title: Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways.
abstract: 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.
authors.affiliation: Department of Child Neurology, VU University Medical Center, De Boelalaan 1117, 1081 HV Amsterdam, The Netherlands. l.vanberge@vumc.nl
authors.forename: Laura
authors.initials: L
authors.lastname: van Berge
authors.forename: Josta
authors.initials: J
authors.lastname: Kevenaar
authors.forename: Emiel
authors.initials: E
authors.lastname: Polder
authors.forename: Agnès
authors.initials: A
authors.lastname: Gaudry
authors.forename: Catherine
authors.initials: C
authors.lastname: Florentz
authors.forename: Marie
authors.initials: M
authors.lastname: Sissler
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Gert C
authors.initials: GC
authors.lastname: Scheper
mesh_terms: D001226:Aspartate-tRNA Ligase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: D001226:Aspartate-tRNA Ligase