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| Title | Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 120, Issue 5, Page e2208960120, Year 2023 |
| Publish date | Jan 31, 2023 |
 Authors | 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 /   |
| PubMed Abstract | The majority of pathogenic mutations in the neurofibromatosis type I () gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well ...The majority of pathogenic mutations in the neurofibromatosis type I () 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. |
 External links | Proc Natl Acad Sci U S A / PubMed:36689660 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.6 Å |
| Structure data | EMDB-27826, PDB-8e20: EMDB-28036, PDB-8edm: |
| Source |
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 Keywords |  SIGNALING PROTEIN / GTPase activating protein / Ras signaling / Cancer |
