Monoallelic CRMP1 gene variants cause neurodevelopmental disorder

Ethiraj Ravindran; Nobuto Arashiki; Lena-Luise Becker; Kohtaro Takizawa; Jonathan Lévy; Thomas Rambaud; Konstantin L Makridis; Yoshio Goshima; Na Li; Maaike Vreeburg; Bénédicte Demeer; Achim Dickmanns; Alexander P A Stegmann; Hao Hu; Fumio Nakamura; Angela M Kaindl

doi:10.7554/eLife.80793

Monoallelic CRMP1 gene variants cause neurodevelopmental disorder

Elife. 2022 Dec 13:11:e80793. doi: 10.7554/eLife.80793.

Authors

Ethiraj Ravindran^#^{1

2

3}, Nobuto Arashiki^#⁴, Lena-Luise Becker^#^{1

2

3}, Kohtaro Takizawa^#⁴, Jonathan Lévy^{5

6}, Thomas Rambaud⁶, Konstantin L Makridis^{1

2

3}, Yoshio Goshima⁷, Na Li⁸, Maaike Vreeburg⁹, Bénédicte Demeer^{10

11}, Achim Dickmanns¹², Alexander P A Stegmann⁹, Hao Hu⁸, Fumio Nakamura⁴, Angela M Kaindl^{1

2

3}

Affiliations

¹ Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
² Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany.
³ Institute for Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Department of Biochemistry, Tokyo Women's Medical University, Tokyo, Japan.
⁵ Department of Genetics, Robert Debré University Hospital, Paris, France.
⁶ Laboratoire de biologie médicale multisites Seqoia, Paris, France.
⁷ Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
⁸ Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
⁹ Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands.
¹⁰ Center for Human Genetics, CLAD Nord de France, CHU Amiens-Picardie, Amiens, France.
¹¹ CHIMERE EA 7516, University Picardie Jules Verne, Amiens, France.
¹² Department of Molecular Structural Biology, Institute for Microbiology and Genetics, Georg-August-University Göttingen, Göttingen, Germany.

^# Contributed equally.

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.

Keywords: CRMP1; autism spectrum disorder; genetics; genomics; human; intellectual disability; neurodevelopmental disorder; neuroscience.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder* / genetics
Humans
Intellectual Disability* / genetics
Intellectual Disability* / metabolism
Mice
Muscle Hypotonia / genetics
Neurodevelopmental Disorders* / genetics
Neurodevelopmental Disorders* / metabolism
Neuronal Outgrowth
Neurons / metabolism

Substances

CRMP1 protein, human

Grants and funding

The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.