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Journal of Inherited Metabolic Disease

, Volume 35, Issue 3, pp 459–467 | Cite as

Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2

  • Emma Glamuzina
  • Ruth Brown
  • Kieran Hogarth
  • Dawn Saunders
  • Isabelle Russell-Eggitt
  • Matthew Pitt
  • Carlos de Sousa
  • Shamima Rahman
  • Garry Brown
  • Stephanie Grunewald
Original Article

Abstract

Pontocerebellar hypoplasia type 6 (PCH6) (MIM #611523) is a recently described disorder caused by mutations in RARS2 (MIM *611524), the gene encoding mitochondrial arginyl-transfer RNA (tRNA) synthetase, a protein essential for translation of all mitochondrially synthesised proteins. This case confirms that progressive cerebellar and cerebral atrophy with microcephaly and complex epilepsy are characteristic features of PCH6. Additional features of PCH subtypes 2 and 4, including severe dystonia, optic atrophy and thinning of the corpus callosum, are demonstrated. Congenital lactic acidosis can be present, but respiratory chain dysfunction may be mild or absent, suggesting that disordered mitochondrial messenger RNA (mRNA) translation may not be the only mechanism of impairment or that a secondary mechanism exists to allow some translation. We report two novel mutations and expand the phenotypic spectrum of this likely underdiagnosed PCH variant, where recognition of the characteristic neuroradiological phenotype could potentially expedite genetic diagnosis and limit invasive investigations.

Keywords

Optic Atrophy Respiratory Chain Enzyme Congenital Muscular Dystrophy Sort Intolerant From Tolerant Anticodon Loop 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgement

We acknowledge our patient’s family for allowing us to publish her medical information and MRI images. Shamima Rahman is funded by Great Ormond Street Hospital Children’s Charity.

Supplementary material

10545_2011_9413_MOESM1_ESM.doc (95 kb)
Supplementary Figure 1 (DOC 95 kb)

