WashU weekly Neuroscience publications

Gene Therapy for Retinal Degeneration
(2018) Cell, 173 (1), p. 5. 

Apte, R.S.

Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St. Louis, MO, United States

Abstract
Biallelic mutations in the RPE65 gene are associated with inherited retinal degenerations/dystrophies (IRD) and disrupt the visual cycle, leading to loss of vision. A new adenoviral vector-based gene therapy surgically delivered to retinal cells provides normal human RPE65 protein that can restore the visual cycle and some vision. To view this Bench to Bedside, open or download the PDF. Biallelic mutations in the RPE65 gene are associated with inherited retinal degenerations/dystrophies (IRD) and disrupt the visual cycle, leading to loss of vision. A new adenoviral vector-based gene therapy surgically delivered to retinal cells provides normal human RPE65 protein that can restore the visual cycle and some vision. To view this Bench to Bedside, open or download the PDF. © 2018

Document Type: Short Survey
Source: Scopus

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
(2018) Neuron, 97 (6), pp. 1268-1283.e6. 

Nicolas, A.^a , Kenna, K.P.^b , Renton, A.E.^{a c d} , Ticozzi, N.^{e f} , Faghri, F.^{g h} , Chia, R.^a , Dominov, J.A.^b , Kenna, B.J.^b , Nalls, M.A.^{g i} , Keagle, P.^b , Rivera, A.M.^a , van Rheenen, W.^j , Murphy, N.A.^a , van Vugt, J.J.F.A.^j , Geiger, J.T.^k , Van der Spek, R.A.^j , Pliner, H.A.^a , Shankaracharya^b , Smith, B.N.^l , Marangi, G.^{a m} , Topp, S.D.^l , Abramzon, Y.^{a n} , Gkazi, A.S.^l , Eicher, J.D.^o , Kenna, A.^b , Logullo, F.O.^eg , Simone, I.^eg , Logroscino, G.^eg , Salvi, F.^eg , Bartolomei, I.^eg , Borghero, G.^eg , Murru, M.R.^eg , Costantino, E.^eg , Pani, C.^eg , Puddu, R.^eg , Caredda, C.^eg , Piras, V.^eg , Tranquilli, S.^eg , Cuccu, S.^eg , Corongiu, D.^eg , Melis, M.^eg , Milia, A.^eg , Marrosu, F.^eg , Marrosu, M.G.^eg , Floris, G.^eg , Cannas, A.^eg , Capasso, M.^eg , Caponnetto, C.^eg , Mancardi, G.^eg , Origone, P.^eg , Mandich, P.^eg , Conforti, F.L.^eg , Cavallaro, S.^eg , Mora, G.^eg , Marinou, K.^eg , Sideri, R.^eg , Penco, S.^eg , Mosca, L.^eg , Lunetta, C.^eg , Pinter, G.L.^eg , Corbo, M.^eg , Riva, N.^eg , Carrera, P.^eg , Volanti, P.^eg , Mandrioli, J.^eg , Fini, N.^eg , Fasano, A.^eg , Tremolizzo, L.^eg , Arosio, A.^eg , Ferrarese, C.^eg , Trojsi, F.^eg , Tedeschi, G.^eg , Monsurrò, M.R.^eg , Piccirillo, G.^eg , Femiano, C.^eg , Ticca, A.^eg , Ortu, E.^eg , La Bella, V.^eg , Spataro, R.^eg , Colletti, T.^eg , Sabatelli, M.^eg , Zollino, M.^eg , Conte, A.^eg , Luigetti, M.^eg , Lattante, S.^eg , Marangi, G.^eg , Santarelli, M.^eg , Petrucci, A.^eg , Pugliatti, M.^eg , Pirisi, A.^eg , Parish, L.D.^eg , Occhineri, P.^eg , Giannini, F.^eg , Battistini, S.