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

Min Liu, Shengliu Pan, Erkuan Dai, Rulian Zhao

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Article in Human genomics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 authors.

Min Liu *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Medical Genetics, The Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu, China.

Shengliu Pan *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Medical Genetics, The Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu, China.

Erkuan DaiDepartment of Ophthalmology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. daierkuan@126.com.

Rulian ZhaoDepartment of Ophthalmology, Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu, China. liansyin@126.com.

Funding

China's Postdoctoral General Program 2024M750365National Natural Science Foundation of China 82401292the fund for Sichuan Provincial People's Hospital 2023BH09

6 · The paper itself

Abstract

backgroundThis 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.

methodsThree 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.

resultsThree 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.

conclusionsKIF11 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.

Indexed as

Familial Exudative VitreoretinopathiesKinesinsMechanistic Target of Rapamycin Complex 1Cell CycleCell ProliferationEndothelial CellsFemaleHEK293 CellsHumansMalePedigreeKIF11 protein, humanKinesinsMechanistic Target of Rapamycin Complex 1Cell cycleFamilial exudative vitreoretinopathyKIF11 genemTORC1Oxidative stress

Identifiers

PMID41258146

DOI10.1186/s40246-025-00849-z

PMCPMC12628542

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LicenceCC BY-NC-ND

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.