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Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.

Lucy C YoungRuby Goldstein de SalazarSae-Won HanZi Yi Stephanie HuangAlan MerkMatthew DrewJoseph DarlingVanessa E WallReinhard GrisshammerAlice ChengMadeline R AllisonMatthew J SaleDwight V NissleyDominic EspositoJana OgnjenovicFrank McCormick
Published in: Proceedings of the National Academy of Sciences of the United States of America (2023)
The majority of pathogenic mutations in the neurofibromatosis type I ( NF1 ) 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-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
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