Monoallelic CRMP1 gene variants cause neurodevelopmental disorder

Collapsing 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 are dominant-negative and impact the oligomerization of CRMP1 proteins. Moreover, overexpression of mutant-CRMP1 variants affect neurite outgrowth of murine cortical neurons. While altered CRMP1 levels have been reported in psychiatric diseases, genetic mutation in CRMP1 gene has never been linked to human disease. We report for the first-time mutations in the CRMP1 gene and emphasize its key role in brain development and function by linking directly to a human neurodevelopmental disease.