Journal of Genetic Medicine

  • 제16권2호
  • /
  • Pages.55-61
  • /
  • 2019
  • /
  • 1226-1769(pISSN)
  • /
  • 2383-8442(eISSN)
대한의학유전학회 (Korean Society of Medical Genetics and Genomics)
권호 표지
DOI QR코드

DOI QR Code

Clinical and genetic characteristics of Korean patients with IARS2-related disorders

  • Lee, Jin Sook (Department of Pediatrics, Gachon University Gil Medical Center, Gachon University College of Medicine) ;
  • Kim, Man Jin (Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Kim, Soo Yeon (Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Lim, Byung Chan (Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Kim, Ki Joong (Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Choi, Murim (Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Seong, Moon-Woo (Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Chae, Jong-Hee (Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine)
  • 투고 : 2019.12.02
  • 심사 : 2019.12.16
  • 발행 : 2019.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Purpose: Genetic defects in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases were first identified as causes of various disorders in 2007. Variants in IARS2, which encodes a mitochondrial isoleucyl-tRNA synthetase, were first reported in 2014. These variants are associated with diverse phenotypes ranging from CAGSSS (CAtaracts, Growth hormone deficiency, Sensory neuropathy, Sensorineural hearing loss, and Skeletal dysplasia) and Leigh syndrome to isolated nonsyndromic cataracts. Here, we describe the phenotypic and genetic spectrum of Korean patients with IARS2-related disorders. Materials and Methods: Using whole-exome sequencing followed by Sanger sequencing, we identified five patients with IARS2 mutations. Their medical records and brain magnetic resonance images were reviewed retrospectively. Results: All five patients presented with developmental delay or regression before 18 months of age. Three patients had bilateral cataracts, but none had hearing loss or sensory neuropathy. No evidence of skeletal dysplasia was noted, but two had short stature. One patient had cardiomyopathy and another exhibited renal tubulopathy and hypoparathyroidism. Their brain imaging findings were consistent with Leigh syndrome. Interestingly, we found the recurrent mutations p.R817H and p.V105Dfs*7 in IARS2. Conclusion: To our knowledge, this is the first report of Korean patients with IARS2-related disorders. Our findings broaden the phenotypic and genotypic spectrum of IARS2-related disorders in Korea and will help to increase clinical awareness of IARS2-related neurodegenerative diseases.

키워드

참고문헌

  1. Boczonadi V, Horvath R. Mitochondria: impaired mitochondrial translation in human disease. Int J Biochem Cell Biol 2014;48:77-84. https://doi.org/10.1016/j.biocel.2013.12.011
  2. Konovalova S, Tyynismaa H. Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 2013;108:206-11. https://doi.org/10.1016/j.ymgme.2013.01.010
  3. Diodato D, Ghezzi D, Tiranti V. The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol 2014;2014:787956. https://doi.org/10.1155/2014/787956
  4. Yao P, Fox PL. Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol Med 2013;5:332-43. https://doi.org/10.1002/emmm.201100626
  5. Meyer-Schuman R, Antonellis A. Emerging mechanisms of aminoacyl- tRNA synthetase mutations in recessive and dominant human disease. Hum Mol Genet 2017;26:R114-27. https://doi.org/10.1093/hmg/ddx231
  6. Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett 2018;592:703-17. https://doi.org/10.1002/1873-3468.12962
  7. Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 2007;39:534-9. https://doi.org/10.1038/ng2013
  8. Schwartzentruber J, Buhas D, Majewski J, Sasarman F, Papillon- Cavanagh S, Thiffault I, et al. Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome. Hum Mutat 2014;35:1285-9. https://doi.org/10.1002/humu.22629
  9. Moosa S, Haagerup A, Gregersen PA, Petersen KK, Altmüller J, Thiele H, et al. Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2. Am J Med Genet A 2017;173:1102-8. https://doi.org/10.1002/ajmg.a.38116
  10. Li J, Leng Y, Han S, Yan L, Lu C, Luo Y, et al. Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract. Orphanet J Rare Dis 2018;13:94. https://doi.org/10.1186/s13023-018-0828-0
  11. Vona B, Maroofian R, Bellacchio E, Najafi M, Thompson K, Alahmad A, et al. Expanding the clinical phenotype of IARS2-related mitochondrial disease. BMC Med Genet 2018;19:196. https://doi.org/10.1186/s12881-018-0709-3
  12. Takezawa Y, Fujie H, Kikuchi A, Niihori T, Funayama R, Shirota M, et al. Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome. Brain Dev 2018;40:934-8. https://doi.org/10.1016/j.braindev.2018.06.010
  13. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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 2015;17:405-24. https://doi.org/10.1038/gim.2015.30
  14. 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. https://doi.org/10.1212/WNL.0000000000000497