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

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 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, Vincenzo Silani, John E Landers, Christopher E Shaw

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 ANXA11 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 (P = 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 ANXA11 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 ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.