Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy

Marisa I. Mendes, Mariana Gutierrez Salazar, Kether Guerrero, Isabelle Thiffault, Gajja S. Salomons, Laurence Gauquelin, Luan T. Tran, Diane Forget, Marie Soleil Gauthier, Quinten Waisfisz, Desiree E.C. Smith, Cas Simons, Marjo S. van der Knaap, Iris Marquardt, Aida Lemes, Hanna Mierzewska, Bernhard Weschke, Wolfgang Koehler, Benoit Coulombe, Nicole I. WolfGeneviève Bernard

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Hypomyelinating leukodystrophies are 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. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations 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 EPRS amounts. EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share 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.

Original languageEnglish
Pages (from-to)676-684
Number of pages9
JournalAmerican journal of human genetics
Issue number4
Early online date22 Mar 2018
Publication statusPublished - 5 Apr 2018


  • EPRS
  • hypomyelinating leukodystrophy
  • tRNA-synthetase

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