^eg , Ricci, C.^eg , Benigni, M.^eg , Cau, T.B.^eg , Loi, D.^eg , Calvo, A.^eg , Moglia, C.^eg , Brunetti, M.^eg , Barberis, M.^eg , Restagno, G.^eg , Casale, F.^eg , Marrali, G.^eg , Fuda, G.^eg , Ossola, I.^eg , Cammarosano, S.^eg , Canosa, A.^eg , Ilardi, A.^eg , Manera, U.^eg , Grassano, M.^eg , Tanel, R.^eg , Pisano, F.^eg , Mora, G.^p , Calvo, A.^q , Mazzini, L.^r , Riva, N.^s , Mandrioli, J.^t , Caponnetto, C.^u , Battistini, S.^v , Volanti, P.^p , La Bella, V.^w , Conforti, F.L.^x , Borghero, G.^y , Messina, S.^z , Simone, I.L.^aa , Trojsi, F.^ab , Salvi, F.^ac , Logullo, F.O.^ad , D’Alfonso, S.^ae , Corrado, L.^ae , Capasso, M.^af , Ferrucci, L.^ag , Harms, M.B.^eh , Goldstein, D.B.^eh , Shneider, N.A.^eh , Goutman, S.^eh , Simmons, Z.^eh , Miller, T.M.^eh , Chandran, S.^eh , Pal, S.^eh , Manousakis, G.^eh , Appel, S.H.^eh , Simpson, E.^eh , Wang, L.^eh , Baloh, R.H.^eh , Gibson, S.^eh , Bedlack, R.^eh , Lacomis, D.^eh , Sareen, D.^eh , Sherman, A.^eh , Bruijn, L.^eh , Penny, M.^eh , Moreno, C.D.A.M.^ah , Kamalakaran, S.^ai , Goldstein, D.B.^ai , Allen, A.S.^ei , Appel, S.^ei , Baloh, R.H.^ei , Bedlack, R.S.^ei , Boone, B.E.^ei , Brown, R.^ei , Carulli, J.P.^ei , Chesi, A.^ei , Chung, W.K.^ei , Cirulli, E.T.^ei , Cooper, G.M.^ei , Couthouis, J.^ei , Day-Williams, A.G.^ei , Dion, P.A.^ei , Gibson, S.^ei , Gitler, A.D.^ei , Glass, J.D.^ei , Goldstein, D.B.^ei , Han, Y.^ei , Harms, M.B.^ei , Harris, T.^ei , Hayes, S.D.^ei , Jones, A.L.^ei , Keebler, J.^ei , Krueger, B.J.^ei , Lasseigne, B.N.^ei , Levy, S.E.^ei , Lu, Y.-F.^ei , Maniatis, T.^ei , McKenna-Yasek, D.^ei , Miller, T.M.^ei , Myers, R.M.^ei , Petrovski, S.^ei , Pulst, S.M.^ei , Raphael, A.R.^ei , Ravits, J.M.^ei , Ren, Z.^ei , Rouleau, G.A.^ei , Sapp, P.C.^ei , Shneider, N.A.^ei , Simpson, E.^ei , Sims, K.B.^ei , Staropoli, J.F.^ei , Waite, L.L.^ei , Wang, Q.^ei , Wimbish, J.R.^ei , Xin, W.W.^ei , Gitler, A.D.^aj , Harris, T.^ak , Myers, R.M.^al , Phatnani, H.^ej , Kwan, J.^ej , Sareen, D.^ej , Broach, J.R.^ej , Simmons, Z.^ej , Arcila-Londono, X.^ej , Lee, E.B.^ej , Van Deerlin, V.M.^ej , Shneider, N.A.^ej , Fraenkel, E.^ej , Ostrow, L.W.^ej , Baas, F.^ej , Zaitlen, N.^ej , Berry, J.D.^ej , Malaspina, A.^ej , Fratta, P.^ej , Cox, G.A.^ej , Thompson, L.M.^ej , Finkbeiner, S.^ej , Dardiotis, E.^ej , Miller, T.M.^ej , Chandran, S.^ej , Pal, S.^ej , Hornstein, E.^ej , MacGowan, D.J.^ej , Heiman-Patterson, T.^ej , Hammell, M.G.^ej , Patsopoulos, N.A.^ej , Dubnau, J.^ej , Nath, A.^ej , Phatnani, H.^am , Musunuri, R.L.^an , Evani, U.S.^an , Abhyankar, A.^an , Zody, M.C.^an , Kaye, J.^ek , Finkbeiner, S.^ek , Wyman, S.^ek , LeNail, A.^ek , Lima, L.^ek , Fraenkel, E.^ek , Rothstein, J.D.^ek , Svendsen, C.N.^ek , Thompson, L.M.^ek , Van Eyk, J.^ek , Maragakis, N.J.