Genetic Risk of Axonal Neuropathy Following Infection
Diğer yayınlar > Diğer · 2024
Yazarlar: J. Robert Harkness, John H. McDermott, Shea Marsden, Peter Jamieson, Kay A. Metcalfe, Naz Khan, William L. Macken, Robert D.S. Pitceathly, Christopher J. Record, Reza Maroofian, Kloepa Kloepas, Ataf Sabir, Lily Islam, Saikat Santra, Enise AVCI DURMUŞALİOĞLU, Tahir ATİK, Esra IŞIK, Muhsin Özgür ÇOĞULU, Jill E. Urquhart, Glenda M. Beaman, Leigh A. Demain, Adam Jackson, Alexander J.M. Blakes, Helen M. Byers, Hayley Bennett, Wei-Hsiang Lin, Antony Adamson, Sanjai Patel, Wyatt W. Yue, Robert W. Taylor, Janine Reunert, Thorsten Marquardt, Rebecca Buchert-Lo, Tobias Haack, Heike Losch, Lukas Ryba, Petra Lassuthova, Radka Valkovičová, Jana Haberlová, Barbora Lauerová, Eva Trúsiková, Kiran Polavarapu, Ozge Aksel Kilicarslan, Hanns Lochmüller, Mina Zamani, Niloofar Chamanrou, Gholamreza Shariati, Saeid Sadeghian, Reza Azizimalamiri, Sateesh Maddirevula, Muhammad AlMuhaizea, Fowzan S. Alkuraya, Rita Horvath, Serdal Gungor, Emma Wakeling, Adnan Manzur, Pinki Munot, Rachael Matthews, Siddharth Banka, Mary M. Reilly, Daimark Bennett, Raymond T. O’Keefe, William G. Newman
Diğer, Uluslararası, 2024,
Özet
Abstract Background Why 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. Methods We 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 humanized Drosophila model was generated to determine the effect of stress on in vivo function. Results We identified deleterious biallelic variants in human RCC1 , 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 a rcc1 deficient hamster cell line. RCC1 Drosophila models revealed a fatal intolerance to oxidative stress. Conclusion We describe a novel autosomal recessive acute onset axonal neuropathy triggered by infection caused by biallelic RCC1 variants, which mimics GBS and has important mechanistic overlap with ALS.