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July 20, 2021; 97 (3) Research Article

Pathogenic Effect of TP73 Gene Variants in People With Amyotrophic Lateral Sclerosis

Kristi L. Russell, Jonathan M. Downie, Summer B. Gibson, Spyridoula Tsetsou, Matthew D. Keefe, Jerry A. Duran, Karla P. Figueroa, Mark B. Bromberg, L. Charles Murtaugh, Joshua L. Bonkowsky, Stefan M. Pulst, Lynn B. Jorde
First published June 16, 2021, DOI: https://doi.org/10.1212/WNL.0000000000012285
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Article Information

vol. 97 no. 3 e225-e235
DOI: 
https://doi.org/10.1212/WNL.0000000000012285
PubMed: 
34135078
Published By: 
Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Print ISSN: 
0028-3878
Online ISSN: 
1526-632X
History: 
  • Received December 3, 2020
  • Accepted in final form April 13, 2021
  • First Published June 16, 2021.

Article Versions

Copyright & Usage: 
© 2021 American Academy of Neurology

Author Disclosures

    1. Kristi L. Russell, BS*,
    2. Jonathan M. Downie, MD, PhD*,
    3. Summer B. Gibson, MD*,
    4. Spyridoula Tsetsou, MD*,
    5. Matthew D. Keefe, PhD,
    6. Jerry A. Duran, BS,
    7. Karla P. Figueroa, BS,
    8. Mark B. Bromberg, MD,
    9. L. Charles Murtaugh, PhD,
    10. Joshua L. Bonkowsky, MD, PhD*,
    11. Stefan M. Pulst, MD* and
    12. Lynn B. Jorde, PhD*
  1. Kristi L. Russell, BS*,
    2. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. (1) NIH, R35 5R35GM118335-04, graduate student, 2016-present

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  2. Jonathan M. Downie, MD, PhD*,
    3. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. (1) National Institute of General Medical Sciences, GM059290, Graduate Research Assistant, 2015-current (2) National Institute of General Medical Sciences, GM118335, Graduate Research Assistant, 2016-current

    Research Support, Academic Entities:

    1. (1) University of Utah Neuroscience Initiative Collaborative Pilot Project Grant

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  3. Summer B. Gibson, MD*,
    4. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. (1) Skin Biopsy for the Evaluation of Peripheral Nerve Disease. UpToDate. Sept 2013- current (2) Amyotrophic lateral sclerosis. Medlink. June 2016-2020 (3) post polio syndrome. Medlink. Jan 2019- current

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. (1) NCATS, TL1TR001066, Trainee, 09/03/2014 - 06/30/2016 Stock/Stock Options, Medical Equipment & Materials: (1) Recursion Pharmaceuticals, 2013-current

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  4. Spyridoula Tsetsou, MD*,
    5. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  5. Matthew D. Keefe, PhD,
    6. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. Nanostring Technology, Scientist I, 2 years. My employment is not related to this manuscript.

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  6. Jerry A. Duran, BS,
    7. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  7. Karla P. Figueroa, BS,
    8. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  8. Mark B. Bromberg, MD,
    9. Scientific Advisory Boards:

    1. Accordant Health Care (1995-present) Baxter Bioscience (2011-present)

    Gifts:

    1. NONE

    Funding for travel or speaker honoraria:

    1. Funds for travel and and speaker honoraria: Grifols Biotherapeutics (2009-present) Baxter Bioscience (2011-present) Sanofi (2017-present)

    Editorial Boards:

    1. Muscle & Nerve, Assistant Editor (1996-1999; 2005-2009; 2016- present) Clinical Neurophysiology, Assistant Editor (2008-2014) J Clinical Neuromuscular Diseases, Assistant Editor (1998-present)

    Patents:

    1. NONE

    Publishing Royalties:

    1. Handbook of Peripheral Neuropathy, Taylor & Francis, 2005 Quality of Life Measurement in Neurodegenerative and Related Conditions, Cambridge University Press, 2010 UpToDate, 2008 to present Motor Neuron Disease in Adults, Oxford University Press, 2014 Navigating Life with ALS, Oxford University Press, 2017 Peripheral Neuropathy, Cambridge University Press, 2018

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. Accordant Health Care Takeda

    Speakers' Bureaus:

    1. Grifols Biotherapeutics (2009-present) Alexion (2018-present)

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. RA Pharma (Drug trial) Orion Pharma (Drug trial)

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  9. L. Charles Murtaugh, PhD,
    10. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. 1. NIH, R01CA194941, PI, 2016-2022 2. DoD, PR172387, PI, 2018-2021 3. NIH, R01DK061220, PI, 2015-2021

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  10. Joshua L. Bonkowsky, MD, PhD*,
    11. Scientific Advisory Boards:

    1. Bluebird Bio (5/2017; 10/2017) Calico (1/2019-present) Denali therapeutics (6/2019) Enzyvant (6/2019)

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. ZEG: Zebrafish Embryo Genotyper. Device to perform automated zebrafish genotyping.

