KIF11 variants in familial exudative vitreoretinopathy leading to mTORC1 overactivation and impaired cell cycle progression.

BACKGROUND: This study aimed to identify potentially pathogenic variants in the KIF11 gene in patients with Familial Exudative Vitreoretinopathy (FEVR) and to evaluate their impact on KIF11 function and associated cellular mechanisms. METHODS: Three unrelated families diagnosed with FEVR were analyzed through Sanger sequencing and gene panel testing to identify genetic variants. Transfected HEK293T cells were used to assess the effects of identified variants on KIF11 protein expression. Human retinal endothelial cells (HRECs) were utilized to model KIF11 dysfunction via lentiviral knockdown, along with the introduction of the identified variants. RESULTS: Three KIF11 variants—p.Arg138His, p.Arg312Ter, and p.Ser348fsTer8—were identified in FEVR patients. Arg312Ter and Ser348fsTer8 caused KIF11 truncation. KIF11 knockdown and Arg138His expression in HRECs impaired proliferation. Arg138His disrupted KIF11-mLST8 interaction, leading to mTORC1 hyperactivation (increased p70S6K/4EBP1 phosphorylation) and ROS generation, activating p53/p21. mTORC1 inhibition partially rescued these effects. Additionally, KIF11 variants independently compromised HRECs cell cycle progression. CONCLUSIONS: KIF11 variants, particularly Arg138His, diminish protein function through distinct mechanisms involving mTORC1 hyperactivation and cell cycle dysregulation, contributing to FEVR pathogenesis. These findings highlight the need for combinatorial therapeutic strategies to address KIF11-related disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00849-z.