Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/19768
Title: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
Authors: Helbig, Katherine L;Lauerer, Robert J;Bahr, Jacqueline C;Souza, Ivana A;Myers, Candace T;Uysal, Betül;Schwarz, Niklas;Gandini, Maria A;Huang, Sun;Keren, Boris;Mignot, Cyril;Mefford, Heather C;Afenjar, Alexandra;Billette de Villemeur, Thierry;Héron, Delphine;Nava, Caroline;Valence, Stéphanie;Buratti, Julien;Fagerberg, Christina R;Soerensen, Kristina P;Kibaek, Maria;Kamsteeg, Erik-Jan;Koolen, David A;Gunning, Boudewijn;Schelhaas, H Jurgen;Kruer, Michael C;Fox, Jordana;Bakhtiari, Somayeh;Jarrar, Randa;Padilla-Lopez, Sergio;Lindstrom, Kristin;Jin, Sheng Chih;Zeng, Xue;Bilguvar, Kaya;Papavasileiou, Antigone;Xin, Qinghe;Zhu, Changlian;Boysen, Katja;Vairo, Filippo;Lanpher, Brendan C;Klee, Eric W;Tillema, Jan-Mendelt;Payne, Eric T;Cousin, Margot A;Kruisselbrink, Teresa M;Wick, Myra J;Baker, Joshua;Haan, Eric;Smith, Nicholas;Corbett, Mark A;MacLennan, Alastair H;Gecz, Jozef;Biskup, Saskia;Goldmann, Eva;Rodan, Lance H;Kichula, Elizabeth;Segal, Eric;Jackson, Kelly E;Asamoah, Alexander;Dimmock, David;McCarrier, Julie;Botto, Lorenzo D;Filloux, Francis;Tvrdik, Tatiana;Cascino, Gregory D;Klingerman, Sherry;Neumann, Catherine;Wang, Raymond;Jacobsen, Jessie C;Nolan, Melinda A;Snell, Russell G;Lehnert, Klaus;Sadleir, Lynette G;Anderlid, Britt-Marie;Kvarnung, Malin;Guerrini, Renzo;Friez, Michael J;Lyons, Michael J;Leonhard, Jennifer;Kringlen, Gabriel;Casas, Kari;El Achkar, Christelle M;Smith, Lacey A;Rotenberg, Alexander;Poduri, Annapurna;Sanchis-Juan, Alba;Carss, Keren J;Rankin, Julia;Zeman, Adam;Raymond, F Lucy;Blyth, Moira;Kerr, Bronwyn;Ruiz, Karla;Urquhart, Jill;Hughes, Imelda;Banka, Siddharth;Hedrich, Ulrike B S;Scheffer, Ingrid E;Helbig, Ingo;Zamponi, Gerald W;Lerche, Holger
Affiliation: Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
The Florey Institute and Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia
Department of Neurology, Royal Children's Hospital, Parkville, VIC 3052, Australia
Perinatal Center, Sahlgrenska Academy, Gothenburg University, 413 46 Gothenburg, Sweden
Hospital of Zhengzhou University, 450001 Zhengzhou, China
Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0QQ, UK
NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
Department of Neuropediatrics, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA
Department of Pediatrics, University of California-Irvine School of Medicine, Irvine, CA 92617, USA
Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA
Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA
Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Department of Physiology & Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA
Department of Neurology, Harvard Medical School, Boston, MA 02215, USA
Medical Genetics, Sanford Health, Fargo, ND 58102, USA
Medical Genetics, Sanford Health, Bemidji, MN 56601, USA
Greenwood Genetic Center, Greenwood, SC 29646, USA
Division of Metabolic Disorders CHOC Children's Hospital, Orange, CA 92868, USA
ARUP Laboratories, Salt Lake City, UT 84108, USA
Division of Pediatric Neurology, Departments of Pediatrics and Neurology, University of Utah, Salt Lake City, UT 84113, USA
Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, USA
Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA
University of Louisville, Louisville, KY 40292, USA
Northeast Regional Epilepsy Group, Hackensack University Medical Center, Hackensack, NJ 07601, USA
Adelaide Medical School, Robinson Research Institute, University of Adelaide, North Adelaide, SA 5006, Australia
Department of Neurology, Women's and Children's Hospital, University of Adelaide, North Adelaide, SA 5006, Australia
Adult Genetics Unit, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia
University of Illinois Chicago College of Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
Department of Health Science Research, Mayo Clinic, Rochester, MN 55905, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Institute of Biomedical Science and Children's Hospital Fudan University, 201102 Shanghai, China
Yale School of Medicine, New Haven, CT 06510, USA
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA
Barrow Neurological Institute, Phoenix Children's Hospital, Departments of Child Health, Genetics, Neurology, and Cellular & Molecular Medicine, University of Arizona College of Medicine, Phoenix, AZ 85013, USA
Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA
Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany..
Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, Département de Génétique et Embryologie Médicale, AP-HP, Hôpital d'Enfants Armand Trousseau, Centre de Référence des Déficits Intellectuels de Causes Rares, 75012 Paris, France
APHP, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et GHUEP Hôpital Trousseau; Sorbonne Université, GRC "Déficience Intellectuelle et Autisme," 75013 Paris, France
H.C. Andersen Children's Hospital, Odense University Hospital, 5000 Odense, Denmark
Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark
Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, the Netherlands
Stichting Epilepsie Instellingen Nederland, 8025 Zwolle, the Netherlands
Department of Neurology, Academic Center for Epileptology, Kempenhaeghe and Maastricht UMC, 5591 Heeze, the Netherlands
Department of Pediatric Neurology, Penteli Children's Hospital, 152 36 Athens, Greece
CeGaT, 72076 Tübingen, Germany
Department of Human Genetics, University of Tübingen, 72076 Tübingen, Germany
Department of Neurology, Starship Children's Health, Auckland 1023, New Zealand
Centre for Brain Research and School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand
Department of Paediatrics and Child Health, University of Otago Wellington, Wellington South 6242, New Zealand
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden
Department of Neuroscience, Azienda Ospedaliero-Universitaria Meyer, University of Florence, 50139 Florence, Italy
Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK
Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK
Yorkshire Regional Genetics Service, Chapel Allerton Hospital Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK
Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK
Wellcome Sanger Institute, Cambridge CB10 1SA, UK
Issue Date: 1-Nov-2018
EDate: 2018-11-01
Citation: American journal of human genetics 2018; 103(5): 666-678
Abstract: Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
URI: http://ahro.austin.org.au/austinjspui/handle/1/19768
DOI: 10.1016/j.ajhg.2018.09.006
ORCID: 0000-0002-2311-2174
PubMed URL: 30343943
Type: Journal Article
Subjects: CACNA1E, ion channel
arthrogryposis
calcium channel
epilepsy
Appears in Collections:Journal articles

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