{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:17:09Z","timestamp":1785403029382,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,9]]},"group-title":"Genetics","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 NS068933"],"award-info":[{"award-number":["R01 NS068933"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R37 NS054154"],"award-info":[{"award-number":["R37 NS054154"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K99 NS130151"],"award-info":[{"award-number":["K99 NS130151"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in\n                  <jats:italic>Tuba4a<\/jats:italic>\n                  (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL\/6J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB\/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (\n                  <jats:italic>\n                    Stk36\n                    <jats:sup>Y1003N<\/jats:sup>\n                  <\/jats:italic>\n                  ) and alpha-tubulin 4A (\n                  <jats:italic>\n                    Tuba4a\n                    <jats:sup>Q176P<\/jats:sup>\n                  <\/jats:italic>\n                  ) in the mapping interval. These SNPs were CRISPR-engineered into C57BL\/6J mice, which confirmed the\n                  <jats:italic>\n                    Tuba4a\n                    <jats:sup>Q176P<\/jats:sup>\n                  <\/jats:italic>\n                  variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant\n                  <jats:italic>TUBA4A<\/jats:italic>\n                  mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia\/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of\n                  <jats:italic>TUBA4A<\/jats:italic>\n                  mutations in neurodegeneration and myopathy.\n                <\/jats:p>","DOI":"10.64898\/2026.03.06.710113","type":"posted-content","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T23:56:36Z","timestamp":1773273396000},"source":"Crossref","is-referenced-by-count":0,"title":["A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in\n                  <i>Tuba4a<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0594-7354","authenticated-orcid":false,"given":"Timothy J.","family":"Hines","sequence":"first","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5145-2010","authenticated-orcid":false,"given":"Jonathan R.","family":"Funke","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609 USA"},{"name":"Neuroscience Ph.D. Program, Graduate School of Biomedical Science, Tufts University, Boston, MA 02111 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2555-5120","authenticated-orcid":false,"given":"Samia L.","family":"Pratt","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609 USA"},{"name":"Neuroscience Ph.D. Program, Graduate School of Biomedical Science, Tufts University, Boston, MA 02111 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8045-3853","authenticated-orcid":false,"given":"Alaura D.","family":"Rice","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7875-6682","authenticated-orcid":false,"given":"Jeffery L.","family":"Twiss","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of South Carolina, Columbia, SC 29208"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-3407","authenticated-orcid":false,"given":"Robert W.","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609 USA"},{"name":"Neuroscience Ph.D. Program, Graduate School of Biomedical Science, Tufts University, Boston, MA 02111 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