Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy
2018
Hypomyelinating
leukodystrophiesare genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in
EPRS, the gene encoding cytoplasmic glutamyl-prolyl-
aminoacyl-tRNA synthetase.
EPRSis a bifunctional
aminoacyl-tRNA synthetasethat catalyzes the
aminoacylationof glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight
aminoacyl-tRNA synthetasesand its three interacting proteins. In total, five different
EPRSmutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced
EPRSamounts.
EPRSactivity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic
aminoacyl-tRNA synthetaseshave previously been implicated in hypomyelinating
leukodystrophiesbearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that
leukodystrophiescaused by mutations in genes encoding cytoplasmic
aminoacyl-tRNA synthetasesshare a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal
aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.
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