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

Kevin Talbot, 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, Janine Kirby, Martin R Turner, Frank Baas, 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, Maryangel Jeon, 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, Pamela J Shaw, 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

Journal: Science translational medicine 2018;9(388):eaad9157

PMID: 28469040

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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.

Address: United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, Camberwell, SE5 9NU London, UK.; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.; Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.; Department of Neurology and Laboratory of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, 20149 Milan, Italy.; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, 20122 Milan, Italy.; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.; Molecular Genetics Laboratory, Viapath, Genetics Centre, Guy's Hospital, Great Maze Pond, SE1 9RT London, UK.; German Center for Neurodegenerative Diseases, Leipziger Str. 44, 39120 Magdeburg, Germany.; Medical & Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, Guy's Tower, London Bridge, SE1 9RT London, UK.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.; Department of Genome Analysis, University of Amsterdam, Academic Medical Centre, P.O. Box 22700, 1100DE Amsterdam, Netherlands.; Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U-723 Madrid, Spain.; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.; Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy.; Trafford Centre for Medical Research, Brighton and Sussex Medical School, BN1 9RY Brighton, UK.; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.; University of Southampton, Southampton General Hospital, SO16 6YD, UK.; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.; Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.; Department of Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.; Neurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, W12 0NN London, UK.; Institute of Ophthalmology, University College London, 11-43 Bath Street, EC1V 9EL London, UK.; Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta," 20133 Milan, Italy.; United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, Camberwell, SE5 9NU London, UK. [email protected].

DOI: 10.1126/scitranslmed.aad9157

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MeSH Terms: Amyotrophic Lateral Sclerosis, Annexins, Human Embryonic Stem Cells, Humans, Mutation, Protein Binding, Protein Transport, S100 Calcium Binding Protein A6