Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is an autosomal recessive white matter disorder.
• Mutations in the DARS2 gene, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS), are the primary cause of LBSL.
• Patients are typically compound heterozygous for DARS2 mutations, with various missense mutations identified.

Purpose of the Study:

• To investigate the functional consequences of missense mutations in DARS2 found in LBSL patients.
• To analyze the effects of these mutations on mtAspRS expression, enzyme activity, localization, and dimerization.
• To elucidate the cellular defects contributing to LBSL pathogenesis.

Main Methods:

• Analysis of nine different missense mutations in the DARS2 gene.
• Assessment of mtAspRS protein expression levels.
• Measurement of mtAspRS enzyme activity.
• Evaluation of mtAspRS protein localization and dimerization properties.

Main Results:

• The analyzed missense mutations exhibited diverse effects on mtAspRS properties.
• Some mutations directly impaired the catalytic activity of mtAspRS.
• Other mutations affected mtAspRS protein expression or dimerization.
• Most mutations significantly impacted at least one studied property of mtAspRS.

Conclusions:

• Missense mutations in DARS2 have varied detrimental effects on mtAspRS function.
• These functional impairments likely contribute to reduced mitochondrial aspartylation activity in LBSL patients.
• Understanding these molecular defects is crucial for comprehending LBSL pathogenesis.