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De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Nature Genetics volume 44, pages 1030–1034 (2012)Cite this article

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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 ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

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Figure 1: ATP1A3 mutations and encoded protein modifications associated with AHC and DYT12.
Figure 2: Pedigree of a family with autosomal dominant AHC1.
Figure 3: Effects of disease-causing mutations on protein expression and enzyme activity in COS-7 cells.

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Acknowledgements

We are deeply indebted to all the AHC-affected families for their participation in this study. We would like to thank the Alternating Hemiplegia of Childhood Foundation (AHCF) for their efforts in coordinating the collection of US samples and the facilitation of US research collaboration. We also would like to thank D. Poncelin (French Family Foundation) and R. Vavassori (Italian AHC Family Foundation) for facilitating the international collaboration.

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.

We also thank the ENRAH for the SMEs Consortium, the ENRAH validation committee and all collaborating physicians for the data collection5. We are also grateful to the DNA and cell bank of Genethon for the processing of French blood samples.

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 Santé et de la Recherche Médicale (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 Française Contre les Myopathies (to S.N. and B.F.); the Association Française de l'Hémiplégie 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-Hôpitaux de Paris.

Author information

Author notes

  1. Erin L Heinzen, Kathryn J Swoboda, Yuki Hitomi and Tsveta Schyns: These authors contributed equally to this work.

  2. Francis Crawley, Sanjay M Sisodiya, Mohamad A Mikati and David B Goldstein: These authors jointly directed this work.

Authors and Affiliations

  1. Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA

    Erin L Heinzen, Yuki Hitomi, Nicole M Walley, Kevin V Shianna, Curtis E Gumbs, Latasha Little & David B Goldstein

  2. Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA

    Erin L Heinzen & Kevin V Shianna

  3. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA

    Kathryn J Swoboda, Matthew T Sweney & Tara M Newcomb

  4. Department of Neurology, University of Utah, Salt Lake City, Utah, USA

    Kathryn J Swoboda, Louis Viollet, Sandra P Reyna & Kelley J Murphy

  5. Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy

    Fiorella Gurrieri, F Danilo Tiziano, Fiorella Gurrieri, Giovanni Neri, Fiorella Gurrieri, Giovanni Neri, Stefania Fiori, Emanuela Abiusi, Lorena Di Pietro & Giovanni Neri

  6. Université Pierre et Marie Curie, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière UMR S975, Paris, France.,

    Sophie Nicole, Bertrand Fontaine, Sophie Nicole & Sophie Nicole

  7. Institut National de la Santé et de la Recherche Médicale, U975, Paris, France.,

    Sophie Nicole, Bertrand Fontaine, Sophie Nicole & Sophie Nicole

  8. Centre National de la Recherche Scientifique, UMR7225, Paris, France.,

    Sophie Nicole, Bertrand Fontaine, Sophie Nicole & Sophie Nicole

  9. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands

    Boukje de Vries, Boukje de Vries, Stephany Koelewijn, Jessica Kamphorst, Marije Geilenkirchen, Arn van den Maagdenberg, Arn van den Maagdenberg & Arn M J M van den Maagdenberg

  10. Département de Neurologie & Centre de Référence Canalopathies Musculaires, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier de la Pitié-Salpêtrière, Paris, France

    Bertrand Fontaine

  11. Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia

    Sinéad Heavin & Ingrid E Scheffer

  12. Sleep and Pediatric Neurophysiology Department, Epilepsy, Woman-Mother-Child Hospital, University Hospitals of Lyon (HCL), Lyon, France

    Eleni Panagiotakaki, Eleni Panagiotakaki, Alexis Arzimanoglou & Alexis Arzimanoglou

  13. Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, USA

    Chad Huff & Lynn B Jorde

  14. Department of Neurology, Comer Children's Hospital, University of Chicago, Chicago, Illinois, USA

    Kenneth Silver

  15. Department of Pediatrics, Comer Children's Hospital, University of Chicago, Chicago, Illinois, USA

    Kenneth Silver

  16. Department of Neurology, University of California, San Francisco, San Francisco, California, USA

    Louis J Ptáček

  17. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA

    Louis J Ptáček

  18. Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands

    Joost Haan & Joost Haan

  19. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

    Nadine Pelzer, Laura Laan, Joost Haan, Michel Ferrari, Arn van den Maagdenberg, Laura Laan, Cacha Peeters-Scholte, Arn van den Maagdenberg, Joost Haan, Michel D Ferrari & Arn M J M van den Maagdenberg

