1. Genetics and Genomics
  2. Neuroscience

Monoallelic CRMP1 gene variants cause neurodevelopmental disorder

  1. Ethiraj Ravindran
  2. Nobuto Arashiki
  3. Lena-Luise Becker
  4. Kohtaro Takizawa
  5. Jonathan Lévy
  6. Thomas Rambaud
  7. Konstantin L Makridis
  8. Yoshio Goshima
  9. Na Li
  10. Maaike Vreeburg
  11. Bénédicte Demeer
  12. Achim Dickmanns
  13. Alexander PA Stegmann
  14. Hao Hu  Is a corresponding author
  15. Fumio Nakamura  Is a corresponding author
  16. Angela M Kaindl  Is a corresponding author
  1. Charité - Universitätsmedizin Berlin, Germany
  2. Tokyo Women's Medical University, Japan
  3. Robert Debré University Hospital, France
  4. Laboratoire de biologie médicale multisites Seqoia, France
  5. Yokohama City University, Japan
  6. Guangzhou Medical University, China
  7. Maastricht University Medical Centre, Netherlands
  8. CHU Amiens-Picardie, France
  9. Georg-August-University Göttingen, Germany
https://doi.org/10.7554/eLife.80793
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Cite this article
  1. Ethiraj Ravindran
  2. Nobuto Arashiki
  3. Lena-Luise Becker
  4. Kohtaro Takizawa
  5. Jonathan Lévy
  6. Thomas Rambaud
  7. Konstantin L Makridis
  8. Yoshio Goshima
  9. Na Li
  10. Maaike Vreeburg
  11. Bénédicte Demeer
  12. Achim Dickmanns
  13. Alexander PA Stegmann
  14. Hao Hu
  15. Fumio Nakamura
  16. Angela M Kaindl
(2022)
Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
eLife 11:e80793.
https://doi.org/10.7554/eLife.80793
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  3. Download .RIS

Abstract

Collapsin response mediator proteins (CRMPs) are key for brain development and function. Here, we link CRMP1 to a neurodevelopmental disorder. We report heterozygous de novo variants in the CRMP1 gene in three unrelated individuals with muscular hypotonia, intellectual disability and/or autism spectrum disorder. Based on in silico analysis these variants are predicted to affect the CRMP1 structure. We further analyzed the effect of the variants on the protein structure/levels and cellular processes. We showed that the human CRMP1 variants impact the oligomerization of CRMP1 proteins. Moreover, overexpression of the CRMP1 variants affect neurite outgrowth of murine cortical neurons. While altered CRMP1 levels have been reported in psychiatric diseases, genetic variants in CRMP1 gene have never been linked to human disease. We report for the first-time variants in the CRMP1 gene and emphasize its key role in brain development and function by linking directly to a human neurodevelopmental disease.

Data availability

All data generated or analysed during this study are included in the manuscript. Source Data files have been provided for Figures 2 and 3

Article and author information

Author details

  1. Ethiraj Ravindran

    Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0095-116X

  2. Nobuto Arashiki

    Department of Biochemistry, Tokyo Women's Medical University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  3. Lena-Luise Becker

    Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Kohtaro Takizawa

    Department of Biochemistry, Tokyo Women's Medical University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Jonathan Lévy

    Department of Genetics, Robert Debré University Hospital, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  6. Thomas Rambaud

    Laboratoire de biologie médicale multisites Seqoia, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  7. Konstantin L Makridis

    Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2609-4557

  8. Yoshio Goshima

    Department of Molecular Pharmacology and Neurobiology, Yokohama City University, Yokohama, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Na Li

    Laboratory of Medical Systems Biology, Guangzhou Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Maaike Vreeburg

    Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  11. Bénédicte Demeer

    Center for Human Genetics, CHU Amiens-Picardie, Amiens, France
    Competing interests
    The authors declare that no competing interests exist.

  12. Achim Dickmanns

    Department of Molecular Structural Biology, Georg-August-University Göttingen, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.

  13. Alexander PA Stegmann

    Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9736-7137

  14. Hao Hu

    Laboratory of Medical Systems Biology, Guangzhou Medical University, Guangzhou, China
    For correspondence
    huh@cougarlab.org
    Competing interests
    The authors declare that no competing interests exist.

  15. Fumio Nakamura

    Department of Biochemistry, Tokyo Women's Medical University, Tokyo, Japan
    For correspondence
    nakamura.fumio@twmu.ac.jp
    Competing interests
    The authors declare that no competing interests exist.

  16. Angela M Kaindl

    Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
    For correspondence
    angela.kaindl@charite.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9454-206X

Funding

Charité - Universitatsmedizin Berlin

  • Ethiraj Ravindran
  • Lena-Luise Becker
  • Konstantin L Makridis
  • Angela M Kaindl

Berlin Institute of Health (CRG1)

  • Angela M Kaindl

Japan Society for the Promotion of Science (16K07062)

  • Fumio Nakamura

Sonnenfeld Stiftung

  • Konstantin L Makridis

German Research Foundation (SFB665,SFB1315,FOR3004)

  • Angela M Kaindl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Joseph G Gleeson, University of California, San Diego, United States

Ethics

Animal experimentation: All animal experimental protocols were checked and approved by the Institutional Animal Care and Use Committee of the Tokyo Women's medical University with protocol No. 'AE21-086'. All animal experiments were performed at daytime. The study was not pre-registered.

Human subjects: Written informed consent was obtained from all parents of the patients. The human study adhered to the World Health Association Declaration of Helsinki (2013) and was approved by the local ethics committees of the Charité (approval no. EA1/212/08).

Version history

  1. Received: June 4, 2022
  2. Preprint posted: July 6, 2022 (view preprint)
  3. Accepted: December 12, 2022
  4. Accepted Manuscript published: December 13, 2022 (version 1)
  5. Version of Record published: December 30, 2022 (version 2)
  6. Version of Record updated: January 6, 2023 (version 3)

Copyright

© 2022, Ravindran et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ethiraj Ravindran
  2. Nobuto Arashiki
  3. Lena-Luise Becker
  4. Kohtaro Takizawa
  5. Jonathan Lévy
  6. Thomas Rambaud
  7. Konstantin L Makridis
  8. Yoshio Goshima
  9. Na Li
  10. Maaike Vreeburg
  11. Bénédicte Demeer
  12. Achim Dickmanns
  13. Alexander PA Stegmann
  14. Hao Hu
  15. Fumio Nakamura
  16. Angela M Kaindl
(2022)
Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
eLife 11:e80793.
https://doi.org/10.7554/eLife.80793

Share this article

https://doi.org/10.7554/eLife.80793

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