Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 23, 2023
- Source ID
- 10.1073/pnas.2208960120
Entities
People
- Alan Merk
- Alice Cheng
- Dominic Esposito
- Dwight V Nissley
- Frank McCormick
- Jana Ognjenovic
- Joseph Darling
- Lucy C. Young
- Madeline R. Allison
- Matt Drew
- Matthew J. Sale
- Reinhard Grisshammer
- Ruby Goldstein De Salazar
- Sae-Won Han
- Vanessa Wall
- Zi Yi Stephanie Huang
Organizations
- Congressionally Directed Medical Research Programs
- Frederick National Laboratory for Cancer Research
- National Cancer Institute
- National Institutes of Health
- Seoul National University Hospital
- University of California