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

• Type of Material: Article
• Authors: Bradley N. Smith, King's College London; Simon D. Topp, King's College London; Claudia Fallini, University of Massachusetts; Hideki Shibata, Nagoya University; Han-Jou Chen, King's College London; Claire Troakes, King's College London; Andrew King, King's College London; Nicola Ticozzi, University of Milan; Kevin P. Kenna, University of Massachusetts; Athina Soragia-Gkazi, King's College London; Jack W. Miller, King's College London; Akane Sato, Nagoya University; Diana Marques Dias, King's College London; Maryangel Jeon, University of Massachusetts; Caroline Vance, King's College London; Chun Hao Wong, King's College London; Martina de Majo, King's College London; Wejdan Kattuah, King's College London; Jacqueline C. Mitchell, King's College London; Emma L. Scotter, University of Auckland; Nicholas W. Parkin, Guy’s Hospital; Peter C. Sapp, University of Massachusetts; Matthew Nolan, King's College London; Peter J. Nestor, German Center for Neurodegenerative Diseases; Michael Simpson, King's College London; Michael Weale, King's College London; Monkel Lek, Massachusetts General Hospital; Frank Baas, University of Amsterdam; J.M. Vanney de Jong, University of Amsterdam; Jonathan Glass, Emory University
• Language: English
• Date: 2017-05-03
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aad9157
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 9
• Issue: 388
• Start Page: eaad9157
• End Page: eaad9157
• Grant/Funding Information: See publication for full funding statement.
• Keywords: GENE; GENOME-WIDE ASSOCIATION; Medicine, Research & Experimental; FRONTOTEMPORAL DEMENTIA; Life Sciences & Biomedicine; S100A6; CU/ZN SUPEROXIDE-DISMUTASE; FAMILIAL ALS; TDP-43; Research & Experimental Medicine; RETICULUM EXIT SITES; Science & Technology; CALCIUM-BINDING; Cell Biology; COMMON FOUNDER
• Research Categories: Biology, Genetics; Biology, Neuroscience

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 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. 2017