Dominant negative variants in CUL1 of the ubiquitin-proteasome cause a neurodevelopmental syndrome

CUL1 encodes a scaffolding protein of the SKP1-CUL1-F-box E3 ubiquitin ligase complex, which mediates substrate ubiquitination and proteasomal degradation. Despite CUL1’s essential roles, it has not been implicated in human disease. We identified ten unrelated individuals with a syndromic neurodevelopmental disorder, with or without movement abnormalities carrying de novo heterozygous CUL1 variants. Patient-derived iPSCs with p.Lys515Glu exhibited elevated cyclin E level, a CUL1 target. Co-transfection with CUL1 and ubiquitin demonstrated that truncating variants (p.Arg565* and p.Gly512Trpfs*51) impaired polyubiquitin chain formation on β-catenin, supporting a dominant-negative mechanism. In vivo , neural-specific knockdown of Cul1 in Drosophila reduced survival and motor function, while enhancing sensory dendrite regeneration. These phenotypes were differentially rescued by human CUL1 wild-type (WT), p.Leu671Val or truncating variants. WT CUL1 or p.Leu671Val failed to rescue the impaired social interaction in Cul1 knockdown flies, whereas the two truncating variants exacerbated the deficit. Overexpression of p.Arg565* and p.Gly512Trpfs*51 in WT flies recapitulated dendrite regeneration and social deficits, confirming their dominant-negative effects. Their overexpression also caused Akt overactivation, previously shown to be a Cul1 substrate and promote dendrite regeneration, implicating Akt as a downstream effector. These findings establish CUL1 as a novel neurodevelopmental disorder gene and suggest that dominant-negative mechanisms underlie its pathogenesis.