loading page

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

Corresponding Author:ashleel@uab.edu

Author Profile
Hui Liu
University of Alabama at Birmingham
Author Profile
Jian Liu
University of Alabama at Birmingham
Author Profile
Michael Daniel
University of Alabama at Birmingham
Author Profile
David Bedwell
University of Alabama at Birmingham Department of Biochemistry and Molecular Genetics
Author Profile
Bruce Korf
University of Alabama at Birmingham
Author Profile
Robert Kesterson
University of Alabama
Author Profile
Deeann Wallis
University of Alabama at Birmingham
Author Profile

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.
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 2021Submission Checks Completed
16 Sep 2021Assigned to Editor
28 Sep 2021Reviewer(s) Assigned
08 Oct 2021Review(s) Completed, Editorial Evaluation Pending
09 Oct 2021Editorial Decision: Revise Minor
13 Oct 20212nd Revision Received
18 Oct 2021Submission Checks Completed
18 Oct 2021Assigned to Editor
18 Oct 2021Review(s) Completed, Editorial Evaluation Pending
20 Oct 2021Editorial Decision: Accept
Jan 2022Published in Human Mutation volume 43 issue 1 on pages 30-41. 10.1002/humu.24290