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

  1. Author:
    Young, Lucy C [ORCID]
    Goldstein de Salazar, Ruby
    Han, Sae-Won [ORCID]
    Huang, Zi Yi Stephanie [ORCID]
    Merk,Alan
    Drew,Matt [ORCID]
    Darling, Joseph
    Wall,Vanessa [ORCID]
    Grisshammer, Reinhard
    Cheng, Alice
    Allison, Madeline R
    Sale, Matthew J
    Nissley,Dwight [ORCID]
    Esposito,Dom [ORCID]
    Ognjenovic, Jana
    McCormick, Frank [ORCID]

  2. Author Address

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94153., Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea., National Cryo-EM Program, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.,
    1. Year: 2023
    2. Date: Jan 31
    3. Epub Date: 2023 01 23
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 120
    2. 5
    3. Pages: e2208960120
  4. Type of Article: Article
  5. Article Number: e2208960120
  1. 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.

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External Sources

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  2. DOI: 10.1073/pnas.2208960120
  3. PMID: 36689660

Library Notes

  1. Fiscal Year: FY2022-2023
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