^ek , Berry, J.D.^ek , Glass, J.D.^ek , Miller, T.M.^ek , Kolb, S.J.^ek , Baloh, R.H.^ek , Cudkowicz, M.^ek , Baxi, E.^ek , Kaye, J.^ao , Finkbeiner, S.^ao , Wyman, S.K.^ao , Finkbeiner, S.^ap , LeNail, A.^aq , Lima, L.^ao , Fraenkel, E.^aq , Fraenkel, E.^ar , Svendsen, C.N.^as , Svendsen, C.N.^at , Thompson, L.M.^au , Thompson, L.M.^av , Van Eyk, J.E.^aw , Berry, J.D.^ax , Berry, J.D.^ay , Miller, T.M.^az , Kolb, S.J.^ba , Cudkowicz, M.^ax , Cudkowicz, M.^ay , Baxi, E.^bb , Benatar, M.^el , Taylor, J.P.^el , Wu, G.^el , Rampersaud, E.^el , Wuu, J.^el , Rademakers, R.^el , Züchner, S.^el , Schule, R.^el , McCauley, J.^el , Hussain, S.^el , Cooley, A.^el , Wallace, M.^el , Clayman, C.^el , Barohn, R.^el , Statland, J.^el , Ravits, J.^el , Swenson, A.^el , Jackson, C.^el , Trivedi, J.^el , Khan, S.^el , Katz, J.^el , Jenkins, L.^el , Burns, T.^el , Gwathmey, K.^el , Caress, J.^el , McMillan, C.^el , Elman, L.^el , Pioro, E.^el , Heckmann, J.^el , So, Y.^el , Walk, D.^el , Maiser, S.^el , Zhang, J.^el , Benatar, M.^bc , Taylor, J.P.^bd , Taylor, J.P.^be , Rampersaud, E.^bf , Wu, G.^bf , Wuu, J.^bc , Silani, V.^em , Ticozzi, N.^em , Gellera, C.^em , Ratti, A.^em , Taroni, F.^em , Lauria, G.^em , Verde, F.^em , Fogh, I.^em , Tiloca, C.^em , Comi, G.P.^em , Sorarù, G.^em , Cereda, C.^em , D’Alfonso, S.^em , Corrado, L.^em , De Marchi, F.^em , Corti, S.^em , Ceroni, M.^em , Mazzini, L.^em , Siciliano, G.^em , Filosto, M.^em , Inghilleri, M.^em , Peverelli, S.^em , Colombrita, C.^em , Poletti, B.^em , Maderna, L.^em , Del Bo, R.^em , Gagliardi, S.^em , Querin, G.^em , Bertolin, C.^em , Pensato, V.^em , Castellotti, B.^em , Lauria, G.^bg , Verde, F.^e , Fogh, I.^e , Tiloca, C.^e , Fogh, I.^l , Comi, G.P.^bh , Sorarù, G.^bi , Cereda, C.^bj , Camu, W.^en , Mouzat, K.^en , Lumbroso, S.^en , Corcia, P.^en , Meininger, V.^en , Besson, G.^en , Lagrange, E.^en , Clavelou, P.^en , Guy, N.^en , Couratier, P.^en , Vourch, P.^en , Danel, V.^en , Bernard, E.^en , Lemasson, G.^en , Corcia, P.^bk , Laaksovirta, H.^bl , Myllykangas, L.^bm , Jansson, L.^bl , Valori, M.^bl , Ealing, J.^bn , Hamdalla, H.^bn , Rollinson, S.^bo , Pickering-Brown, S.^bo , Orrell, R.W.^bp , Sidle, K.C.^bq , Malaspina, A.^br , Hardy, J.^bq , Singleton, A.B.^g , Johnson, J.O.^a , Arepalli, S.^bs , Sapp, P.C.^b , McKenna-Yasek, D.^b , Polak, M.^bt , Asress, S.^bt , Al-Sarraj, S.^l , King, A.^l , Troakes, C.^l , Vance, C.^l , de Belleroche, J.^bu , Baas, F.^bv , ten Asbroek, A.L.M.A.^bw , Muñoz-Blanco, J.L.^bx , Hernandez, D.G.^bs , Ding, J.^by , Gibbs, J.R.^by , Scholz, S.W.^k , Scholz, S.W.^bb , Floeter, M.K.^bz , Campbell, R.H.^h , Landi, F.^ca , Bowser, R.^cb , Pulst, S.M.^cc , Ravits, J.M.^cd , MacGowan, D.J.L.^ce , Kirby, J.^cf , Pioro, E.P.^cg , Pamphlett, R.^ch , Broach, J.