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It has been shown in vitro to possess both double\u2010stranded RNA and DNA unwinding activity that is ATP\u2010dependent. Here we report the first two patients for this gene who presented with a homozygous preliminary stop codon resulting in a C\u2010terminal truncation of the <jats:italic>SUPV3L1 protein<\/jats:italic>. They presented with a characteristic phenotype of neurodegenerative nature with progressive spastic paraparesis, growth restriction, hypopigmentation, and predisposition to autoimmune disease. Ophthalmological examination showed severe photophobia with corneal erosions, optic atrophy, and pigmentary retinopathy, while neuroimaging showed atrophy of the optic chiasm and the pons with calcification of putamina, with intermittent and mild elevation of lactate. We show that the amino acids that are eliminated by the preliminary stop codon are highly conserved and are predicted to form an amphipathic helix. To investigate if the mutation causes mitochondrial dysfunction, we examined fibroblasts of the proband. We observed very low expression of the truncated protein, a reduction in the mature <jats:italic>ND6<\/jats:italic> mRNA species as well as the accumulation of double\u2010stranded RNA. Lentiviral complementation with the full\u2010length <jats:italic>SUPV3L1<\/jats:italic> cDNA partly restored the observed RNA phenotypes, supporting that the <jats:italic>SUPV3L1<\/jats:italic> mutation in these patients is pathogenic and the cause of the disease.<\/jats:p>","DOI":"10.1002\/jimd.12476","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T12:17:24Z","timestamp":1642076244000},"page":"292-307","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Mitochondrial <scp>RNA<\/scp> processing defect caused by a <scp><i>SUPV3L1<\/i><\/scp> mutation in two siblings with a novel neurodegenerative syndrome"],"prefix":"10.1002","volume":"45","author":[{"given":"Selma L.","family":"van Esveld","sequence":"first","affiliation":[{"name":"Radboud Center for Mitochondrial Medicine &amp; Center for Molecular and Biomolecular Informatics Radboud Institute for Molecular Life Sciences  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