Journal article
De novo mutations in ATP1A3 cause alternating hemiplegia of childhood
Erin L Heinzen, Kathryn J Swoboda, Yuki Hitomi, Fiorella Gurrieri, Sophie Nicole, Boukje de Vries, F Danilo Tiziano, Bertrand Fontaine, Nicole M Walley, Sinead Heavin, Eleni Panagiotakaki, Stefania Fiori, Emanuela Abiusi, Lorena Di Pietro, Matthew T Sweney, Tara M Newcomb, Louis Viollet, Chad Huff, Lynn B Jorde, Sandra P Reyna Show all
Nature Genetics | NATURE PUBLISHING GROUP | Published : 2012
DOI: 10.1038/ng.2358
Abstract
Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1..
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Awarded by Joseph and Kathleen Bryan Alzheimer's Disease Research Center from the National Institutes of Health (NIH), including the National Institute of Allergy and Infectious Disease
Awarded by National Institute on Aging
Awarded by National Institute of Neurological Disorders and Stroke
Awarded by National Institute of Mental Health
Awarded by Wellcome Trust
Awarded by National Center for Research Resources
Awarded by NIH
Awarded by Center for Medical Systems Biology established in The Netherlands Genomics Initiative and The Netherlands Organisation for Scientific Research
Awarded by NATIONAL CENTER FOR RESEARCH RESOURCES
Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH
Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Awarded by NATIONAL INSTITUTE ON AGING
Funding Acknowledgements
We thank the Italian Patient Association for Alternating Hemiplegia (AISEA Onlus) for coordinating and funding the project I.B.AHC Biobank and Clinical Registry for Alternating Hemiplegia. Specifically, we thank M.T. Bassi and E. Tenderini for preparing all of the samples from AHC-affected individuals for analysis. Many thanks also to the Scientific Institute E. Medea, which hosts the I.B.AHC Biobank according to the I.B.AHC protocol.The following individuals contributed next-generation sequenced control samples to this study: D. Attix, E. Behr, R. Brown, J. Burke, D. Daskalakis, V. Dixon, Z. Farfel, R. Gbadegesin, A. Holden, E. Holtzman, J. Hoover-Fong, C. Hulette, S. Kerns, D. Lancet, D. Levy, N. Liang, W. Lowe, P. Lugar, D. Marchuk, J. McEvoy, J. Milner, H. Oster, R. Ottman, S. Palmer, E. Pras, V. Shashi, N. Sobriera, D. Valle, K. Welsh-Bohmer and M. Winn, as well as the MURDOCK study community registry. Funding for the collection and sequencing of control samples was provided by the Center for Human Genome Variation, the Center for HIV/AIDS Vaccine Immunology and the Joseph and Kathleen Bryan Alzheimer's Disease Research Center under grants from the National Institutes of Health (NIH), including the National Institute of Allergy and Infectious Disease (UO1AIO67854); the National Institute on Aging (P30 AG028377); the National Institute of Neurological Disorders and Stroke (RC2NS070344 and 1RC2NS070342-01) and the National Institute of Mental Health (RC2MH089915).This study was funded in part by grants from the AHCF (to K.J.S., S.P.R. and T.M.N.); the ENRAH for SMEs Consortium under the European Commission Sixth Framework Programme; the Institut National de la Sante et de la Recherche Medicale (to S.N. and B.F.); the Centre National de la Recherche Scientifique (to S.N. and B.F.); the University Pierre and Marie Curie (to S.N. and B.F.); the Association Francaise Contre les Myopathies (to S.N. and B.F.); the Association Francaise de l'Hemiplegie Alternante (to S.N., A.M.J.M.v.d.M. and B.d.V.); AISEA Onlus (to F.G. and G.N.); the Center for Human Genome Variation; the Wellcome Trust (084730 to S.M.S.); the National Center for Research Resources (UL1RR025764 to the University of Utah Center for Clinical and Translational Sciences; K.J.S.); the NIH (1T32HL105321-01 to C.H.); the University of Luxembourg Institute for Systems Biology Program (to C.H.) and the Center for Medical Systems Biology established in The Netherlands Genomics Initiative and The Netherlands Organisation for Scientific Research (project 050-060-409 to A.M.J.M.v.d.M. and M.D.F.). S.N. is a recipient of a Contrat d'Interface from Assistance Publique-Hopitaux de Paris.