^ci , Gerhard, G.^cj , Dunckley, T.L.^ck , Brady, C.B.^cl , Brady, C.B.^cm , Kowall, N.W.^cn , Troncoso, J.C.^{co cz da} , Le Ber, I.^cp , Mouzat, K.^cq , Lumbroso, S.^cq , Mouzat, K.^cr , Lumbroso, S.^cr , Heiman-Patterson, T.D.^cs , Heiman-Patterson, T.D.^ct , Kamel, F.^cu , Van Den Bosch, L.^cv , Van Den Bosch, L.^cw , Baloh, R.H.^cx , Strom, T.M.^cy , Meitinger, T.^cy , Strom, T.M.^cz , Shatunov, A.^l , Van Eijk, K.R.^j , de Carvalho, M.^db , de Carvalho, M.^dc , Kooyman, M.^dd , Middelkoop, B.^j , Moisse, M.^cv , Moisse, M.^cw , McLaughlin, R.L.^de , Van Es, M.A.^j , Weber, M.^df , Boylan, K.B.^dg , Van Blitterswijk, M.^dh , Rademakers, R.^dh , Morrison, K.E.^di , Basak, A.N.^dj , Mora, J.S.^dk , Drory, V.E.^dl , Shaw, P.J.^cf , Turner, M.R.^dm , Talbot, K.^dm , Hardiman, O.^dn , Williams, K.L.^do , Fifita, J.A.^do , Nicholson, G.A.^do , Blair, I.P.^do , Nicholson, G.A.^dp , Rouleau, G.A.^dq , Esteban-Pérez, J.^dr , García-Redondo, A.^dr , Al-Chalabi, A.^l , Al Kheifat, A.^eo , Al-Chalabi, A.^eo , Andersen, P.^eo , Basak, A.N.^eo , Blair, I.P.^eo , Chio, A.^eo , Cooper-Knock, J.^eo , Corcia, P.^eo , Couratier, P.^eo , de Carvalho, M.^eo , Dekker, A.^eo , Drory, V.^eo , Redondo, A.G.^eo , Gotkine, M.^eo , Hardiman, O.^eo , Hide, W.^eo , Iacoangeli, A.^eo , Glass, J.^eo , Kenna, K.^eo , Kiernan, M.^eo , Kooyman, M.^eo , Landers, J.^eo , McLaughlin, R.^eo , Middelkoop, B.^eo , Mill, J.^eo , Neto, M.M.^eo , Moisse, M.^eo , Pardina, J.M.^eo , Morrison, K.^eo , Newhouse, S.^eo , Pinto, S.^eo , Pulit, S.^eo , Robberecht, W.^eo , Shatunov, A.^eo , Shaw, P.^eo , Shaw, C.^eo , Silani, V.^eo , Sproviero, W.^eo , Tazelaar, G.^eo , Ticozzi, N.^eo , van Damme, P.^eo , van den Berg, L.^eo , van der Spek, R.^eo , van Eijk, K.^eo , van Es, M.^eo , van Rheenen, W.^eo , van Vugt, J.^eo , Veldink, J.^eo , Weber, M.^eo , Williams, K.L.^eo , Van Damme, P.^{cw dx} , Robberecht, W.^dx , Zatz, M.^eo , Robberecht, W.^cw , Bauer, D.C.^eo , Twine, N.A.^eo , Rogaeva, E.^ds , Zinman, L.^dt , Ostrow, L.W.^bb , Maragakis, N.J.^bb , Rothstein, J.D.^bb , Simmons, Z.^du , Cooper-Knock, J.^cf , Brice, A.^cp , Goutman, S.A.^dv , Feldman, E.L.^dv , Gibson, S.B.^cc , Taroni, F.^dw , Ratti, A.^e , Ratti, A.^f , Gellera, C.^dw , Van Damme, P.^cv , Robberecht, W.^{cv ep} , Fratta, P.^{n ep} , Sabatelli, M.^{dy ep ep} , Lunetta, C.^{dz ep ep} , Ludolph, A.C.^{ea ep ep} , Andersen, P.M.^{eb ep ep} , Weishaupt, J.H.^{ea ep ep} , Camu, W.^{ec ep ep} , Trojanowski, J.Q.^{ed ep ep} , Van Deerlin, V.M.^ed , Brown, R.H., Jr.^b , van den Berg, L.H.^j , Veldink, J.H.^j , Harms, M.B.^ah , Glass, J.D.^bt , Stone, D.J.^ee , Tienari, P.^bl , Silani, V.^e , Silani, V.^f , Chiò, A.^q , Shaw, C.E.^l , Chiò, A.^ef , Traynor, B.J.^a , Landers, J.E.^b , Traynor, B.J.^bb