  20. Department of Paediatric Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia

    Ann M Bye

  21. University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales, Australia.,

    Geoffrey K Herkes

  22. Northern Clinical School, University of Sydney, and Royal North Shore Hospital, Sydney, Australia

    Charlotte M Whitelaw

  23. Our Lady's Children's Hospital, Crumlin, Dublin, Ireland

    David Webb

  24. The Children's University Hospital, Temple Street, Dublin, Ireland.,

    Bryan J Lynch & Mary D King

  25. Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Peter Uldall

  26. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia

    Ingrid E Scheffer

  27. Florey Neuroscience Institutes, Melbourne, Australia

    Ingrid E Scheffer

  28. Institut National de la Santé et de la Recherche Médicale, U1028, Centre de Recherche en Neurosciences de Lyon, Lyon, France

    Alexis Arzimanoglou & Alexis Arzimanoglou

  29. Centre National de la Recherche Scientifique, UMR 5292, Lyon, France.,

    Alexis Arzimanoglou & Alexis Arzimanoglou

  30. Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK

    Sanjay M Sisodiya

  31. Division of Pediatric Neurology, Duke University Medical Center, Durham, North Carolina, USA

    Mohamad A Mikati

  32. Department of Neurobiology, Duke University, Durham, North Carolina, USA

    Mohamad A Mikati

  33. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA

    David B Goldstein

  34. Clinical Neurophysiology Unit, Scientific Institute E. Medea, Lecco, Italy

    Claudio Zucca & Claudio Zucca

  35. Laboratory of Molecular Biology, Scientific Institute E. Medea, Lecco, Italy

    Maria Teresa Bassi & Maria Teresa Bassi

  36. Associazione Italiana per la Sindrome di Emiplegia Alternante (AISEA) Onlus, Lecco, Italy

    Filippo Franchini, Rosaria Vavassori & Rosaria Vavassori

  37. Child Neurology Unit, Maggiore Hospital, Bologna, Italy

    Melania Giannotta, Giuseppe Gobbi, Melania Giannotta & Giuseppe Gobbi

  38. Department of Child Neurology, National Neurological Institute C. Besta, Milan, Italy

    Tiziana Granata & Nardo Nardocci

  39. Department of Child Neuropsychiatry, G. Gaslini Hospital, University of Genoa, Genoa, Italy

    Elisa De Grandis, Edvige Veneselli & Michela Stagnaro

  40. Division of Neurology, Bambino Gesù Children's Hospital, Rome, Italy

    Federico Vigevano

  41. Department of Child Neurology, Heidelberg University Hospital, Heidelberg, Germany

    Claudia Oechsler & Friedrich Ebinger

  42. Neurosciences Unit, University College London Institute of Child Health, London, UK

    Miriam Ninan & Brian Neville

  43. Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain

    Carmen Fons & Jaume Campistol

  44. Department of Neurology, Charles University, First Faculty of Medicine and Teaching Hospital, Prague, Czech Republic

    David Kemlink & Sona Nevsimalova

  45. Department of Child Neurology, University Hospital Gasthuisberg, Leuven, Belgium

    Paul Casaer

  46. Department of Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy

    Giorgio Casari & Filippo Martinelli Boneschi

  47. Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy

    Giorgio Casari & Filippo Martinelli Boneschi

  48. Department of Neurology and Psychiatry of Children and Adolescents, General Hospital, Klagenfurt, Austria

    Guenter Sange & Georg Spiel

  49. The ENRAH Association, Brussels, Belgium

    Tsveta Schyns

  50. Good Clinical Practice Alliance—Europe (GCPA), Kessel-Lo, Belgium

    Francis Crawley

  51. Association Française de l'Hémiplégie Alternante (AFHA), St. Germain les Arpajon, France

    Dominique Poncelin

Authors
  1. Erin L Heinzen
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  2. Kathryn J Swoboda
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  3. Yuki Hitomi
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  4. Fiorella Gurrieri
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  5. Sophie Nicole
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  6. Boukje de Vries
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  7. F Danilo Tiziano
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  8. Bertrand Fontaine
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  9. Nicole M Walley
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  10. Sinéad Heavin
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  11. Eleni Panagiotakaki
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  12. Stefania Fiori
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  13. Emanuela Abiusi
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  14. Lorena Di Pietro
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  15. Matthew T Sweney
