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Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.
journal contribution
posted on 2023-06-09, 14:28 authored by Bradley N Smith, Simon D Topp, Claudia Fallini, Hideki Shibata, Han-Jou Chen, Claire Troakes, Andrew King, Nicola Ticozzi, Kevin P Kenna, Athina Soragia-Gkazi, Jack W Miller, Akane Sato, Diana Marques Dias, Maryangel Jeon, Caroline Vance, Chun Hao Wong, Martina de Majo, Wejdan Kattuah, Jacqueline C Mitchell, Emma L Scotter, Nicholas W Parkin, Peter C Sapp, Matthew Nolan, Peter J Nestor, Michael Simpson, Michael Weale, Monkel Lek, Frank Baas, J M Vianney de Jong, Anneloor L M A ten Asbroek, Alberto Garcia Redondo, Jesús Esteban-Pérez, Cinzia Tiloca, Federico Verde, Stefano Duga, Nigel LeighNigel Leigh, Hardev Pall, Karen E Morrison, Ammar Al-Chalabi, Pamela J Shaw, Janine Kirby, Martin R Turner, Kevin Talbot, Orla Hardiman, Jonathan D Glass, Jacqueline De Belleroche, Masatoshi Maki, Stephen E Moss, Christopher Miller, Cinzia Gellera, Antonia Ratti, Safa Al-Sarraj, Robert H Brown Jr, Vincenzo Silani, John E Landers, Christopher E ShawAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases ( = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
History
Publication status
- Published
Journal
Science Translational MedicineISSN
1946-6242Publisher
American Association for the Advancement of ScienceExternal DOI
Issue
388Volume
9Page range
1Article number
eaad9157Department affiliated with
- BSMS Neuroscience Publications
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- No
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-09Usage metrics
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