^a Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, United States
^b Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States
^c Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^e Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
^f Department of Pathophysiology and Transplantation, “Dino Ferrari” Center – Università degli Studi di Milano, Milan, Italy
^g Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, United States
^h Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States
ⁱ Data Tecnica International, Glen Echo, MD, United States
^j Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht the, Netherlands
^k Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, NIH Bethesda, MD, United States
^l Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London, United Kingdom
^m Institute of Genomic Medicine, Catholic University, Roma, Italy
ⁿ Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom
^o Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA, United States
^p ALS Center, Salvatore Maugeri Foundation, IRCCS, Mistretta, Messina, Italy
^q “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy
^r “Maggiore della Carità” University Hospital, Novara, Italy
^s Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
^t Department of Neuroscience, St. Agostino Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy
^u Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation, Maternal and Child Health, Ospedale Policlinico San Martino, Genoa, Italy
^v Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
^w ALS Clinical Research Center, University of Palermo, Palermo, Italy
^x Institute of Neurological Sciences, National Research Council, Mangone Cosenza, Italy
^y Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy
^z Department of Clinical and Experimental Medicine, University of Messina and Nemo Sud Clinical Center for Neuromuscular Diseases, Aurora Foundation, Messina, Italy
^aa Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
^ab Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy
^ac “Il Bene” Center for Immunological and Rare Neurological Diseases at Bellaria Hospital, IRCCS, Istituto delle Scienze Neurologiche, Bologna, Italy
^ad Neurological Clinic, Marche Polytechnic University, Ancona, Italy
^ae Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
^af Department of Neurology, University of Chieti, Chieti, Italy
^ag Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, NIH Baltimore, MD, United States
^ah Department of Neurology, Columbia University, New York, NY, United States
^ai Institute for Genomic Medicine, Columbia University, New York, NY, United States
^aj Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
^ak Bioverativ, 225 2nd Avenue, Waltham, MA, United States
^al HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States
^am Center for Genomics of Neurodegenerative Diseases (CGND), New York Genome Center, New York, NY, United States
^an Computational Biology, New York Genome Center, New York, NY, United States
^ao Gladstone Institute of Neurological Disease, San Francisco, CA, United States
^ap Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA, United States
^aq Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, United States
^ar Broad Institute, 415 Main Street, Cambridge, MA, United States
^as Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^at Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^au Department of Neurobiology and Behavior, Institute of Memory Impairment and Neurological Disorders, University of California, Irvine Irvine, CA, United States
^av Department of Psychiatry and Human Behavior, Institute of Memory Impairment and Neurological Disorders, University of California, Irvine Irvine, CA, United States
^aw The Heart Institute and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^ax Harvard Medical School, Department of Neurology, Massachusetts General Hospital (MGH), Boston, MA, United States
^ay Neurological Clinical Research Institute (NCRI), Massachusetts General Hospital, Boston, MA, United States
^az Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^ba Department of Neurology, The Ohio State University Wexner Medical Center, ColumbusOH, United States
^bb Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^bc Department of Neurology, University of Miami, Miami, FL, United States
^bd Howard Hughes Medical Institute, Chevy Chase, MD, United States
^be Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^bf Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^bg 3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico “Carlo Besta, ” and Department of Biomedical and Clinical Sciences “Luigi Sacco” University of Milan, Milan, Italy
^bh Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
^bi Department of Neurosciences, University of Padova, Padova, Italy
^bj Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy
^bk ALS Center, CHU Bretonneau, Tours University, Tours, France
^bl Department of Neurology, Helsinki University Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki FIN-02900, Finland
^bm Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^bn Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Salford, United Kingdom
^bo Faculty of Human and Medical Sciences, University of Manchester, Manchester, United Kingdom
^bp Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom
^bq Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London, United Kingdom
