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Analysis of patient-specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine
  • +5
  • Ashlee Long,
  • Hui Liu,
  • Jian Liu,
  • Michael Daniel,
  • David Bedwell,
  • Bruce Korf,
  • Robert Kesterson,
  • Deeann Wallis
Ashlee Long
University of Alabama at Birmingham
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Hui Liu
University of Alabama at Birmingham
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Jian Liu
University of Alabama at Birmingham
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Michael Daniel
University of Alabama at Birmingham
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David Bedwell
University of Alabama at Birmingham Department of Biochemistry and Molecular Genetics
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Bruce Korf
University of Alabama at Birmingham
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Robert Kesterson
University of Alabama
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Deeann Wallis
University of Alabama at Birmingham
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Abstract

We have created a panel of twenty-nine NF1 variant cDNAs representing benign missense (MS) variants, pathogenic MS variants, many with clinically relevant phenotypes, in-frame deletions, splice variants, and nonsense (NS) variants. We have determined the functional consequences of the variants, assessing their ability to produce mature neurofibromin and restore Ras signaling activity in NF1 null (-/-) cells. cDNAs demonstrate variant-specific differences in neurofibromin protein levels, suggesting that some variants lead to protein instability or enhanced degradation. When expressed at high levels, some variant proteins are still able to repress Ras activity, indicating that the NF1 phenotype may be due to protein instability. In contrast, other variant proteins are incapable of repressing Ras activity, indicating that some do not functionally engage Ras and stimulate GTP-ase activity. We observed that stability and Ras activity can be mutually exclusive. These assays allow us to categorize variants by functional effects, may help to classify variants of unknown significance, and may have future implications for more directed therapeutics.

Peer review status:IN REVISION

19 Jun 2021Submitted to Human Mutation
22 Jun 2021Submission Checks Completed
22 Jun 2021Assigned to Editor
05 Jul 2021Reviewer(s) Assigned
28 Jul 2021Review(s) Completed, Editorial Evaluation Pending
07 Aug 2021Editorial Decision: Revise Minor
14 Sep 20211st Revision Received
16 Sep 2021Assigned to Editor
16 Sep 2021Submission Checks Completed