References

  1. Antonellis A, Green ED (2008) The role of aminoacyl-tRNA synthetases in genetic diseases. Annu Rev Genomics Hum Genet 9:87–107PubMedCrossRefGoogle Scholar
  2. Antonellis A, Ellsworth RE, Sambuughin N et al (2003) Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet 72:1293–1299PubMedCrossRefGoogle Scholar
  3. Barkovich JA (1998) Neuroimaging manifestations and classification of congenital muscular dystrophies. AJNR Am J Neuroradiol 19:1389–1396PubMedGoogle Scholar
  4. Belostotsky R, Ben-Shalom E, Rinat C et al (2011) Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 88:193–200PubMedCrossRefGoogle Scholar
  5. Budde BS, Namavar Y, Barth PG et al (2008) tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet 40:1113–1118PubMedCrossRefGoogle Scholar
  6. Cavarelli J, Delagoutte B, Eriani G et al (1998) L-arginine recognition by yeast arginyl-tRNA synthetase. EMBO J 17:5438–5448PubMedCrossRefGoogle Scholar
  7. Chang BS, Piao X, Bodell A et al (2003) Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 53:596–606PubMedCrossRefGoogle Scholar
  8. Clement E, Mercuri E, Godfrey C et al (2008) Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann Neurol 64:573–582PubMedCrossRefGoogle Scholar
  9. Delagoutte B, Moras D, Caravelli J (2000) tRNA aminoacylation by arginyl-tRNA synthetase: induced conformations during substrates binding. EMBO J 21:5599–5610CrossRefGoogle Scholar
  10. Durmaz B, Wollnik B, Cogulu O et al (2009) Pontocerebellar hypoplasia type III (CLAM): extended phenotype and novel molecular findings. J Neurol 256:416–419PubMedCrossRefGoogle Scholar
  11. Edvardson S, Shaag A, Kolesnikova O et al (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81:857–862PubMedCrossRefGoogle Scholar
  12. Garcia-Cazorla A, Duarte S, Serrano M et al (2008) Mitochondrial diseases mimicking neurotransmitter defects. Mitochondrion 8:273–278PubMedCrossRefGoogle Scholar
  13. Götz A, Tyynismaa H, Euro L et al (2011) Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet 88:635–642PubMedCrossRefGoogle Scholar
  14. Guo M, Yang XL, Schimmel P (2010) New functions of aminoacyl tRNA synthetases. Nat Rev Mol Cell Biol 11:668–674PubMedCrossRefGoogle Scholar
  15. Hargreaves P, Rahman S, Guthrie P et al (2002) Diagnostic value of succinate ubiquinone reductase activity in the identification of patients with mitochondrial DNA depletion. J Inherit Metab Dis 25:7–16PubMedCrossRefGoogle Scholar
  16. Hausmann CD, Ibba M (2008) Aminoacyl-tRNA synthetase complexes: molecular multitasking revealed. FEMS Microbiol Rev 32:705–721PubMedCrossRefGoogle Scholar
  17. Jordanova A, Irobi J, Thomas FP et al (2006) Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Toot neuropathy. Nat Genet 38:197–202PubMedCrossRefGoogle Scholar
  18. Latour P, Thauvin-Robinet C, Baudelet-Méry C et al (2010) A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet 86:77–82PubMedCrossRefGoogle Scholar
  19. Namavar Y, Chitayat D, Barth PG et al (2011a) TSEN54 mutations cause pontocerebellar hypoplasia type 5. Eur J Hum Genet 19:724–726PubMedCrossRefGoogle Scholar
  20. Namavar Y, Barth P, Kasher P et al (2011b) Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 134:143–156PubMedCrossRefGoogle Scholar
  21. Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814PubMedCrossRefGoogle Scholar
  22. Parsyan A, Svitkin Y, Shahbazian D et al (2011) mRNA helicases: the tacticians of translational control. Nat Rev Mol Cell Biol 12:235–245PubMedCrossRefGoogle Scholar
  23. Patel MS, Becker LE, Toi A et al (2006) Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am J Med Genet 140A:594–603CrossRefGoogle Scholar
  24. Piao X, Chang BS, Bodell A et al (2005) Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol 8:680–687CrossRefGoogle Scholar
  25. Pierce SB, Chisholm KM, Lynch ED et al (2011) Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA 108:6543–6548PubMedCrossRefGoogle Scholar
  26. Rahman S, Hanna MG (2009) Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases. J Neurol Neurosurg Psychiatry 80:943–953PubMedCrossRefGoogle Scholar
  27. Rajab A, Mochida GH, Hill A et al (2003) A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 60:1664–1667PubMedGoogle Scholar
  28. Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900PubMedCrossRefGoogle Scholar
  29. Rankin J, Brown R, Dobyns WB et al (2010) Pontocerebellar hypoplasia type 6: a British case with PEHO-like features. Am J Med Genet A 152A:2079–2084PubMedCrossRefGoogle Scholar
  30. Renbaum P, Kellerman E, Jaron R et al (2009) Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet 85:281–289PubMedCrossRefGoogle Scholar
  31. Riley LG, Cooper S, Hickey P et al (2010) Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia–MLASA syndrome. Am J Hum Genet 87:52–59PubMedCrossRefGoogle Scholar
  32. Scheper GC, van der Klok T, van Andel RJ et al (2007) Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39:534–539PubMedCrossRefGoogle Scholar
  33. Stum M, McLaughlin HM, Kleinbrink EL et al (2011) An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations. Mol Cell Neurosci 46:432–443PubMedCrossRefGoogle Scholar
  34. Valbuena A, Sanz-García M, López-Sánchez I et al (2011) Roles of VRK1 as a new player in the control of biological processes required for cell division. Cell Signal. Apr 14 [Epub ahead of print]Google Scholar
  35. Zelnik N, Dobyns WB, Forem S et al (1996) Congenital pontocerebellar atrophy in three patients: clinical, radiologic and etiologic considerations. Neuroradiology 38:684–687PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • Emma Glamuzina
    • 1
    • 8
  • Ruth Brown
    • 2
  • Kieran Hogarth
    • 6
  • Dawn Saunders
    • 6
  • Isabelle Russell-Eggitt
    • 5
  • Matthew Pitt
    • 3
  • Carlos de Sousa
    • 4
  • Shamima Rahman
    • 1
    • 7
  • Garry Brown
    • 2
  • Stephanie Grunewald
    • 1
    • 7
  1. 1.Department of Metabolic MedicineGreat Ormond Street Hospital for ChildrenLondonUK
  2. 2.Department of BiochemistryUniversity of OxfordOxfordUK
  3. 3.Department of NeurophysiologyGreat Ormond Street Hospital for ChildrenLondonUK
  4. 4.Department of NeurologyGreat Ormond Street Hospital for ChildrenLondonUK
  5. 5.Department of Ophthalmology, Ulverscroft Vision Research GroupGreat Ormond Street Hospital for ChildrenLondonUK
  6. 6.Department of RadiologyGreat Ormond Street Hospital for ChildrenLondonUK
  7. 7.UCL Institute of Child HealthUniversity College LondonLondonUK
  8. 8.National Metabolic ServiceStarship Children’s HospitalAucklandNew Zealand

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