Alanyl-tRNA Synthetase 2 (AARS2)-Related Ataxia Without Leukoencephalopathy

  • Molly E. Kuo
  • Anthony AntonellisEmail author
  • Vikram G. ShakkottaiEmail author
Short Reports


Mutations in the mitochondrial alanyl-tRNA synthetase gene, AARS2, have been reported to cause leukoencephalopathy associated with early ovarian failure, a clinical presentation described as “ovarioleukodystrophy.” We present a sibling pair: one with cerebellar ataxia and one with vision loss and cognitive impairment in addition to ataxia. Neither shows evidence of leukoencephalopathy on MRI imaging. Exome sequencing revealed that both siblings are compound heterozygous for AARS2 variants (p.Phe131del and p.Ile328Met). Yeast complementation assays indicate that p.Phe131del AARS2 dramatically impairs gene function and that p.Ile328Met AARS2 is a hypomorphic allele. This work expands the phenotypic spectrum of AARS2-associated disease to include ataxia without leukoencephalopathy.


AARS2 Cerebellar ataxia Ovarioleukodystrophy Leukoencephalopathy Recessive ataxia 


Funding Information

M.E.K. is supported by the NIH Medical Scientist Training Program Training Grant (GM007863), the NIH Cellular and Molecular Biology Training Grant (GM007315), and an NIH National Research Service Award (F31) from the National Institute of Neurological Disorders and Stroke (NS113515). A.A. is supported by a grant from the National Institute of General Medical Sciences (GM118647). V.G.S is supported by a grant from the NINDS (NS085054).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Antonellis A, Green ED. The role of aminoacyl-tRNA synthetases in genetic diseases. Annu Rev Genomics Hum Genet. 2008;9:87–107. Scholar
  2. 2.
    Meyer-Schuman R, Antonellis A. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. Hum Mol Genet. 2017;26:R114–R27. Scholar
  3. 3.
    Wang JY, Chen SF, Zhang HQ, Wang MY, Zhu JH and Zhang X. A homozygous mutation of alanyl-transfer RNA synthetase 2 in a patient of adult-onset leukodystrophy: a case report and literature review. Brain Behav 2019:e01313. doi
  4. 4.
    Srivastava S, Butala A, Mahida S, Richter J, Mu W, Poretti A, et al. Expansion of the clinical spectrum associated with AARS2-related disorders. Am J Med Genet A. 2019.
  5. 5.
    Peragallo JH, Keller S, van der Knaap MS, Soares BP, Shankar SP. Retinopathy and optic atrophy: expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene. Ophthalmic Genet. 2018;39:99–102. Scholar
  6. 6.
    Sun M, Johnson AK, Nelakuditi V, Guidugli L, Fischer D, Arndt K, et al. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. Genet Med. 2019;21:195–206. Scholar
  7. 7.
    Weterman MAJ, Kuo M, Kenter SB, Gordillo S, Karjosukarso DW, Takase R, et al. Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities. Hum Mol Genet. 2018;27:4036–50. Scholar
  8. 8.
    Chien CI, Chen YW, Wu YH, Chang CY, Wang TL, Wang CC. Functional substitution of a eukaryotic glycyl-tRNA synthetase with an evolutionarily unrelated bacterial cognate enzyme. PLoS One. 2014;9:e94659. Scholar
  9. 9.
    McLaughlin HM, Sakaguchi R, Giblin W, Program NCS, Wilson TE, Biesecker L, et al. A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2 N (CMT2N). Hum Mutat. 2012;33:244–53. Scholar
  10. 10.
    Boeke JD, Trueheart J, Natsoulis G, Fink GR. 5-Fluoroorotic acid as a selective agent in yeast molecular genetics. Methods Enzymol. 1987;154:164–75.CrossRefGoogle Scholar
  11. 11.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91. Scholar
  12. 12.
    Gotz A, Tyynismaa H, Euro L, Ellonen P, Hyotylainen T, Ojala T, et al. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet. 2011;88:635–42. Scholar
  13. 13.
    Swairjo MA, Otero FJ, Yang XL, Lovato MA, Skene RJ, McRee DE, et al. Alanyl-tRNA synthetase crystal structure and design for acceptor-stem recognition. Mol Cell. 2004;13:829–41.CrossRefGoogle Scholar
  14. 14.
    Guo M, Chong YE, Beebe K, Shapiro R, Yang XL, Schimmel P. The C-Ala domain brings together editing and aminoacylation functions on one tRNA. Science. 2009;325:744–7. Scholar
  15. 15.
    Tang HL, Yeh LS, Chen NK, Ripmaster T, Schimmel P, Wang CC. Translation of a yeast mitochondrial tRNA synthetase initiated at redundant non-AUG codons. J Biol Chem. 2004;279:49656–63. Scholar
  16. 16.
    Motley WW, Griffin LB, Mademan I, Baets J, De Vriendt E, De Jonghe P, et al. A novel AARS mutation in a family with dominant myeloneuropathy. Neurology. 2015;84:2040–7. Scholar
  17. 17.
    Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ, Salomons GS, et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology. 2014;82:2063–71. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Cellular and Molecular Biology ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Medical Scientist Training ProgramUniversity of MichiganAnn ArborUSA
  3. 3.Department of Human GeneticsUniversity of MichiganAnn ArborUSA
  4. 4.Department of NeurologyUniversity of MichiganAnn ArborUSA
  5. 5.Medical Science IIAnn ArborUSA
  6. 6.Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUSA
  7. 7.BSRBAnn ArborUSA

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