2. Academic Validation
  3. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization

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

  • Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2208960120. doi: 10.1073/pnas.2208960120.
Lucy C Young 1,  Ruby Goldstein de Salazar 1,  Sae-Won Han 2,  Zi Yi Stephanie Huang 1,  Alan Merk 3,  Matthew Drew 4,  Joseph Darling 3,  Vanessa Wall 4,  Reinhard Grisshammer 3,  Alice Cheng 1,  Madeline R Allison 1,  Matthew J Sale 1,  Dwight V Nissley 4,  Dominic Esposito 4,  Jana Ognjenovic 3,  Frank McCormick 1
Affiliations

Affiliations

  • 1 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94153.
  • 2 Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
  • 3 National Cryo-EM Program, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
  • 4 National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
PMID: 36689660 DOI: 10.1073/pnas.2208960120
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.

Keywords

NFI; cryo-EM; neurofibromatosis type I.

Figures
Products