Letter abstract
Nature Genetics 39, 534 - 539 (2007)
Published online: 25 March 2007 | doi:10.1038/ng2013
Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
Gert C Scheper1, Thom van der Klok1, Rob J van Andel1, Carola G M van Berkel1, Marie Sissler2, Joél Smet3, Tatjana I Muravina4, Sergey V Serkov5, Graziella Uziel6, Marianna Bugiani6, Raphael Schiffmann7, Ingeborg Krägeloh-Mann8, Jan A M Smeitink9, Catherine Florentz2, Rudy Van Coster3, Jan C Pronk10 & Marjo S van der Knaap1
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy1. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.
- Department of Pediatrics and Child Neurology, Vrije University Medical Center, 1081 HV Amsterdam, The Netherlands.
- Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur, F-67084 Strasbourg, France.
- Department of Pediatrics, Division of Neurology and Metabolism, University Hospital, B-9000 Gent, Belgium.
- Institute of Neurology, Burdenko Neurosurgery Institute, Russian Academy of Medical Sciences, Moscow, Russia.
- Department of Neuroimaging, Burdenko Neurosurgery Institute, Russian Academy of Medical Sciences, Moscow, Russia.
- Child Neurology Department, Istituto Nazionale Neurologico "C. Besta", 20133 Milan, Italy.
- Developmental and Metabolic Neurology Branch, National Institute for Neurological Disorders and Stroke, US National Institutes of Health, Bethesda, Maryland 20892, USA.
- Department of Pediatric Neurology, University Children's Hospital, 72076 Tübingen, Germany.
- Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen Center for Mitochondrial Disorders, 6500 HB Nijmegen, The Netherlands.
- Department of Human Genetics, Vrije University Medical Center, 1081 BT Amsterdam, The Netherlands.
Correspondence to: Gert C Scheper1 e-mail: gc.scheper@vumc.nl
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