    Publishing Royalties:

    1. Pediatric Neurology (Medical Color Handbook Series) 1st Edition Series: Medical Color Handbook Series Paperback: 352 pages Publisher: CRC Press; 1st edition (December 15, 2011) 2nd edition (2017)

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. Denali Therapeutics Calico Neurogene Autobahn

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NIH grant, DP2 MH10008, PI, 2012-2017. NIH grant, R21, NIMH , PI, 2015-2017 NIH grant R43, co-PI, 2016-2017 European Leukodystrophy Association, PI, 2016-2018

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. March of Dimes Foundation, 2013-2015.

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. spouse: 1. FilmArray Respiratory Virus Panel, Biofire Inc., 2013-2019 Stock/Stock Options, Medical Equipment & Materials: Orchard Therapeutics, 2019.

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  11. Stefan M. Pulst, MD* and
    12. Scientific Advisory Boards:

    1. National Ataxia Foundation, Medical Research Advisory Board Hertie Institute for Brain Science, University of Tuebingen

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. Nucleic acids encoding ataxin-2 binding proteins; Nucleic acid encoding Schwannomin-binding-proteins and products related thereto; Transgenic mouse expressing a polynucleotide encoding a human ataxin-2 polypeptide; Methods of detecting spinocerebellar ataxia-2 nucleic acids; Nucleic acid encoding spinocerebellar ataxia-2 and products related thereto; Schwannomin-binding-proteins; Compositions and methods for spinocerebellar ataxia; Methods For Modulating Ataxin2 Expression

    Publishing Royalties:

    1. The Ataxias (Churchill Livingston, 2007), Genetics in Neurology (ANN Press, 2005), Genetics of Movement Disorders (Academic Press, 2003), Neurogenetics (Oxford University Press, 2000), Molecular Genetic Testing in Neurology, 2nd - 5th (AAN Press, 1996)

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. 2014-2021 National Institutes of Health (R37NS33123): Spinocerebellar ataxia type 2: gene and gene product. 9/30/14-6/30/2021. (Principal Investigator). 2018-2020 Harrington Discovery Institute Harrington Rare Disease Award: Development of a therapeutic for SCA2 and other rare neurodegenerative diseases. 3/1/18-2/28/20. Co-Investigator (Principal Investigator: D. Scoles) 2014-2021 National Institutes of Health Senator Jacob Javits Merit Award (R37 NS033123): Spinocerebellar ataxia type 2: gene and gene product. 10/1/14-6/30/21. Principal Investigator 2017-2020 National Institutes of Health (R21 NS104799-01): Deep cerebellar stimulation to treat degenerative cerebellar ataxia. 9/1/17-8/31/20. Principal Investigator 2017-2022 National Institutes of Health (R01 NS097903): RNA granules in cerebellar neurodegeneration. 4/1/17-3/31/22. Co-Investigator (Principal Investigator: D. Scoles) 2018-2021 National Institute of Neurological Disorders and Stroke (U01 NS103883): Antisense Oligonucleotides for treating spinocerebellar ataxia type 2. 2/15/18-1/31/21. Principal Investigator (with D. Scoles) 2018-2023 National Institute of Neurological Disorders and Stroke (U01 NS104326): Clinical Trial readiness for SCA1 and SCA3. 1/1/18-12/31/2023. Site Investigator (Principal Investigator: T. Ashizawa) 2018-2020 National Institute of Neurological Disorders and Stroke (R21NS103009): Characterization of ATXN2 as a target for ALS in SCA2 motor neurons. 7/1/18-6/30/21. Principal Investigator. 2019-2024 National Institute of Neurological Disorders and Stroke (R01 NS085054): Identifying symptomatic and neuroprotective strategies for cerebellar ataxia. 4/15/2019-3/31/2024. Site Investigator (Principal Investigator: V. Shakkottai) 2020-2023 CYDAN: SCA1 and SCA2 Studies With Cck1 Receptor Agonist. 1/1/2020-12/31/23. Principal Investigator

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License fee payments, Technology or Inventions:

    1. University of Utah (license for invention & technologies

    Royalty Payments, Technology or Inventions:

    1. University of Utah

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  12. Lynn B. Jorde, PhD*
    13. Scientific Advisory Boards:

    1. Telethon Italy; nonprofit

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. Genetics; associate editor

    Patents:

    1. NONE

    Publishing Royalties:

    1. Medical Genetics; Elsevier; 2020

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NIH -- multiple grants from NIGMS, NHGRI

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  1. From the Departments of Human Genetics (K.L.R., J.A.D., L.C.M., L.B.J.), Neurology (S.B.G., K.P.F., M.B.B., S.M.P.), and Pediatrics (M.D.K., J.L.B.), University of Utah School of Medicine, Salt Lake City; Department of Medicine (J.M.D.), Massachusetts General Hospital, Boston; Department of Neurosurgery (S.T.), Mount Sinai Hospital, Icahn School of Medicine, New York, NY; and Brain and Spine Center (J.L.B.), Primary Children's Hospital, Salt Lake City, UT.
  1. Correspondence
    Mrs. Russell kristi.russell{at}utah.edu
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