Most of the 19 mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) involved in mitochondrial protein synthesis are already linked to specific entities, one of the exceptions being PARS2 mutations for which pathogenic significance is not finally validated. The aim of the study was to characterize the PARS2- related phenotype.
Three siblings with biallelic PARS2 mutations presented from birth with infantile spasms, secondary microcephaly, and similar facial dysmorphy. Mental development was deeply impaired with speech absence and no eye contact. A dilated cardiomyopathy and multiorgan failure developed in childhood at the terminal stage, together with mitochondrial dysfunction triggered by valproate administration.
Brain MRI showed progressive volume loss of the frontal lobes, both cortical and subcortical, with widening of the cortical sulci and frontal horns of the lateral ventricles. Hypoplasia of the corpus callosum and progressive demyelination were additional findings. Similar brain features were seen in three already reported PARS2 patients and seemed specific for this defect when compared with other mt-aaRSs defects (DARS2, EARS2, IARS2, and RARS2).
Striking resemblance of the phenotype and Alpers-like brain MRI changes with predominance of frontal cerebral volume loss (FCVL-AS) in six patients from three families of different ethnicity with PARS2 mutations, justifies to distinguish the condition as a new disease entity.
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Bonnefond L, Fender A, Rudinger-Thirion J, Giege R, Florentz C, Sissler M. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry. 2005;44:4805–16.
Mayr JA, Haack TB, Freisinger P, Karall D, Makowski C, Koch J, et al. Spectrum of combined respiratory chain defects. J Inherit Metab Dis. 2015;38:629–40.
Konovalova S, Tyynismaa H. Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab. 2013;108:206–11.
Theisen, BE, Rumyantseva, A, Cohen, JS, Alcaraz, WA, Shinde, DN, Tang, S et al. Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. Am J Med Genet A. 2017;173:2505-10.
Sofou K, Kollberg G, Holmstrom M, Davila M, Darin N, Gustafsson CM, et al. 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 Genom Med. 2015;3:59–68.
Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucinska-Wieckowska A, et al. New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre. J Transl Med. 2016;14:174.
Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, et al. PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. J Hum Genet. 2017;62:525–9.
Tylki-Szymanska A, Jurkiewicz E, Zakharova EY, Bobek-Billewicz B. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation: high outcome variation between two siblings. Neuropediatrics. 2014;45:188–91.
Sofou K, Moslemi AR, Kollberg G, Bjarnadottir I, Oldfors A, Nennesmo I, et al. Phenotypic and genotypic variability in Alpers syndrome. Eur J Paediatr Neurol. 2012;16:379–89.
Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389–402.
Li W, Godzik A. Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics. 2006;22:1658–9.
Pei J, Sadreyev R, Grishin NV. PCMA: fast and accurate multiple sequence alignment based on profile consistency. Bioinformatics. 2003;19:427–8.
Kurowski MA, Bujnicki JM. GeneSilico protein structure prediction meta-server. Nucleic Acids Res. 2003;31:3305–7.
Crepin T, Yaremchuk A, Tukalo M, Cusack S. Structures of two bacterial prolyl-tRNA synthetases with and without a cis-editing domain. Structure. 2006;14:1511–25.
Ginalski K, Rychlewski L. Protein structure prediction of CASP5 comparative modeling and fold recognition targets using consensus alignment approach and 3D assessment. Proteins. 2003;53 Suppl 6:410–7.
Fiser A, Sali A. Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol. 2003;374:461–91.
Wiederstein M, Sippl MJ. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007;35:W407–410.
Chen VB, Arendall WB 3rd, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010;66:12–21.
Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29:845–54.
Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, et al. Erratum: PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. J Hum Genet. 2017;62:587
Holman KM, Wu J, Ling J, Simonovic M. The crystal structure of yeast mitochondrial ThrRS in complex with the canonical threonine tRNA. Nucleic Acids Res. 2016;44:1428–39.
Abbott JA, Francklyn CS, Robey-Bond SM. Transfer RNA and human disease. Front Genet. 2014;5:158.
Steenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D, van Berkel CG, et al. Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain. 2012;135:1387–94.
Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, et al. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81:857–62.
Lakshmanan R, Adams ME, Lynch DS, Kinsella JA, Phadke R, Schott JM, et al. Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy. Neurol Genet. 2017;3:e135.
Benussi A, Padovani A, Borroni B. Phenotypic heterogeneity of monogenic frontotemporal dementia. Front Aging Neurosci. 2015;7:171.
Linnankivi T, Neupane N, Richter U, Isohanni P, Tyynismaa H. Splicing defect in mitochondrial seryl-tRNA synthetase gene causes progressive spastic paresis instead of HUPRA syndrome. Hum Mutat. 2016;37:884–8.
Moraes CT, Ciacci F, Bonilla E, Ionasescu V, Schon EA, DiMauro S. A mitochondrial tRNA anticodon swap associated with a muscle disease. Nat Genet. 1993;4:284–8.
Morel G, Bannwarth S, Chaussenot A, Cano A, Fragaki K, Ait-El-Mkadem S, et al. A new mutation in the mitochondrial tRNAPro gene associated with early-onset neuromuscular phenotype and ragged-red fibers. Neuromuscul Disord. 2016;26:885–9.
Blakely EL, Trip SA, Swalwell H, He L, Wren DR, Rich P, et al. A new mitochondrial transfer RNAPro gene mutation associated with myoclonic epilepsy with ragged-red fibers and other neurological features. Arch Neurol. 2009;66:399–402.
Pang YL, Poruri K, Martinis SA. tRNA synthetase: tRNA aminoacylation and beyond. Wiley Interdiscip Rev RNA. 2014;5:461–80.
Datt M, Sharma A. Evolutionary and structural annotation of disease-associated mutations in human aminoacyl-tRNA synthetases. BMC Genom. 2014;15:1063.
Perli E, Giordano C, Tuppen HA, Montopoli M, Montanari A, Orlandi M, et al. Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T > C mitochondrial tRNA(Ile) mutation causing hypertrophic cardiomyopathy. Hum Mol Genet. 2012;21:85–100.
Perli E, Fiorillo A, Giordano C, Pisano A, Montanari A, Grazioli P, et al. Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations. Hum Mol Genet. 2016;25:903–15.
Cassandrini D, Cilio MR, Bianchi M, et al. Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients. J Inherit Metab Dis. 2013;36:43–53.
This work was supported by the CMHI grants 134/13, 136/13, 216/12 and EU Structural Funds, project POIG.02.01.00-14-059/09. ML and DP are supported by the Polish National Science Centre (Grant Number 2014/15/B/ST6/05082) and Foundation for Polish Science (TEAM to DP).
Conflict of interest
The author declare that they have no conflict of interest.
Elżbieta Ciara, Dariusz Rokicki, and Michal Lazniewski contributed equally to this work.
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