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The p.L218P variant in WDR83 disrupts neuronal development, leading to neurodevelopmental disorder
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The p.L218P variant in WDR83 disrupts neuronal development, leading to neurodevelopmental disorder
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Journal Article
The p.L218P variant in WDR83 disrupts neuronal development, leading to neurodevelopmental disorder
2025
Overview
WDR83 (WD Repeat Domain 83), also known as MORG1 (Mitogen-activated protein kinase Organizer 1), functions as a scaffold protein regulating diverse cellular processes, including cell signaling, proliferation, protein degradation, cell polarity, and autophagy. Through whole-exome sequencing, we identified a novel de novo
WDR83
variant [NM_001099737; c.653 T > C,p.(L218P)] in a Japanese female patient presenting with global developmental delay, intellectual disability, and dysmorphic features. As the p.L218P variant was suspected to exert a dominant-negative effect, we investigated its impact on neuronal development. In vivo, acute expression via in utero electroporation promoted premature cell cycle exit of neural stem cells, impaired cortical neuron migration, and disrupted dendritic arborization, whereas axonal projections to the contralateral hemisphere remained unaffected. Additionally, cortical neurons expressing WDR83-L218P exhibited reduced spine head diameter. In vitro, WDR83-L218P expression inhibited axon elongation in primary cultured hippocampal neurons. Collectively, these findings suggest that WDR83 is a novel gene associated with neurodevelopmental disorders. Based on expression profiles and functional analyses, we conclude that WDR83 plays a crucial role in regulating neuronal morphology during brain development, and that the p.L218P variant disrupts this function, contributing to the patient’s phenotype.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 692/617
/ Adaptor Proteins, Signal Transducing - genetics
/ Animals
/ Brain
/ Female
/ Females
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mice
/ MORG1
/ Mutation
/ Neural Stem Cells - metabolism
/ Neurodevelopmental disorders
/ Neurodevelopmental Disorders - genetics
/ Neurodevelopmental Disorders - pathology
/ Neurons
/ Proteins
/ Science
/ Spine
/ WDR83
