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Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (<jats:italic>ATP5MC3)<\/jats:italic>. The identified variant was submitted to the \u201cGeneMatcher\u201d program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient\u2010derived fibroblast cell lines. Transgenic <jats:italic>Drosophila<\/jats:italic> carrying mutants were studied for movement behavior and mitochondrial function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Exome analysis revealed a variant (c.318C\u2009&gt;\u2009G; p.Asn106Lys) (NM_001689.4) in <jats:italic>ATP5MC3<\/jats:italic> in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper\u2010limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. <jats:italic>Drosophila<\/jats:italic> carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous <jats:italic>ATP5MC3<\/jats:italic> variant that also reduces mitochondrial complex V activity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28821","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T08:39:32Z","timestamp":1634200772000},"page":"375-383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A Novel Variant of <scp><i>ATP5MC3<\/i><\/scp> Associated with Both Dystonia and Spastic Paraplegia"],"prefix":"10.1002","volume":"37","author":[{"given":"Derek 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