Genetic Risk of Axonal Neuropathy Following Infection

• DOI: 10.2139/ssrn.5087374
• Publication Date: 2025-01-09T20:48:34Z
• Authors: J. Robert Harkness; John Henry McDer...; Shea Marsden; Peter Jamieson; Kay A. Metcalfe; Naz Khan; William L. Macken; Robert D.S. Pitc...; Christopher J. R...; Reza Maroofian; Kloepa Kloepas; Ataf Sabir; Lily Islam; Saikat Santra; Enise Avci Durmu...; Tahir Atik; Esra Isik; Ozgur Cogulu; Jill Urquhart; Glenda M. Beaman; Leigh AM Demain; Adam Jackson; Alexander J.M. B...; Helen Byers; Hayley Bennett; Wei-Hsiang Lin; Antony Adamson; Sanjai Patel; Wyatt Yue; Robert W. Taylor; Janine Reunert; Thorsten Marquardt; Rebecca Buchert; Tobias B. Haack; Heike Losch; Lukas Ryba; Petra Lassuthova; Radka Valkovičová; Jana Haberlová; Barbora Lauerová; Eva Trúsiková; Kiran Polavarapu; Ozge Aksel Kilic...; Hanns Lochmuller; Mina Zamani; Niloofar Chamanrou; Gholamreza Shariati; Saeid Sadeghian; Reza Azizimalmairi; Sateesh Maddirevula; Muhammad AlMuhaizea; Fowzan S. Alkuraya; Rita Horvath; Serdal Güngör; Emma Wakeling; Adnan Manzur; Pinki Munot; Rachael Matthews; Siddharth Banka; Mary M. Reilly; Daimark Bennett; Raymond O'Keefe; William G. Newman

AbstractBackgroundWhy some individuals experience severe neuropathy following infection is unknown. Nucleocytoplasmic trafficking (NCT) is an essential process in nucleated cells, and its disruption has been implicated in many neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.MethodsWe performed genomic and clinical studies in 24 individuals from 12 families with acute onset axonal neuropathy. Genetic variants were characterized by thermal stability and enzymatic assays using recombinantly expressed protein. Protein localization was determined in patient fibroblasts using immunofluorescence following heat or oxidative stress. A humanizedDrosophilamodel was generated to determine the effect of stress onin vivofunction.ResultsWe identified deleterious biallelic variants in humanRCC1, encoding a GTP exchange factor essential in maintaining Ran GTPase-dependent NCT function. Clinical presentations ranged from a rapidly progressive, fatal axonal neuropathy with encephalopathy to a mild motor neuropathy resulting in impaired walking. In most patients (n=22/24), neurological presentation was secondary to infection, resulting in prior diagnosis of Guillain-Barré syndrome (GBS) in 13. The efficiency of cellular Ran GDP-GTP exchange and the thermal stability of Rcc1 protein was reduced by disease-associated variants. Heat shock or oxidative stress revealed defects in Ran nuclear localization, impaired NCT, and TDP-43 mislocalization in patient fibroblasts. Disease associated variants were unable to rescue the thermosensitive phenotype of arcc1deficient hamster cell line.RCC1 Drosophilamodels revealed a fatal intolerance to oxidative stress.ConclusionWe describe a novel autosomal recessive acute onset axonal neuropathy triggered by infection caused by biallelicRCC1variants, which mimics GBS and has important mechanistic overlap with ALS.