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