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Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2 |
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| Authors: | Derek E. Neilson Mark D. Adams Deborah K. Schelling Douglas S. Kerr Alexander G. Bassuk Anne-Marie Childs Yanick J. Crow Christian Dohna-Schwake Alfonso E. Fasano Dimitris Gionnis Padraic J. Grattan-Smith Alice Kuster Eduardo Lopez-Laso Sotiria Mastroyianni Thomas Schmitt-Mechelke Angeliki Skardoutsou Marjo S. van der Knaap David L. Tefft Cristin Aubin David Hafler |
| Affiliation: | 1 Department of Genetics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA 2 Center for Human Genetics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA 3 Department of Pediatrics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA 4 MetroHealth Medical Center, Cleveland, OH 44109, USA 5 Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94118, USA 6 Division of Child Neurology, University of California, San Francisco, San Francisco, CA 94118, USA 7 Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, IA 52242, USA 8 Sydney Children's Hospital, Randwick, NSW 2031, Australia 9 Department of Paediatric Neurology, Leeds Teaching Hospitals Trust, Leeds LS2 9NS, UK 10 Department of Paediatric Neurology, St George's Hospital, London SW17 OQT, UK 11 Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds LS9 7TF, UK 12 Unit of Rare Diseases, II Division of Pediatrics, Gaslini Institute, Genoa 16147, Italy 13 Department of Pediatrics, Neuropediatrics, Neonatal and Pediatric Intensive Care, University Children's Hospital Essen, D-45130 Essen, Germany 14 Department of Neurology, Gemelli Hospital, Catholic University of Sacred Heart, Rome 00168, Italy 15 Pediatric Intensive Care Unit, University of Athens, “P &; A Kyriakou” Children's Hospital, Athens 11527, Greece 16 Department of Neurology, University of Athens, “P &; A Kyriakou” Children's Hospital, Athens 11527, Greece 17 Second Department of Pediatrics, University of Athens, “P &; A Kyriakou” Children's Hospital, Athens 11527, Greece 18 Department of Neurology, Children's Hospital Boston, Boston, MA 02115, USA 19 Professor-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen 28177, Germany 20 Metabolic Unit, University Hospital of Nantes, Nantes F-44093, France 21 Department of Paediatric Neurology, University Hospital of Nantes, Nantes F-44093, France 22 MR and PET-CT centre Bremen-Mitte, Bremen 28177, Germany 23 Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía, Córdoba 14004, Spain 24 Neuropediatric Department, Children's Hospital, Lucerne CH-6000, Switzerland 25 Department of Child Neurology, Rigshospitalet, Copenhagen DK-2100, Denmark 26 Department of Child Neurology, VU University Medical Center, Amsterdam 1081 HV, The Netherlands 27 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA 28 Division of Molecular Immunology, Center for Neurologic Disease, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA |
| Abstract: | Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE. |
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