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In insulin-secreting INS-1E cells, <jats:italic>Nexmif<\/jats:italic> expression increased strongly in response to oxidative stress. CRISPR Cas9-generated <jats:italic>Nexmif<\/jats:italic> knockout mice exhibited a reduced number of proliferating beta cells in pancreatic islets. RNA sequencing of pancreatic islets showed that the downregulated genes in <jats:italic>Nexmif<\/jats:italic> mutant islets are involved in stress response and the deposition of epigenetic marks. They include <jats:italic>H3f3b<\/jats:italic>, encoding histone H3.3, which is associated with the regulation of beta-cell proliferation and maintains genomic integrity by silencing transposable elements, particularly LINE1 elements. LINE1 activity has been associated with autism and neurodevelopmental disorders in which patients share characteristics with <jats:italic>NEXMIF<\/jats:italic> patients, and can cause genomic instability and genetic variation through retrotransposition. <jats:italic>Nexmif<\/jats:italic> knockout mice exhibited various other phenotypes. Mortality and phenotypic abnormalities increased in each generation in both <jats:italic>Nexmif<\/jats:italic> mutant and non-mutant littermates. In <jats:italic>Nexmif<\/jats:italic> mutant mice, LINE1 element expression was upregulated in the pancreas, brain, and testis, possibly inducing genomic instability in <jats:italic>Nexmif<\/jats:italic> mutant mice and causing phenotypic variability in their progeny.<\/jats:p>","DOI":"10.1038\/s41598-022-17845-1","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T09:03:23Z","timestamp":1660554203000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Loss of Nexmif results in the expression of phenotypic variability and loss of genomic integrity"],"prefix":"10.1038","volume":"12","author":[{"given":"Caroline","family":"Stekelenburg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Blouin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Santoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norann","family":"Zaghloul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth A.","family":"O\u2019Hare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolphe","family":"Dusaulcy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Maechler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie M.","family":"Schwitzgebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,15]]},"reference":[{"key":"17845_CR1","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/s41436-020-00988-9","volume":"23","author":"H Stamberger","year":"2021","unstructured":"Stamberger, H. et al. 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