CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of...

Microcephaly is a neurodevelopmental anomaly characterized by reduced head circumference and impaired brain growth, often accompanied by intellectual disability (ID), developmental delays, and seizures. While numerous genes have been implicated in microcephaly, the role of the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, particularly its core component CUL1, remains poorly understood. In this study, we identified heterozygous de novo and inherited variants in the CUL1 gene in four unrelated families with severe microcephaly, ID, and developmental delays. To investigate the functional consequences of CUL1 loss of function, we developed a zebrafish model with knockdown of cul1a&b, which exhibited significant reductions in central nervous system size and behavioral defects, mirroring the clinical phenotypes observed in patients. These findings establish CUL1 as a novel gene associated with severe neurodevelopmental disorders (NDDs) and highlight its critical role in brain development. Our study provides genotype-phenotype correlations for CUL1 in NDDs, expanding the genetic spectrum of disorders linked to the SCF complex and underscoring its importance in neurodevelopment.