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  16. Tara M Newcomb
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  17. Louis Viollet
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  18. Chad Huff
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  19. Lynn B Jorde
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  20. Sandra P Reyna
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  21. Kelley J Murphy
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  22. Kevin V Shianna
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  23. Curtis E Gumbs
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  24. Latasha Little
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  25. Kenneth Silver
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  27. Joost Haan
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  28. Michel D Ferrari
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  29. Ann M Bye
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  30. Geoffrey K Herkes
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  31. Charlotte M Whitelaw
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  32. David Webb
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  33. Bryan J Lynch
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  36. Ingrid E Scheffer
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  37. Giovanni Neri
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  38. Alexis Arzimanoglou
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  40. Sanjay M Sisodiya
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  41. Mohamad A Mikati
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  42. David B Goldstein
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Consortia

European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium

  • Sophie Nicole
  • , Fiorella Gurrieri
  • , Giovanni Neri
  • , Boukje de Vries
  • , Stephany Koelewijn
  • , Jessica Kamphorst
  • , Marije Geilenkirchen
  • , Nadine Pelzer
  • , Laura Laan
  • , Joost Haan
  • , Michel Ferrari
  •  & Arn van den Maagdenberg

Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium

  • Claudio Zucca
  • , Maria Teresa Bassi
  • , Filippo Franchini
  • , Rosaria Vavassori
  • , Melania Giannotta
  • , Giuseppe Gobbi
  • , Tiziana Granata
  • , Nardo Nardocci
  • , Elisa De Grandis
  • , Edvige Veneselli
  • , Michela Stagnaro
  • , Fiorella Gurrieri
  • , Giovanni Neri
  •  & Federico Vigevano

European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium

  • Eleni Panagiotakaki
  • , Claudia Oechsler
  • , Alexis Arzimanoglou
  • , Sophie Nicole
  • , Melania Giannotta
  • , Giuseppe Gobbi
  • , Miriam Ninan
  • , Brian Neville
  • , Friedrich Ebinger
  • , Carmen Fons
  • , Jaume Campistol
  • , David Kemlink
  • , Sona Nevsimalova
  • , Laura Laan
  • , Cacha Peeters-Scholte
  • , Arn van den Maagdenberg
  • , Paul Casaer
  • , Giorgio Casari
  • , Guenter Sange
  • , Georg Spiel
  • , Filippo Martinelli Boneschi
  • , Claudio Zucca
  • , Maria Teresa Bassi
  • , Tsveta Schyns
  • , Francis Crawley
  • , Dominique Poncelin
  •  & Rosaria Vavassori

Contributions

E.L.H., Y.H., S.M.S., M.A.M. and D.B.G. conceived and designed the study. Genetic data were generated and analyzed by E.L.H., K.J.S., Y.H., F.G., S.N., B.d.V., F.D.T., S.F., E.A., L.D.P., C.H., L.B.J., K.V.S., C.E.G., L.L., G.N., A.A. A.M.J.M.v.d.M and D.B.G. DNA samples and phenotypic information for AHC patients were collected, compiled and analyzed by K.J.S., F.G., S.N., N.M.W., B.d.V., F.D.T., B.F., S.H., E.P., M.T.S., T.M.N., L.V., S.P.R., K.J.M., K.S., L.J.P., J.H., M.D.F., A.M.B., G.K.H., C.M.W., D.W., B.J.L., P.U., M.D.K., I.E.S., G.N., A.A., S.M.S., M.A.M., the European AHC Genetics Consortium, the I.B.AHC Consortium and the ENRAH for SMEs Consortium. E.L.H., A.M.J.M.v.d.M., S.M.S., M.A.M. and D.B.G. wrote the paper. All authors reviewed the compiled manuscript.

Corresponding authors

Correspondence to Mohamad A Mikati or David B Goldstein.

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Competing interests

D.B.G., E.L.H., K.V.S., M.A.M. and Duke University are named on a patent application filed by Duke University on the basis of this work.

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A full list of members and affiliations appears at the end of this paper.

A full list of members and affiliations appears at the end of this paper.

A full list of members and affiliations appears at the end of this paper.

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Heinzen, E., Swoboda, K., Hitomi, Y. et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 44, 1030–1034 (2012). https://doi.org/10.1038/ng.2358

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