Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.

Smith, Bradley N, Topp, Simon D, Fallini, Claudia, Shibata, Hideki, Chen, Han-Jou, Troakes, Claire, King, Andrew, Ticozzi, Nicola, Kenna, Kevin P, Soragia-Gkazi, Athina, Miller, Jack W, Sato, Akane, Dias, Diana Marques, Jeon, Maryangel, Vance, Caroline, Wong, Chun Hao, de Majo, Martina, Kattuah, Wejdan, Mitchell, Jacqueline C, Scotter, Emma L, Parkin, Nicholas W, Sapp, Peter C, Nolan, Matthew, Nestor, Peter J, Simpson, Michael, Weale, Michael, Lek, Monkel, Baas, Frank, Vianney de Jong, J M, ten Asbroek, Anneloor L M A, Redondo, Alberto Garcia, Esteban-Pérez, Jesús, Tiloca, Cinzia, Verde, Federico, Duga, Stefano, Leigh, Nigel, Pall, Hardev, Morrison, Karen E, Al-Chalabi, Ammar, Shaw, Pamela J, Kirby, Janine, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Glass, Jonathan D, De Belleroche, Jacqueline, Maki, Masatoshi, Moss, Stephen E, Miller, Christopher, Gellera, Cinzia, Ratti, Antonia, Al-Sarraj, Safa, Brown Jr, Robert H, Silani, Vincenzo, Landers, John E and Shaw, Christopher E (2017) Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Science Translational Medicine, 9 (388). eaad9157 1 -15. ISSN 1946-6242

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Abstract

Amyotrophic 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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
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Depositing User: Patricia Butler
Date Deposited: 09 Aug 2018 12:25
Last Modified: 09 Aug 2018 12:28
URI: http://sro.sussex.ac.uk/id/eprint/77724
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