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

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.

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).

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.

Metrics

  • 1,227
    views
  • 176
    downloads
  • 6
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Hans Tobias Gustafsson, Lucas Ferguson ... Oliver J Rando
    Research Article

    Among the major classes of RNAs in the cell, tRNAs remain the most difficult to characterize via deep sequencing approaches, as tRNA structure and nucleotide modifications can each interfere with cDNA synthesis by commonly-used reverse transcriptases (RTs). Here, we benchmark a recently-developed RNA cloning protocol, termed Ordered Two-Template Relay (OTTR), to characterize intact tRNAs and tRNA fragments in budding yeast and in mouse tissues. We show that OTTR successfully captures both full-length tRNAs and tRNA fragments in budding yeast and in mouse reproductive tissues without any prior enzymatic treatment, and that tRNA cloning efficiency can be further enhanced via AlkB-mediated demethylation of modified nucleotides. As with other recent tRNA cloning protocols, we find that a subset of nucleotide modifications leave misincorporation signatures in OTTR datasets, enabling their detection without any additional protocol steps. Focusing on tRNA cleavage products, we compare OTTR with several standard small RNA-Seq protocols, finding that OTTR provides the most accurate picture of tRNA fragment levels by comparison to "ground truth" Northern blots. Applying this protocol to mature mouse spermatozoa, our data dramatically alter our understanding of the small RNA cargo of mature mammalian sperm, revealing a far more complex population of tRNA fragments - including both 5′ and 3′ tRNA halves derived from the majority of tRNAs – than previously appreciated. Taken together, our data confirm the superior performance of OTTR to commercial protocols in analysis of tRNA fragments, and force a reappraisal of potential epigenetic functions of the sperm small RNA payload.

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.