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Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile\u2010onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Trio whole\u2010exome sequencing was used in 5 index patients with infantile\u2010onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Distinct heterozygous <jats:italic>KPNA3<\/jats:italic> missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them <jats:italic>KPNA3<\/jats:italic> variants had occurred de novo. Mutant karyopherin\u2010\u03b13 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our genetic findings implicate heterozygous variants in <jats:italic>KPNA3<\/jats:italic> as a novel cause for autosomal dominant, early\u2010onset, and pure HSP. Mutant karyopherin\u2010\u03b13 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738\u2013750<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26228","type":"journal-article","created":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T11:28:40Z","timestamp":1632655720000},"page":"738-750","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dominant <scp><i>KPNA3<\/i><\/scp> Mutations Cause Infantile\u2010Onset Hereditary Spastic Paraplegia"],"prefix":"10.1002","volume":"90","author":[{"given":"Claudia","family":"Schob","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja","family":"Hempel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Safka 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