Abstract
Biallelic variants in the NARS2 gene are the cause of a continuous spectrum of neurodegenerative disorders presenting with various severity-from spastic paraplegia, progressive neurodegeneration to Leigh and Alpers syndrome. Common clinical signs result from a mitochondrial dysfunction based on OXPHOS deficiency. Here, we present a patient with infantile-onset severe epilepsy leading to fatal refractory status epilepticus. Whole exome sequencing with Exomiser analysis based on HPO terms detected two novel NARS2 variants in a compound heterozygous state. To date, 18 different NARS2 disease-causing mutations have been described. Our study adds to the understanding of this mitochondrial disorder.
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References
Ibba M, Soll D (2000) Aminoacyl-tRNA synthesis. Annu Rev Biochem 69:617–650. https://doi.org/10.1146/annurev.biochem.69.1.617
Konovalova S, Tyynismaa H (2013) Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 108(4):206–211. https://doi.org/10.1016/j.ymgme.2013.01.010
Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, Mandel H, Eran A, Toyono M, Sawaishi Y, Motoi H, Shiina M, Ogata K, Miyatake S, Miyake N, Saitsu H, Matsumoto N (2017) PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. J Hum Genet 62(5):525–529. https://doi.org/10.1038/jhg.2016.163
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database C, Neale BM, Daly MJ, MacArthur DG (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809):434–443. https://doi.org/10.1038/s41586-020-2308-7
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. https://doi.org/10.1038/nmeth0410-248
Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC (2012) SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 40(Web Server issue):W452-457. https://doi.org/10.1093/nar/gks539
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362. https://doi.org/10.1038/nmeth.2890
Tavtigian SV, Greenblatt MS, Lesueur F, Byrnes GB, Group IUGVW (2008) In silico analysis of missense substitutions using sequence-alignment based methods. Hum Mutat 29(11):1327–1336. https://doi.org/10.1002/humu.20892
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30
Ramani R, Krumholz K, Huang YF, Siepel A (2019) PhastWeb: a web interface for evolutionary conservation scoring of multiple sequence alignments using phastCons and phyloP. Bioinformatics 35(13):2320–2322. https://doi.org/10.1093/bioinformatics/bty966
Seaver LH, DeRoos S, Andersen NJ, Betz B, Prokop J, Lannen N, Jordan R, Rajasekaran S (2018) Lethal NARS2-related disorder associated with rapidly progressive intractable epilepsy and global brain atrophy. Pediatr Neurol 89:26–30. https://doi.org/10.1016/j.pediatrneurol.2018.07.014
Simon M, Richard EM, Wang X, Shahzad M, Huang VH, Qaiser TA, Potluri P, Mahl SE, Davila A, Nazli S, Hancock S, Yu M, Gargus J, Chang R, Al-Sheqaih N, Newman WG, Abdenur J, Starr A, Hegde R, Dorn T, Busch A, Park E, Wu J, Schwenzer H, Flierl A, Florentz C, Sissler M, Khan SN, Li R, Guan MX, Friedman TB, Wu DK, Procaccio V, Riazuddin S, Wallace DC, Ahmed ZM, Huang T, Riazuddin S (2015) Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLoS Genet 11(3):e1005097. https://doi.org/10.1371/journal.pgen.1005097
Sofou K, Kollberg G, Holmstrom M, Davila M, Darin N, Gustafsson CM, Holme E, Oldfors A, Tulinius M, Asin-Cayuela J (2015) Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the mitochondrial asparaginyl-tRNA synthetase and prolyl-tRNA synthetase, in patients with Alpers syndrome. Mol Genet Genomic Med 3(1):59–68. https://doi.org/10.1002/mgg3.115
Lee JS, Yoo T, Lee M, Lee Y, Jeon E, Kim SY, Lim BC, Kim KJ, Choi M, Chae JH (2020) Genetic heterogeneity in Leigh syndrome: highlighting treatable and novel genetic causes. Clin Genet 97(4):586–594. https://doi.org/10.1111/cge.13713
Souza PVS, Bortholin T, Dias RB, Chieia MAT, Burlin S, Naylor FGM, Pinto W, Oliveira ASB (2017) New genetic causes for complex hereditary spastic paraplegia. J Neurol Sci 379:283–292. https://doi.org/10.1016/j.jns.2017.06.019
Han XD, Fang F, Li H, Liu ZM, Shi YQ, Wang JL, Ren XT, Ding CH, Chen CH, Li JW, Zhang WH, Deng J (2019) Clinical and genetic characteristics of 62 children with mitochondrial epilepsy. Zhonghua Er Ke Za Zhi 57(11):844–851. https://doi.org/10.3760/cma.j.issn.0578-1310.2019.11.006
Vanlander AV, Menten B, Smet J, De Meirleir L, Sante T, De Paepe B, Seneca S, Pearce SF, Powell CA, Vergult S, Michotte A, De Latter E, Vantomme L, Minczuk M, Van Coster R (2015) Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2). Hum Mutat 36(2):222–231. https://doi.org/10.1002/humu.22728
Wang J, Yu H, Zhang VW, Tian X, Feng Y, Wang G, Gorman E, Wang H, Lutz RE, Schmitt ES, Peacock S, Wong LJ (2016) Capture-based high-coverage NGS: a powerful tool to uncover a wide spectrum of mutation types. Genet Med 18(5):513–521. https://doi.org/10.1038/gim.2015.121
Funding
The study was supported by the MHCR AZV NU20-04-00279 and by RVO-VFN 64165 project of the Ministry of Health of the Czech Republic.
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KS wrote the first draft of the manuscript; MV, PP and VS contributed to the clinical interpretation and description; HH performed biochemical analysis and interpretation of data in muscle biopsy; LS and PL performed NGS data analysis and interpretation; PL revised the final version of the manuscript and coordinated the study.
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The study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki), and the molecular genetic study was approved by the Institutional Review Board of the University Hospital Motol. Informed consent was obtained from both patient’s parents.
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Štěrbová, K., Vlčková, M., Hansíková, H. et al. Novel variants in the NARS2 gene as a cause of infantile-onset severe epilepsy leading to fatal refractory status epilepticus: case study and literature review. Neurogenetics 22, 359–364 (2021). https://doi.org/10.1007/s10048-021-00659-0
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DOI: https://doi.org/10.1007/s10048-021-00659-0