Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
- Charité - Universitätsmedizin Berlin, Germany
- Tokyo Women's Medical University, Japan
- Robert Debré University Hospital, France
- Laboratoire de biologie médicale multisites Seqoia, France
- Yokohama City University, Japan
- Guangzhou Medical University, China
- Maastricht University Medical Centre, Netherlands
- CHU Amiens-Picardie, France
- 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
Konstantin L Makridis
Alexander PA Stegmann
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.
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Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
eLife 11:e80793.
https://doi.org/10.7554/eLife.80793
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