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 McCormickPublished 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.
Keyphrases
- copy number
- signaling pathway
- case report
- lps induced
- electron microscopy
- wild type
- pi k akt
- nuclear factor
- oxidative stress
- genome wide
- small molecule
- protein protein
- gene expression
- amino acid
- dna methylation
- binding protein
- cell proliferation
- toll like receptor
- smoking cessation
- hiv infected
- autism spectrum disorder
- hiv testing