A homozygous variant in IVNS1ABP was identified in three siblings, displaying progeroid features with severe neuropathy. By generating isogenic induced pluripotent stem cells (iPSCs) from the patients fibroblasts and differentiating the iPSCs into neural progenitor cells (NPCs), we found that mutant IVNS1ABP fibroblasts, iPSCs, and NPCs exhibited disrupted cytokinesis, DNA damage and cellular senescence. Correspondingly, cerebral organoids displayed premature differentiation of NPCs to neurons. Molecular profiling as well as biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin /actin-associated proteins and dysregulated actin dynamics during cytokinesis. Taken together, we propose that mutant IVNS1ABP dysregulates actin polymerization and organization which is at least partly responsible for the cellular senescence phenotypes in this progeroid neuropathy syndrome.

The authors have declared no competing interest.

Duke-NUS Medical School Khoo Postdoctoral Fellowship-(KPFA/2020/0038); National Medical Research Council Open Fund (OFYIRG22jul-0021); National Medical Research Council Open Fund (OF-YIRG/0048/2017); Branco Weiss Foundation (Switzerland); National Research Foundation; Strategic Positioning Fund for Genetic Orphan Diseases (SPF2012/005) Singapore Ministry of Education Research Fund, MOE2018-T2-2-103; Singapore Ministry of Health Research Fund, MOH-000207 and 000212.

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National University of Singapore Institutional Review Board has approved the related protocol (LH-18-027R).

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