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 Wolf; Geneviève Bernard

doi:10.1016/j.ajhg.2018.02.011

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

Am J Hum Genet. 2018 Apr 5;102(4):676-684. doi: 10.1016/j.ajhg.2018.02.011. Epub 2018 Mar 22.

Authors

Marisa I Mendes¹, Mariana Gutierrez Salazar², Kether Guerrero³, Isabelle Thiffault⁴, Gajja S Salomons¹, Laurence Gauquelin⁵, Luan T Tran³, Diane Forget⁶, Marie-Soleil Gauthier⁶, Quinten Waisfisz⁷, Desiree E C Smith¹, Cas Simons⁸, Marjo S van der Knaap⁹, Iris Marquardt¹⁰, Aida Lemes¹¹, Hanna Mierzewska¹², Bernhard Weschke¹³, Wolfgang Koehler¹⁴, Benoit Coulombe¹⁵, Nicole I Wolf¹⁶, Geneviève Bernard¹⁷

Affiliations

¹ Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, and Amsterdam Neuroscience Amsterdam, 1081 HZ Amsterdam, the Netherlands.
² Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montreal, QC H2W 1R7, Canada.
³ Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
⁴ Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
⁵ Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada.
⁶ Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montreal, QC H2W 1R7, Canada.
⁷ Department of Clinical Genetics, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands.
⁸ Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
⁹ Department of Child Neurology, VU University Medical Center, and Amsterdam Neuroscience, 1081 HZ Amsterdam, the Netherlands; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, 1081 HZ Amsterdam, the Netherlands.
¹⁰ Department of Neuropediatrics, Center for Child and Adolescent Medicine, Oldenburg Hospital, 26131 Oldenburg, Germany.
¹¹ Inborn Errors of Metabolism Unit, National Reference Center of Congenital Defects and Rare Diseases, 11200 Montevideo, Uruguay.
¹² Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
¹³ Department of Pediatric Neurology, Center for Chronically Sick Children, Charité University Medicine Berlin, Berlin, Germany.
¹⁴ Department of Neurology, University Medical Center, Leipzig, Germany.
¹⁵ Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montreal, QC H2W 1R7, Canada; Department of Biochemistry, Université de Montréal, Montreal, QC H3T 1J4, Canada.
¹⁶ Department of Child Neurology, VU University Medical Center, and Amsterdam Neuroscience, 1081 HZ Amsterdam, the Netherlands.
¹⁷ Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada; Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, QC H4A 3J1, Canada. Electronic address: [email protected].

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.

Keywords: EPRS; hypomyelinating leukodystrophy; tRNA-synthetase.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Alleles*
Amino Acyl-tRNA Synthetases / genetics*
Child
Child, Preschool
Fatal Outcome
Female
Hereditary Central Nervous System Demyelinating Diseases
Humans
Magnetic Resonance Imaging
Male
Mutation / genetics*
Young Adult

Substances

Amino Acyl-tRNA Synthetases
glutamyl-prolyl-tRNA synthetase