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

Abstract

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.

Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients

“…11 HBSL was the first reported hypomyelinating leukodystrophy with spinal cord involvement, Recently, spinal cord involvement is documented in cases with variants in glutamylprolyl-tRNA synthetase gene (EPRS). 12 We found this imaging feature in one of our cases. In view of structural analysis, As the N-terminal segment of normal RARS enzyme probably plays a major role in attachment to eukaryotes, glutaminyl-tRNA synthetase (QARS) and aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1) within the MSC.…”

“…10 Variants in aspartyl-tRNA synthetase (DARS) and glutamylprolyl-tRNA synthetase (EPRS) genes, encoding two other cytoplasmic tRNA synthetase, could also lead to hypomyelination. 11,12 In cases with variant leading to HBSL (hypomyelination with brain stem and spinal cord involvement and leg spasticity), spasticity of legs was reported as a common clinical feature. 11 HBSL was the first reported hypomyelinating leukodystrophy with spinal cord involvement, Recently, spinal cord involvement is documented in cases with variants in glutamylprolyl-tRNA synthetase gene (EPRS).…”

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails

“…1 Mutations in 32 ARS loci have been implicated in recessive disease, and the associated phenotypes tend to involve a wide array of tissues. [2][3][4] The genotypes of subjects with ARS-mediated recessive disorders suggest a loss-of-function mechanism for disease pathogenesis but are also consistent with the presumbed lethality of complete loss of ARS function. Specifically, subjects are compound heterozygous for one missense mutation and one null allele, compound heterozygous for two missense mutations, or homozygous for a single missense mutation.…”

eIF2B activator prevents neurological defects caused by a chronic Integrated Stress Response

“…The mechanism of downregulation is unclear and could be due to ATF4-driven downstream effects or a reduction in the rate of protein synthesis, or a combination of both outputs of the ISR. Interestingly, ATF4 is chronically induced in various mouse models of mitochondrial dysfunction, and mutations in human mitochondrial proteins can lead to loss of myelin or leukoencephalopathies (Carvalho, 2013;Dogan et al, 2014;Huang et al, 2013;Mendes et al, 2018;Moisoi et al, 2009;Pereira et al, 2017;Quirós et al, 2017;Taylor et al, 2014). Whether these diseases are also characterized by a chronic ISR, and which cell types are susceptible to its induction, remains to be explored.…”