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.
Metrics
-
- 1,180
- views
-
- 171
- downloads
-
- 5
- 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)
Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
eLife 11:e80793.
https://doi.org/10.7554/eLife.80793
Further reading
-
- Biochemistry and Chemical Biology
- Genetics and Genomics
Yerba mate (YM, Ilex paraguariensis) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here, we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes. Comparative analyses revealed that the large YM genome size is partly due to a whole-genome duplication (Ip-α) during the early evolutionary history of Ilex, in addition to the hexaploidization event (γ) shared by core eudicots. Characterization of the genome allowed us to clone the genes encoding methyltransferase enzymes that catalyse multiple reactions required for caffeine production. To our surprise, this species has converged upon a different biochemical pathway compared to that of coffee and tea. In order to gain insight into the structural basis for the convergent enzyme activities, we obtained a crystal structure for the terminal enzyme in the pathway that forms caffeine. The structure reveals that convergent solutions have evolved for substrate positioning because different amino acid residues facilitate a different substrate orientation such that efficient methylation occurs in the independently evolved enzymes in YM and coffee. While our results show phylogenomic constraint limits the genes coopted for convergence of caffeine biosynthesis, the X-ray diffraction data suggest structural constraints are minimal for the convergent evolution of individual reactions.
-
- Genetics and Genomics
There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that are relatively inexpensive compared to traditional drug development. In the absence of a validated drug target, phenotypic screening in model organisms provides a route for identifying candidate treatments. Success requires a screenable phenotype. However, the right phenotype and assay may not be obvious for pleiotropic neuromuscular disorders. Here, we show that high-throughput imaging and quantitative phenotyping can be conducted systematically on a panel of C. elegans disease model strains. We used CRISPR genome-editing to create 25 worm models of human Mendelian diseases and phenotyped them using a single standardised assay. All but two strains were significantly different from wild-type controls in at least one feature. The observed phenotypes were diverse, but mutations of genes predicted to have related functions led to similar behavioural differences in worms. As a proof-of-concept, we performed a drug repurposing screen of an FDA-approved compound library, and identified two compounds that rescued the behavioural phenotype of a model of UNC80 deficiency. Our results show that a single assay to measure multiple phenotypes can be applied systematically to diverse Mendelian disease models. The relatively short time and low cost associated with creating and phenotyping multiple strains suggest that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.
