neurogenetics

, Volume 13, Issue 3, pp 245–250 | Cite as

New mitochondrial DNA mutations in tRNA associated with three severe encephalopamyopathic phenotypes: neonatal, infantile, and childhood onset

  • María del Mar O’Callaghan
  • Sonia Emperador
  • Ester López-Gallardo
  • Cristina Jou
  • Nuria Buján
  • Raquel Montero
  • Àngels Garcia-Cazorla
  • Diana Gonzaga
  • Isidre Ferrer
  • Paz Briones
  • Eduardo Ruiz-Pesini
  • Mercè Pineda
  • Rafael Artuch
  • Julio Montoya
Original Article

Abstract

The reported cases showed clinical, biochemical, histopathological, and molecular features lending support to the hypothesis of a pathogenic effect of the detected mutations. Case 1 was a neonatal presentation who showed multiple mitochondrial respiratory chain enzyme defects in muscle associated with a new homoplasmic m.5514A > G transition in the tRNATrp gene. Case 2 was a late infantile presentation who also showed mitochondrial respiratory chain enzyme deficiencies in muscle together with a new m.1643A > G tRNAVal mutation in homoplasmy. Case 3 showed a MERRF phenotype presented in childhood associated with the once previously reported m.15923A > G mutation in heteroplasmy in all the tissues studied.

Keywords

Mitochondrial DNA tRNA mutations Homoplasmic mutations Mitochondrial respiratory chain Encephalopamyopathic phenotypes 

Notes

Acknowledgments

The work was supported by grants PI080663, PI080264, and PI1000662 from the Instituto de Salud Carlos III (ISCIII), Ministry of Science and Innovation (MICIN), Spain. M.OC, S.E, E.LG, and R.M are supported by CIBERER. R.A is supported by the program Intensificación de la Actividad Investigadora, of the ISCIII-MICIN. CIBERER is an initiative from ISCIII.

