1. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
- Author
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Young, Lucy C, Goldstein de Salazar, Ruby, Han, Sae-Won, Huang, Zi Yi Stephanie, Merk, Alan, Drew, Matthew, Darling, Joseph, Wall, Vanessa, Grisshammer, Reinhard, Cheng, Alice, Allison, Madeline R, Sale, Matthew J, Nissley, Dwight V, Esposito, Dominic, Ognjenovic, Jana, and McCormick, Frank
- Subjects
Humans ,Neurofibromatosis 1 ,Neurofibromin 1 ,Dimerization ,Mutation ,Mutation ,Missense ,NFI ,cryo-EM ,neurofibromatosis type I ,Genetics ,Rare Diseases ,Neurosciences ,Neurofibromatosis ,Aetiology ,2.1 Biological and endogenous factors - Abstract
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.
- Published
- 2023