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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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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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.
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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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DOI: https://doi.org/10.1038/ng2013
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