Letter | Published:

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

Nature Genetics volume 39, pages 534539 (2007) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

GenBank/EMBL/DDBJ

References

  1. 1.

    et al. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann. Neurol. 53, 252–258 (2003).

  2. 2.

    & Magnetic Resonance of Myelination and Myelin Disorders (Springer Verlag, Berlin, 2005).

  3. 3.

    et al. Five new cases of a recently described leukoencephalopathy with high brain lactate. Neurology 63, 688–692 (2004).

  4. 4.

    et al. Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate. Neuropediatrics 35, 1–5 (2004).

  5. 5.

    et al. Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate. J. Neurol. Neurosurg. Psychiatry 77, 889–891 (2006).

  6. 6.

    , , , & Synthesis of aspartyl-tRNA(Asp) in Escherichia coli–a snapshot of the second step. EMBO J. 18, 6532–6541 (1999).

  7. 7.

    et al. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am. J. Hum. Genet. 79, 869–877 (2006).

  8. 8.

    et al. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N. Engl. J. Med. 351, 2080–2086 (2004).

  9. 9.

    & Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 348, 2656–2668 (2003).

  10. 10.

    Mitochondrial disease. Lancet 368, 70–82 (2006).

  11. 11.

    Nuclear genetic defects of oxidative phosphorylation. Hum. Mol. Genet. 10, 2277–2284 (2001).

  12. 12.

    , & Tissue-specific differences in human transfer RNA expression. PLoS Genet. 2, e221 (2006).

  13. 13.

    , & Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. Trends Biochem. Sci. 30, 569–574 (2005).

  14. 14.

    et al. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 44, 4805–4816 (2005).

  15. 15.

    et al. A mitochondrial tRNA aspartate mutation causing isolated mitochondrial myopathy. Am. J. Med. Genet. A. 137, 170–175 (2005).

  16. 16.

    et al. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat. Genet. 38, 197–202 (2006).

  17. 17.

    et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299 (2003).

  18. 18.

    et al. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443, 50–55 (2006).

  19. 19.

    et al. Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. J. Neurosci. 26, 10397–10406 (2006).

  20. 20.

    & Nuclear genes and mitochondrial translation: a new class of genetic disease. Trends Genet. 21, 312–314 (2005).

  21. 21.

    et al. Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene. Diabetes 54, 1892–1895 (2005).

  22. 22.

    et al. The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27. Am. J. Hum. Genet. 65, 728–734 (1999).

  23. 23.

    & SCAMP: a spreadsheet to collate autozygosity mapping projects. J. Med. Genet. 41, e125 (2004).

  24. 24.

    , , & Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13 (2000).

  25. 25.

    et al. Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. J. Neuropathol. Exp. Neurol. 65, 707–715 (2006).

  26. 26.

    et al. Active heroin administration induces specific genomic responses in the nucleus accumbens shell. FASEB J. 16, 1961–1963 (2002).

  27. 27.

    et al. Assessment of deficiencies of fatty acyl-CoA dehydrogenases in fibroblasts, muscle and liver. J. Inherit. Metab. Dis. 15, 347–352 (1992).

  28. 28.

    , , & Nondenaturing polyacrylamide gel electrophoresis as a method for studying protein interactions: applications in the analysis of mitochondrial OXPHOS complexes. in Cell Biology: a Laboratory Handbook (ed. Celis, J.) 259–264 (Academic, San Diego, 2005).

  29. 29.

    et al. Blue native polyacrylamide gel electrophoresis: a powerful tool in diagnosis of oxidative phosphorylation defects. Pediatr. Res. 50, 658–665 (2001).

  30. 30.

    et al. Diagnostic value of immunostaining in cultured skin fibroblasts from patients with oxidative phosphorylation defects. Pediatr. Res. 59, 2–6 (2006).

Download references

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).

Author information

Affiliations

  1. Department of Pediatrics and Child Neurology, Vrije University Medical Center, 1081 HV Amsterdam, 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, F-67084 Strasbourg, France.

    • Marie Sissler
    •  & Catherine Florentz
  3. Department of Pediatrics, Division of Neurology and Metabolism, University Hospital, B-9000 Gent, 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”, 20133 Milan, Italy.

    • Graziella Uziel
    •  & Marianna Bugiani
  7. Developmental and Metabolic Neurology Branch, National Institute for Neurological Disorders and Stroke, US National Institutes of Health, Bethesda, Maryland 20892, USA.

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

    • Ingeborg Krägeloh-Mann
  9. Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen Center for Mitochondrial Disorders, 6500 HB Nijmegen, The Netherlands.

    • Jan A M Smeitink
  10. Department of Human Genetics, Vrije University Medical Center, 1081 BT Amsterdam, The Netherlands.

    • Jan C Pronk

Authors

  1. Search for Gert C Scheper in:

  2. Search for Thom van der Klok in:

  3. Search for Rob J van Andel in:

  4. Search for Carola G M van Berkel in:

  5. Search for Marie Sissler in:

  6. Search for Joél Smet in:

  7. Search for Tatjana I Muravina in:

  8. Search for Sergey V Serkov in:

  9. Search for Graziella Uziel in:

  10. Search for Marianna Bugiani in:

  11. Search for Raphael Schiffmann in:

  12. Search for Ingeborg Krägeloh-Mann in:

  13. Search for Jan A M Smeitink in:

  14. Search for Catherine Florentz in:

  15. Search for Rudy Van Coster in:

  16. Search for Jan C Pronk in:

  17. Search for Marjo S van der Knaap in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gert C Scheper.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Conservation of altered amino acids in mtAspRS.

  2. 2.

    Supplementary Fig. 2

    Splicing variants of exon 3.

  3. 3.

    Supplementary Fig. 3

    Expression of COXI in fibroblasts.

  4. 4.

    Supplementary Table 1

    MRI criteria for LBSL.

  5. 5.

    Supplementary Table 2

    Activities of the repiratory chain complexes.

  6. 6.

    Supplementary Table 3

    mtAspRS mRNA expression.

  7. 7.

    Supplementary Table 4

    Primers.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng2013

Further reading