The autosomal recessive white matter disorder LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is caused by mutations in DARS2, coding for mtAspRS (mitochondrial aspartyl-tRNA synthetase). Generally, patients are compound heterozygous for mutations in DARS2. Many different mutations have been identified in patients, including several missense mutations. In the present study, we have examined the effects of missense mutations found in LBSL patients on the expression, enzyme activity, localization and dimerization of mtAspRS, which is important for understanding the cellular defect underlying the pathogenesis of the disease. Nine different missense mutations were analysed and were shown to have various effects on mtAspRS properties. Several mutations have a direct effect on the catalytic activity of the enzyme; others have an effect on protein expression or dimerization. Most mutations have a clear impact on at least one of the properties of mtAspRS studied, probably resulting in a small contribution of the missense variants to the mitochondrial aspartylation activity in the cell.
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Research Article|
February 15 2013
Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways
Laura van Berge;
Laura van Berge
1
*Department of Child Neurology, VU University Medical Center, De Boelalaan 1117, 1081 HV Amsterdam, The Netherlands
1To whom correspondence should be addressed (email l.vanberge@vumc.nl).
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Josta Kevenaar;
Josta Kevenaar
*Department of Child Neurology, VU University Medical Center, De Boelalaan 1117, 1081 HV Amsterdam, The Netherlands
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Emiel Polder;
Emiel Polder
*Department of Child Neurology, VU University Medical Center, De Boelalaan 1117, 1081 HV Amsterdam, The Netherlands
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Agnès Gaudry;
Agnès Gaudry
†Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084 Strasbourg, France
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Catherine Florentz;
Catherine Florentz
†Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084 Strasbourg, France
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Marie Sissler;
Marie Sissler
†Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084 Strasbourg, France
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Marjo S. van der Knaap;
Marjo S. van der Knaap
*Department of Child Neurology, VU University Medical Center, De Boelalaan 1117, 1081 HV Amsterdam, The Netherlands
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Gert C. Scheper
Gert C. Scheper
*Department of Child Neurology, VU University Medical Center, De Boelalaan 1117, 1081 HV Amsterdam, The Netherlands
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Publisher: Portland Press Ltd
Received:
October 11 2012
Revision Received:
December 04 2012
Accepted:
December 10 2012
Accepted Manuscript online:
December 10 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 450 (2): 345–350.
Article history
Received:
October 11 2012
Revision Received:
December 04 2012
Accepted:
December 10 2012
Accepted Manuscript online:
December 10 2012
Citation
Laura van Berge, Josta Kevenaar, Emiel Polder, Agnès Gaudry, Catherine Florentz, Marie Sissler, Marjo S. van der Knaap, Gert C. Scheper; Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways. Biochem J 1 March 2013; 450 (2): 345–350. doi: https://doi.org/10.1042/BJ20121564
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