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1. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Author

Kenna, K.P., van Doormaal, P.T.C., Dekker, A.M., Ticozzi, N., Kenna, B.J., Diekstra, F.P., van Rheenen, W., van Eijk, K.R., Jones, A.R., Keagle, P., Shatunov, A., Sproviero, W., Smith, B.N., van Es, M.A., Topp, S.D., Kenna, A., Miller, J.W., Fallini, C., Tiloca, C., McLaughlin, R.L., Vance, C., Troakes, C., Colombrita, C., Mora, G., Calvo, A., Verde, F., Al-Sarraj, S., King, A., Calini, D., de Belleroche, J., Baas, F., van der Kooi, A.J., de Visser, M., ten Asbroek, A.L.M.A., Sapp, P.C., McKenna-Yasek, D., Polak, M., Asress, S., Muñoz-Blanco, J.L., Strom, T.M., Meitinger, T., Morrison, K.E., D'Alfonso, S., Mazzini, L., Comi, G.P., Del Bo, R., Ceroni, M., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Corti, S., Cereda, C., Corrado, L., Sorarù, G., Lauria, G., Williams, K.L., Leigh, P.N., Nicholson, G.A., Blair, I.P., Leblond, C.S., Dion, P.A., Rouleau, G.A., Pall, H., Shaw, P.J., Turner, M.R., Talbot, K., Taroni, F., Boylan, K.B., Van Blitterswijk, M., Rademakers, R., Esteban-Pérez, J., García-Redondo, A., Van Damme, P., Robberecht, W., Chio, A., Gellera, C., Drepper, C., Sendtner, M., Ratti, A., Glass, J.D., Mora, J.S., Basak, N.A., Hardiman, O., Ludolph, A.C., Andersen, P.M., Weishaupt, J.H., Brown, R.H., Al-Chalabi, A., Silani, V., Shaw, C.E., van den Berg, L.H., Veldink, J.H., Landers, J.E., Medical Research Council (MRC), Human Genetics, Neurology, ANS - Neurodegeneration, and SLAGEN Consortium

Subjects
0301 basic medicine, medicine.medical_specialty, Genomics, Biology, medicine.disease_cause, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Genetics, medicine, Humans, Comparative Study, Exome, Genetic Predisposition to Disease, SLAGEN Consortium, Risk factor, Amyotrophic lateral sclerosis, Gene, Genetic Association Studies, Netherlands, Mutation, Amyotrophic Lateral Sclerosis, Case-control study, 11 Medical And Health Sciences, 06 Biological Sciences, medicine.disease, 3. Good health, NIMA-Related Kinase 1, 030104 developmental biology, RC0346, Case-Control Studies, Medical genetics, Human medicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology. ispartof: Nature Genetics vol:48 issue:9 pages:1037-+ ispartof: location:United States status: published

Published
2016
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2. Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Author

Amitai D. Mandelbaum, Jesus S. Mora, Giancarlo Costaguta, Timothy M. Miller, Guy Haim, Revital Ravid, Ofer Yizhar, Cristiane de Araújo Martins Moreno, Irit Reichenstein, Tsviya Olender, Nicole M. Bode, Smita Saxena, Karen E. Morrison, Hemali Phatnani, Natali Rivkin, Orla Hardiman, Robert H. Brown, Matthew B. Harms, Kim A. Lennox, Kristel R. van Eijk, Jing Liang, Sandra Diaz-Garcia, A. Nazli Basak, Gilad Beck, Samuel L. Pfaff, John Ravits, Chen Eitan, Thomas Möller, Beáta Tóth, Jan H. Veldink, Eran Yanowski, Sali M.K. Farhan, Pamela J. Shaw, Ammar Al-Chalabi, Iddo Magen, Mark A. Behlke, Leonard H. van den Berg, John Landers, Rivka Levy, Elena Ainbinder, Jeffrey K. Rymer, Eran Hornstein, Christina Gross, Aviad Siany, Mariah L. Hoye, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Reichenstein,I., Eitan, C., Diaz-Garcia, S., Haim, G., Magen, I., Siany, A., Hoye, M.L., Rivkin, N., Olender, T., Toth, B., Ravid, R., Mandelbaum, A.D., Yanowski, E., Liang, J., Rymer, J.K., Levy, R., Beck, G., Ainbinder, E., Farhan,S.M.K., Lennox, K.A., Bode, N.M., Behlke, M.A., Möller, T., Saxena, S., Moreno, C.A.M., Costaguta, G., van Eijk, K.R., Phatnani, H., Al-Chalabi, A., van den Berg, L.H., Hardiman, O., Landers, J.E., Mora, J.S., Morrison, K.E., Shaw, P.J., Veldink, J.H., Pfaff S.L., Yizhar, O., Gross, C., Brown, R.H. Jr., Ravits, J.M., Harms, M.B., Miller, T.M., Hornstein, E., and Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM)

Subjects
Neuropathology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Journal Article, Premovement neuronal activity, Animals, Humans, Amyotrophic lateral sclerosis, 610 Medicine & health, Gene, 030304 developmental biology, Motor Neurons, Neurons, 0303 health sciences, biology, Amyotrophic Lateral Sclerosis, General Medicine, Motor neuron, medicine.disease, Transgenic mouse model, In-situ detection, Motor-neurons, RNA interference, Rare variants, Microrna, ALS, Motoneurons, Disease, Excitability, Human genetics, Ether-A-Go-Go Potassium Channels, MicroRNAs, medicine.anatomical_structure, nervous system, biology.protein, 570 Life sciences, Cell biology, Medicine, research and experimental, Neuron, Neuroscience, 030217 neurology & neurosurgery, Dicer
Abstract

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre

Published
2018

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