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Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein |
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| Authors: | Tiranti Valeria D'Adamo Pio Briem Egill Ferrari Gianfrancesco Mineri Rossana Lamantea Eleonora Mandel Hanna Balestri Paolo Garcia-Silva Maria-Teresa Vollmer Brigitte Rinaldo Piero Hahn Si Houn Leonard James Rahman Shamima Dionisi-Vici Carlo Garavaglia Barbara Gasparini Paolo Zeviani Massimo |
| Institution: | 1 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children’s Mitochondrial Disorders, National Neurological Institute “Carlo Besta,” Milan 2 Linkage Unit &; Service, Telethon Institute for Genetic Medicine (TIGEM), Naples 3 Metabolic Disease Unit, Department of Pediatrics, Rambam Medical Center, Technion Faculty of Medicine, Haifa, Israel 4 Department of Pediatrics, University of Siena, Siena 5 Department of Pediatrics, Hospital 12 de Octubre, Madrid 6 Children’s Hospital, University of Tübingen, Tübingen, Germany 7 Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Biochemical Genetics Laboratory, Rochester, MN 8 Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health, London 9 Metabolic Disease Unit, Children’s Hospital “Bambino Gesù,” Rome |
| Abstract: | Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism. |
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