Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy Marisa I. Mendes, Mariana.

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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 The American Journal of Human Genetics Volume 102, Issue 4, Pages 676-684 (April 2018) DOI: 10.1016/j.ajhg.2018.02.011 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 MRI Characteristics of Hypomyelinating Leukodystrophy Caused by Mutations in EPRS Brain MRI findings in the four affected individuals with EPRS pathogenic variants. Axial and sagittal (D, L, and T) T2-weighted images of affected individual P1 at age 13 years (A–D), affected individual P2 at age 20 years (E–H), affected individual P3 (I–L: age 3 years; M–P: age 4 years), and affected individual P4 (Q–S: age 3 years; T: age 5 years; U–X: age 8 years). All affected individuals show diffusely elevated T2 signal of the entire supratentorial white matter. There is no (Q–S) or only mild (I–K) atrophy in the younger affected individuals, whereas in the older affected individuals (A–C, E–G, and U–W) there is pronounced supratentorial atrophy with preserved (D and H) or mildly atrophic cerebellum. Affected individuals P3 and P4 show hyperintense T2 signal in the posterior columns of the spinal cord (L, T, and X; black arrows) and also in the ventrolateral thalami (J, N, and R; white arrowheads). In addition, affected individual P3 has elevated T2 signal of the pyramidal tracts in the midbrain (O, black arrowhead) and pons (K, black arrowhead). The cerebellar white matter (H and P) and the middle cerebellar peduncles (P and W; white arrows) were also hyperintense on T2. The American Journal of Human Genetics 2018 102, 676-684DOI: (10.1016/j.ajhg.2018.02.011) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 EPRS Pathogenic Variants are Found within the Proline tRNA Synthetase Core Domain (A) The locations of the EPRS pathogenic variants are shown according to their position within the different functional domains. (B) Genomic organization of EPRS in humans (UCSC Genome Browser hg19): positions of EPRS pathogenic variants (in red) within the EPRS gDNA. (C) EPRS mutations in individuals with leukodystrophy affect amino acids that are conserved through species. (D) 3D representations (created with MacPyMOL) of identified EPRS missense variants: point mutations identified in EPRS are displayed according to their equivalent positions in the proline tRNA synthetase domain of the human EPRS (PDB 4K86). The American Journal of Human Genetics 2018 102, 676-684DOI: (10.1016/j.ajhg.2018.02.011) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 EPRS Protein Amount and Activity Are Decreased in Affected Individuals with Hypomyelinating Leukodystrophy-Causing Mutations in EPRS (A) Immunoblot with protein extracted from hypomyelinating leukodystrophy-affected individuals and age- and sex-matched control fibroblasts. Immunoblot analysis with anti-EPRS revealed a reduced abundance of EPRS, ∼60% of the control amount (control 1 [C1], control 2 [C2]), in individuals P1 and P2. Anti-GAPDH was used as a loading control. (B) Endogenous amounts of EPRS in fibroblasts between affected individuals and age-sex-matched controls were quantified by a ratio of EPRS band intensity over GAPDH with the three immunoblot analysis experiments, one of which is shown in (A). Abundance of EPRS relative to GAPDH was assessed in three independent experiments using three different protein extracts from each sample. Bar chart shows quantification of EPRS protein amounts compared to control in each condition. (C) Activity of wild-type and mutated recombinant prolyl-tRNA synthetase protein (p.Pro1115Arg) (nmol released Pi/min/mg protein). Assay was performed at least in triplicate. (D) 5 μg of total protein was used for determining EPRS activity in lymphoblast lysates from affected individual P4. Error bars show standard deviation, ∗p < 0.05. The American Journal of Human Genetics 2018 102, 676-684DOI: (10.1016/j.ajhg.2018.02.011) Copyright © 2018 American Society of Human Genetics Terms and Conditions