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.
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).
Reviewing Editor
- Joseph G Gleeson, University of California, San Diego, United States
Publication 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.
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Further reading
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Cardiometabolic diseases encompass a range of interrelated conditions that arise from underlying metabolic perturbations precipitated by genetic, environmental, and lifestyle factors. While obesity, dyslipidaemia, smoking, and insulin resistance are major risk factors for cardiometabolic diseases, individuals still present in the absence of such traditional risk factors, making it difficult to determine those at greatest risk of disease. Thus, it is crucial to elucidate the genetic, environmental, and molecular underpinnings to better understand, diagnose, and treat cardiometabolic diseases. Much of this information can be garnered using systems genetics, which takes population-based approaches to investigate how genetic variance contributes to complex traits. Despite the important advances made by human genome-wide association studies (GWAS) in this space, corroboration of these findings has been hampered by limitations including the inability to control environmental influence, limited access to pertinent metabolic tissues, and often, poor classification of diseases or phenotypes. A complementary approach to human GWAS is the utilisation of model systems such as genetically diverse mouse panels to study natural genetic and phenotypic variation in a controlled environment. Here, we review mouse genetic reference panels and the opportunities they provide for the study of cardiometabolic diseases and related traits. We discuss how the post-GWAS era has prompted a shift in focus from discovery of novel genetic variants to understanding gene function. Finally, we highlight key advantages and challenges of integrating complementary genetic and multi-omics data from human and mouse populations to advance biological discovery.
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Background: Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems.
Methods: Here, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2,600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations (p < 0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels.
Results: Our results identified 7 disease traits reaching Bonferroni-corrected significance in both the discovery (p < 1.92 × 10-5) and replication analyses (p < 2.26 × 10-4), suggesting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24-1.43, p = 2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis (p < 0.05), identifying plasma TG levels as a novel potential risk factor for 9 non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10-1.29, p = 1.17 × 10-5).
Conclusions: Taking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents, as well as mechanistic insights for future studies.
Funding: RD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).