A significant effect of the HUWE1 copy number on autistic spectrum disorder and the development of zebrafish

Abstract Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder. The copy number variation (CNV) of genes in the X-chromosome is speculated to play a critical role in ASD. The HECT, UBA and WWE domain containing the E3 ubiquitin protein ligase 1 (HUWE1) gene is located on the X-chromosome and is associated with neurodevelopment. However, the CNV of HUWE1 has not been linked to ASD. In this study, we identified increased copy numbers of HUWE1 in ASD patients compared to the controls. Moreover, an elevated severity of ASD phenotype was observed in patients with more HUWE1 copy numbers. In vitro, overexpression HUWE1 could decrease the proliferation of nervous system derived cells and promote their apoptosis, declining the G2/M phase transition. The functional assay showed that HUWE1, an E3 ubiquitin protein ligase, regulated the ubiquitination degradation of key mediators in the Wnt/β-catenin signaling pathway, which is involved in neurodevelopment. Consistent with the ASD patients, overexpression of huwe1 in zebrafish embryos caused defective brain development, small eyes, cardiac edema and a curly spinal cord, supporting the pivotal role of the HUWE1 CNV in neurodevelopmental disorders. In this study, we demonstrated the role of the HUWE1 CNV for complement pathway factors in the origin of ASD for the first time. Genetic analysis of the HUWE1 copy number could inform the clinical counseling of ASD patients.