^br Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, NorthEast London and Essex Regional Motor Neuron Disease Care Centre, London, United Kingdom
^bs Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, United States
^bt Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^bu Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom
^bv Department of Clinical Genetics, Leiden University Medical Center, Leiden the, Netherlands
^bw Department of Neurogenetics and Neurology, Academic Medical Centre, Amsterdam the, Netherlands
^bx ALS-Neuromuscular Unit, Hospital General Universitario Gregorio Marañón, IISGM Madrid, Spain
^by Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD, United States
^bz Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, NIH Bethesda, MD, United States
^ca Center for Geriatric Medicine, Department of Geriatrics, Neurosciences and Orthopedics, Catholic University of Sacred HeartRome, Italy
^cb Division of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^cc Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, United States
^cd Department of Neuroscience, University of California, San Diego, La JollaCA, United States
^ce Mount Sinai Beth Israel Hospital, Mount Sinai School of Medicine, New York, NY, United States
^cf Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
^cg Department of Neurology, Neuromuscular Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
^ch Discipline of Pathology, Brain and Mind Centre, The University of Sydney, 94 Mallett Street, Camperdown, NSW, Australia
^ci Department of Biochemistry, Penn State College of Medicine, Hershey, PA, United States
^cj Department of Pathology, Penn State College of Medicine, Hershey, PA, United States
^ck Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
^cl Research and Development Service, Veterans Affairs Boston Healthcare System, Boston, MA, United States
^cm Department of Neurology, Program in Behavioral Neuroscience, Boston University School of Medicine, Boston, MA, United States
^cn Neurology Service, VA Boston Healthcare System and Boston University Alzheimer’s Disease Center, Boston, MA, United States
^co Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^cp Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), Assistance Publique Hôpitaux de Paris (AP-HP) – Hôpital Pitié-Salpêtrière, Paris, France
^cq INM, University Montpellier, Montpellier, France
^cr Department of Biochemistry, CHU Nîmes, Nîmes, France
^cs Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, United States
^ct Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
^cu Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC, United States
^cv KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium
^cw VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium
^cx Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^cy Institute of Human Genetics, Technische Universität München, Munich, Germany
^cz Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^da Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^db Institute of Physiology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
^dc Department of Neurosciences, Hospital de Santa Maria-CHLN, Lisbon, Portugal
^dd SURFsara, Amsterdam, Netherlands
^de Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
^df Neuromuscular Diseases Center/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland
^dg Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
^dh Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
^di Faculty of Medicine, University of Southampton, Southampton, United Kingdom
^dj Suna and Inan Kırac Foundation, Neurodegeneration Research Laboratory, Bogazici University, Istanbul, Turkey
^dk ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain
^dl Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel
^dm Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
^dn Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
^do Centre for MND Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
^dp ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, NSW, Australia
^dq Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
^dr Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid, Spain
^ds Tanz Centre for Research of Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
^dt Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
^du Department of Neurology, Penn State Hershey Medical Center, Hershey, PA, United States
^dv Department of Neurology, University of Michigan, Ann Arbor, MI, United States
^dw Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
^dx University Hospitals Leuven, Department of Neurology, Leuven, Belgium
^dy Centro Clinico NeMO, Institute of Neurology, Catholic University, Largo F. Vito 1, Rome, Italy
^dz NEuroMuscular Omnicenter (NEMO), Serena Onlus Foundation, Milan, Italy
^ea Neurology Department, Ulm University, Albert-Einstein-Allee 11, Ulm, Germany
^eb Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
^ec ALS Center, CHU Gui de Chauliac, University of Montpellier, Montpellier, France
^ed Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ee Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., West PointPA, United States
^ef Neuroscience Institute of Torino, Turin, Italy

Abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS. © 2018 Elsevier Inc.

Author Keywords
ALS;  axonal transport;  cargo;  GWAS;  KIF5A;  WES;  WGS

Document Type: Article
Source: Scopus