IVNS1ABP Deficiency Disrupts Actin Filament Organization and Leads to Cellular Senescence in a Newly Identified Progeroid Neuropathy Syndrome

Summary 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement 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. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: National University of Singapore Institutional Review Board has approved the related protocol (LH-18-027R). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data and code availability RNA-sequencing data were deposited to Gene Expression Omnibus (GEO) under GSE270946 and raw proteomics data were deposited to ProteomeXchange (Identifier: PXD053645). These are publically available as of the date of publication. This paper does not report original code.