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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