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Despite the identification of several HSP\u2010related genes, many patients lack a genetic diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The aims were to confirm the pathogenic role of biallelic <jats:italic>COQ4<\/jats:italic> mutations in HSP and elucidate the clinical, genetic, and functional molecular features of <jats:italic>COQ4<\/jats:italic>\u2010associated HSP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequences of 310 index patients with HSP of unknown cause from three distinct populations were analyzed to identify potential HSP causal genes. Clinical data obtained from patients harboring candidate causal mutations were examined. Functional characterization of COQ4 variants was performed using bioinformatic tools, single\u2010cell RNA sequencing, biochemical assays in cell lines, primary fibroblasts, induced pluripotent stem cell\u2013derived pyramidal neurons, and zebrafish.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compound heterozygous variants in <jats:italic>COQ4<\/jats:italic>, which cosegregated with HSP in pedigrees, were identified in 7 patients from six unrelated families. Patients from four of the six families presented with pure HSP, whereas probands of the other two families exhibited complicated HSP with epilepsy or with cerebellar ataxia. In patient\u2010derived fibroblasts and <jats:italic>COQ4<\/jats:italic> knockout complementation lines, stable expression of these missense variants exerted loss\u2010of\u2010function effects, including mitochondrial reactive oxygen species accumulation, decreased mitochondrial membrane potential, and lower ubiquinone biosynthesis. Whereas differentiated pyramidal neurons expressed high <jats:italic>COQ4<\/jats:italic> levels, <jats:italic>coq4<\/jats:italic> knockdown zebrafish displayed severe motor dysfunction, reflecting motor neuron dysregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study confirms that loss\u2010of\u2010function, compound heterozygous, pathogenic <jats:italic>COQ4<\/jats:italic> variants are causal for autosomal recessive pure and complicated HSP. Moreover, reduced COQ4 levels attributable to variants correspond with decreased ubiquinone biosynthesis, impaired mitochondrial function, and higher phenotypic disease severity. \u00a9 2023 International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.29664","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T04:23:04Z","timestamp":1701145384000},"page":"152-163","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Biallelic <scp><i>COQ4<\/i><\/scp> Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization"],"prefix":"10.1002","volume":"39","author":[{"given":"Xiang","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurology, Department of Rare Diseases Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical 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