References

  1. 1.
    Scaglia F, Wong LJ (2008) Human mitochondrial transfer RNAs: role of pathogenic mutation in disease. Muscle Nerve 37(2):150–71PubMedCrossRefGoogle Scholar
  2. 2.
    Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127(10):2153–72PubMedCrossRefGoogle Scholar
  3. 3.
    Zifa E, Giannouli S, Theotokis P, Stamatis C, Mamuris Z, Stathopoulos C (2007) Mitochondrial tRNA mutations: clinical and functional perturbations. RNA Biol 4(1):38–66PubMedCrossRefGoogle Scholar
  4. 4.
    DiMauro S, Schon EA (2001) Mitochondrial DNA mutations in human disease. Am J Med Genet 106(1):18–26PubMedCrossRefGoogle Scholar
  5. 5.
    McFarland R, Clark KM, Morris AA et al (2002) Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet 30(2):145–6PubMedCrossRefGoogle Scholar
  6. 6.
    McFarland R, Schaefer AM, Gardner JL et al (2004) Familial myopathy: new insights into the T14709C mitochondrial tRNA mutation. Ann Neurol 55(4):478–84, AprilPubMedCrossRefGoogle Scholar
  7. 7.
    Sacconi S, Salviati L, Nishigaki Y et al (2008) A functionally dominant mitochondrial DNA mutation. Hum Mol Genet 17(12):1814–20, Jun 15PubMedCrossRefGoogle Scholar
  8. 8.
    Casali C, Santorelli FM, Damati G, Bernucci P, Debiase L, Dimauro S (1995) A novel mtDNA point mutation in maternally inherited cardiomyopathy. Biochem Biophys Res Commun 213(2):588–593, Aug 15PubMedCrossRefGoogle Scholar
  9. 9.
    Limongelli A, Schaefer J, Jackson S et al (2004) Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNA(Ile) homoplasmic mutation in the mitochondrial genome. J Med Genet 41(5):342–9, MayPubMedCrossRefGoogle Scholar
  10. 10.
    Taylor RW, Giordano C, Davidson MM et al (2003) A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J Am Coll Cardiol 41(10):1786–96, May 21PubMedCrossRefGoogle Scholar
  11. 11.
    Montero R, Sánchez-Alcázar JA, Briones P et al (2008) Analysis of coenzyme Q10 in muscle and fibroblasts for the diagnosis of CoQ10 deficiency syndromes. Clin Biochem 41(9):697–700, JunPubMedCrossRefGoogle Scholar
  12. 12.
    Gibson K, Halliday JL, Kirby DM, Yaplito-Lee J, Thorburn DR, Boneh (2008) Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics 122(5):1003–8, NovPubMedCrossRefGoogle Scholar
  13. 13.
    Saneto RP, Friedman SD, Shaw DW (2008) Neuroimaging of mitochondrial disease. Mitochondrion 8(5–6):396–413, DecPubMedCrossRefGoogle Scholar
  14. 14.
    Diogo L, Cordeiro M, Garcia P et al (2010) Value of brain magnetic resonance imaging in mitochondrial respiratory chain disorders. Pediatr Neurol 42(3):196–200PubMedCrossRefGoogle Scholar
  15. 15.
    Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59(9):1406–11, Nov 12PubMedCrossRefGoogle Scholar
  16. 16.
    Naviaux RK (2004) Developing a systematic approach to the diagnosis and classification of mitochondrial disease. Mitochondrion 4(5–6):351–61, SepPubMedCrossRefGoogle Scholar
  17. 17.
    Morava E, Van den Heuvel L, Hol F et al (2006) Mitochondrial disease criteria: diagnostic applications in children. Neurology 67(10):1823–6, Nov 28PubMedCrossRefGoogle Scholar
  18. 18.
    Rorbach J, Yusoff AA, Tuppen H et al (2008) Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation. Nucleic Acids Res 36(9):3065–74PubMedCrossRefGoogle Scholar
  19. 19.
    Perli E, Giordano C, Tuppen HA et al (2012) Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T > C mitochondrial tRNA(Ile) mutation causing hypertrophic cardiomyopathy. Hum Mol Genet 21:85–100PubMedCrossRefGoogle Scholar
  20. 20.
    Stickler DE, Valenstein E, Neiberger RE et al (2006) Peripheral neuropathy in genetic mitochondrial diseases. Pediatr Neurol 34(2):127–31PubMedCrossRefGoogle Scholar
  21. 21.
    McFarland R, Elson JL, Taylor RW, Howell N, Turnbull DM (2004) Assigning pathogenicity to mitochondrial tRNA mutations: when "definitely maybe" is not good enough. Trends Genet 20(12):591–6, DecPubMedCrossRefGoogle Scholar
  22. 22.
    Yarham JW, Al-Dosary M, Blakely EL et al (2011) A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat 32(11):1319–25, NovPubMedCrossRefGoogle Scholar
  23. 23.
    Yoon KL, Aprille JR, Ernst SG (1991) Mitochondrial tRNA(thr) mutation in fatal infantile respiratory enzyme deficiency. Biochem Biophys Res Commun 176:1112–5PubMedCrossRefGoogle Scholar
  24. 24.
    Yoon KL, Ernst SG, Rasmussen C, Dooling EC, Aprille JR (1993) Mitochondrial disorder associated with newborn cardiopulmonary arrest. Pediatr Res 33:433–40PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • María del Mar O’Callaghan
    • 1
    • 5
  • Sonia Emperador
    • 2
    • 5
  • Ester López-Gallardo
    • 2
    • 5
  • Cristina Jou
    • 1
  • Nuria Buján
    • 4
    • 5
  • Raquel Montero
    • 1
    • 5
  • Àngels Garcia-Cazorla
    • 1
    • 5
  • Diana Gonzaga
    • 1
  • Isidre Ferrer
    • 3
  • Paz Briones
    • 4
    • 5
    • 6
  • Eduardo Ruiz-Pesini
    • 2
    • 5
  • Mercè Pineda
    • 1
    • 5
  • Rafael Artuch
    • 1
    • 5
  • Julio Montoya
    • 2
    • 5
  1. 1.Departments of Pediatric Neurology, Pathology, and Clinical BiochemistryHospital Sant Joan de DéuBarcelonaSpain
  2. 2.Departamento de Bioquímica, Biología Molecular y Celular, Universidad de ZaragozaInstituto Aragonés de Ciencias de la SaludZaragozaSpain
  3. 3.Institut de Neuropatologia, Hospital Universitari de BellvitgeHospitalet de LlobregatBarcelonaSpain
  4. 4.Institut de Bioquímica ClínicaCorporació Sanitaria Clínic-CSICBarcelonaSpain
  5. 5.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)Instituto de Salud Carlos IIIMadridSpain
  6. 6.Consejo Superior de Investigaciones Científicas (CSIC)BarcelonaSpain

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