagannathan3Christina Puff4Enrice Hünerfauth5Holger A. Volk6Wolfgang Baumgärtner7Tessa C. Koch8Wencke Schäfer9Miriam Kleiter10Tosso Leeb11Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, SwitzerlandDepartment of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyDepartment for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, SwitzerlandDepartment of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyDepartment of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyDepartment of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyDepartment of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyBundeswehr School of Dog Handling, 56766 Ulmen, GermanyBundeswehr School of Dog Handling, 56766 Ulmen, GermanyDepartment for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaInstitute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, SwitzerlandSeveral 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 <i>RALGAPA1</i> 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 <i>RALGAPA1</i> develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about <i>RALGAPA1</i> variants and their functional impact in other species, suggest the <i>RALGAPA1</i> deletion is the likely causative defect for the observed phenotype in the affected dogs.https://www.mdpi.com/2073-4425/14/8/1520<i>Canis lupus familiaris</i>neurologyneurogeneticscerebellum<i>GARNL1</i>precision medicine |
| spellingShingle | Matthias Christen Isabel Zdora Michael Leschnik Vidhya Jagannathan Christina Puff Enrice Hünerfauth Holger A. Volk Wolfgang Baumgärtner Tessa C. Koch Wencke Schäfer Miriam Kleiter Tosso Leeb <i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia Genes <i>Canis lupus familiaris</i> neurology neurogenetics cerebellum <i>GARNL1</i> precision medicine |
| title | <i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia |
| title_full | <i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia |
| title_fullStr | <i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia |
| title_full_unstemmed | <i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia |
| title_short | <i>RALGAPA1</i> Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia |
| title_sort | i ralgapa1 i deletion in belgian shepherd dogs with cerebellar ataxia |
| topic | <i>Canis lupus familiaris</i> neurology neurogenetics cerebellum <i>GARNL1</i> precision medicine |
| url | https://www.mdpi.com/2073-4425/14/8/1520 |
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