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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,31]]},"abstract":"<jats:p>\n                    The majority of pathogenic mutations in the neurofibromatosis type I (\n                    <jats:italic>NF1<\/jats:italic>\n                    ) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype\u2013phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2208960120","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T15:10:11Z","timestamp":1674486611000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":37,"title":["Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2703-2347","authenticated-orcid":false,"given":"Lucy C.","family":"Young","sequence":"first","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94153"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruby","family":"Goldstein de 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