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Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Nature Genetics volume 39, pages 534–539 (2007)Cite this article

Abstract

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.

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Figure 1: Characteristic MRI pattern of LBSL.
Figure 2: Localization of the gene involved in LBSL on chromosome 1.
Figure 3: Mitochondrial activity.

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GenBank/EMBL/DDBJ

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Acknowledgements

We thank P. Heutink for helpful discussions. We thank J. Powers for critical reading of the manuscript. We thank K. de Groot and T. Vriesman for technical assistance. We are grateful for the generous collaboration of many colleagues and most of all for the contributions from LBSL patients and their families. This study was supported by ZonMW (TOP grant 9120.6002), the Optimix Foundation for Scientific Research and the Centre for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NWO).

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Authors and Affiliations

  1. Department of Pediatrics and Child Neurology, Vrije University Medical Center, Amsterdam, 1081 HV, The Netherlands

    Gert C Scheper, Thom van der Klok, Rob J van Andel, Carola G M van Berkel & Marjo S van der Knaap

  2. Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur, Strasbourg, F-67084, France

    Marie Sissler & Catherine Florentz

  3. Department of Pediatrics, Division of Neurology and Metabolism, University Hospital, Gent, B-9000, Belgium

    Joél Smet & Rudy Van Coster

  4. Institute of Neurology, Burdenko Neurosurgery Institute, Russian Academy of Medical Sciences, Moscow, Russia

    Tatjana I Muravina

  5. Department of Neuroimaging, Burdenko Neurosurgery Institute, Russian Academy of Medical Sciences, Moscow, Russia

    Sergey V Serkov

  6. Child Neurology Department, Istituto Nazionale Neurologico “C. Besta”, Milan, 20133, Italy

    Graziella Uziel & Marianna Bugiani

  7. Developmental and Metabolic Neurology Branch, National Institute for Neurological Disorders and Stroke, US National Institutes of Health, Bethesda, 20892, Maryland, USA

    Raphael Schiffmann

  8. Department of Pediatric Neurology, University Children's Hospital, Tübingen, 72076, Germany

    Ingeborg Krägeloh-Mann

  9. Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen Center for Mitochondrial Disorders, Nijmegen, 6500 HB, The Netherlands

    Jan A M Smeitink

  10. Department of Human Genetics, Vrije University Medical Center, Amsterdam, 1081 BT, The Netherlands

    Jan C Pronk

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  1. Gert C Scheper
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Contributions

G.C.S. supervised the genetic study and cloned and purified the wild-type and mutant proteins. T.v.d.K. performed the genome-wide scan. R.J.v.A. and C.G.M.v.B. performed sequence analysis. M.S. and C.F. were involved in the synthetase assay. J.S. and R.V.C. contributed to the measurement of the mitochondrial activities in cultured cells. T.I.M., S.V.S., G.U., M.B., R.S., I.K.-M., J.A.M.S., R.V.C. and M.S.v.d.K. all contributed key patients to the study. J.A.M.S. measured mitochondrial activities on a muscle biopsy of the first patient. J.C.P. contributed to the analysis of the genome-wide scan. M.S.v.d.K. originally described the disease, selected the patients on the basis of MRI criteria and supervised the study. G.C.S. and M.S.v.d.K. designed the study and wrote the paper with contributions from many of the other coauthors.

Corresponding author

Correspondence to Gert C Scheper.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Conservation of altered amino acids in mtAspRS. (PDF 22 kb)

Supplementary Fig. 2

Splicing variants of exon 3. (PDF 49 kb)

Supplementary Fig. 3

Expression of COXI in fibroblasts. (PDF 22 kb)

Supplementary Table 1

MRI criteria for LBSL. (PDF 7 kb)

Supplementary Table 2

Activities of the repiratory chain complexes. (PDF 8 kb)

Supplementary Table 3

mtAspRS mRNA expression. (PDF 17 kb)

Supplementary Table 4

Primers. (PDF 22 kb)

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Scheper, G., van der Klok, T., van Andel, R. et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39, 534–539 (2007). https://doi.org/10.1038/ng2013

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