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A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing\n                    <jats:sup>2\u20134<\/jats:sup>\n                    . Single nucleotide polymorphisms in\n                    <jats:italic>UNC13A<\/jats:italic>\n                    are among the strongest hits associated with FTD and ALS in human genome-wide association studies\n                    <jats:sup>5,6<\/jats:sup>\n                    , but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in\n                    <jats:italic>UNC13A<\/jats:italic>\n                    . Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in\n                    <jats:italic>UNC13A<\/jats:italic>\n                    mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase\n                    <jats:italic>UNC13A<\/jats:italic>\n                    cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (\n                    <jats:italic>UNC13A<\/jats:italic>\n                    genetic variants), and loss of TDP-43 function.\n                  <\/jats:p>","DOI":"10.1038\/s41586-022-04424-7","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T12:04:19Z","timestamp":1645617859000},"page":"124-130","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":590,"title":["TDP-43 represses cryptic exon inclusion in the FTD\u2013ALS gene UNC13A"],"prefix":"10.1038","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8297-4279","authenticated-orcid":false,"given":"X. 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