Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
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
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
- 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
- Received: June 4, 2022
- Preprint posted: July 6, 2022 (view preprint)
- Accepted: December 12, 2022
- Accepted Manuscript published: December 13, 2022 (version 1)
- Version of Record published: December 30, 2022 (version 2)
- 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.
Metrics
-
- 1,003
- views
-
- 153
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Genetics and Genomics
PARP-1 is central to transcriptional regulation under both normal and stress conditions, with the governing mechanisms yet to be fully understood. Our biochemical and ChIP-seq-based analyses showed that PARP-1 binds specifically to active histone marks, particularly H4K20me1. We found that H4K20me1 plays a critical role in facilitating PARP-1 binding and the regulation of PARP-1-dependent loci during both development and heat shock stress. Here, we report that the sole H4K20 mono-methylase, pr-set7, and parp-1 Drosophila mutants undergo developmental arrest. RNA-seq analysis showed an absolute correlation between PR-SET7- and PARP-1-dependent loci expression, confirming co-regulation during developmental phases. PARP-1 and PR-SET7 are both essential for activating hsp70 and other heat shock genes during heat stress, with a notable increase of H4K20me1 at their gene body. Mutating pr-set7 disrupts monomethylation of H4K20 along heat shock loci and abolish PARP-1 binding there. These data strongly suggest that H4 monomethylation is a key triggering point in PARP-1 dependent processes in chromatin.
-
- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.