Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité–Universitätsmedizin Berlin, Berlin, Germany; Institute for Cell Biology and Neurobiology, Charité–Universitätsmedizin Berlin, Berlin, Germany
Nobuto Arashiki
Department of Biochemistry, Tokyo Women’s Medical University, Tokyo, Japan
Lena-Luise Becker
Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité–Universitätsmedizin Berlin, Berlin, Germany; Institute for Cell Biology and Neurobiology, Charité–Universitätsmedizin Berlin, Berlin, Germany
Kohtaro Takizawa
Department of Biochemistry, Tokyo Women’s Medical University, Tokyo, Japan
Jonathan Lévy
Department of Genetics, Robert Debré University Hospital, Paris, France; Laboratoire de biologie médicale multisites Seqoia, Paris, France
Thomas Rambaud
Laboratoire de biologie médicale multisites Seqoia, Paris, France
Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité–Universitätsmedizin Berlin, Berlin, Germany; Institute for Cell Biology and Neurobiology, Charité–Universitätsmedizin Berlin, Berlin, Germany
Yoshio Goshima
Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
Na Li
Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
Maaike Vreeburg
Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
Bénédicte Demeer
Center for Human Genetics, CLAD Nord de France, CHU Amiens-Picardie, Amiens, France; CHIMERE EA 7516, University Picardie Jules Verne, Amiens, France
Achim Dickmanns
Department of Molecular Structural Biology, Institute for Microbiology and Genetics, Georg-August-University Göttingen, Göttingen, Germany
Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité–Universitätsmedizin Berlin, Berlin, Germany; Institute for Cell Biology and Neurobiology, Charité–Universitätsmedizin Berlin, Berlin, Germany
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.
