{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:15:05Z","timestamp":1791335705133,"version":"4.3.1"},"reference-count":27,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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 \u03b1 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\u2013phenotype 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.<\/jats:p>","DOI":"10.3390\/genes14081520","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:45:02Z","timestamp":1690332302000},"page":"1520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3275-5929","authenticated-orcid":false,"given":"Matthias","family":"Christen","sequence":"first","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Zdora","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"},{"name":"Center of Systems Neuroscience, Hannover Graduate School for Neurosciences, Infection Medicine, and Veterinary Sciences (HGNI), 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Leschnik","sequence":"additional","affiliation":[{"name":"Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidhya","family":"Jagannathan","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2592-6868","authenticated-orcid":false,"given":"Christina","family":"Puff","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrice","family":"H\u00fcnerfauth","sequence":"additional","affiliation":[{"name":"Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7312-638X","authenticated-orcid":false,"given":"Holger A.","family":"Volk","sequence":"additional","affiliation":[{"name":"Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-5644","authenticated-orcid":false,"given":"Wolfgang","family":"Baumg\u00e4rtner","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa C.","family":"Koch","sequence":"additional","affiliation":[{"name":"Bundeswehr School of Dog Handling, 56766 Ulmen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencke","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Bundeswehr School of Dog Handling, 56766 Ulmen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Kleiter","sequence":"additional","affiliation":[{"name":"Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-4880","authenticated-orcid":false,"given":"Tosso","family":"Leeb","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.cvsm.2014.07.005","article-title":"Canine Hereditary Ataxia","volume":"44","author":"Urkasemsin","year":"2014","journal-title":"Vet. 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