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

Proceedings of the National Academy of Sciences of the United States of America 2023 Jan 31

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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.

Citation

Lucy C Young, Ruby Goldstein de Salazar, Sae-Won Han, Zi Yi Stephanie Huang, Alan Merk, Matthew Drew, Joseph Darling, Vanessa Wall, Reinhard Grisshammer, Alice Cheng, Madeline R Allison, Matthew J Sale, Dwight V Nissley, Dominic Esposito, Jana Ognjenovic, Frank McCormick. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization. Proceedings of the National Academy of Sciences of the United States of America. 2023 Jan 31;120(5):e2208960120