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Recent Advances in the Genetics of Mitochondrial Encephalopathies

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Abstract

Mitochondrial encephalopathy, the most common neurometabolic disorder, may be caused by mutations in approximately 100 different genes and may present with various symptoms, such as seizures, ataxia, myopathy, cognitive impairment, blindness, and stroke. Fewer than 50% of patients with mitochondrial encephalopathy receive a molecular diagnosis, primarily because of the large degree of clinical and genetic heterogeneity among patients and the limited knowledge of the genes involved in mitochondrial function. Here we review the most recent discoveries of genes associated with mitochondrial disease with variable neuropathology. All these genes have been identified via homozygosity mapping or linkage analysis; however, advances in sequencing technology indicate that the future of genetic diagnosis and disease gene discovery likely lies in high-throughput sequencing.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Skladal D, Halliday J, Thorburn DR: Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003, 126:1905–1912.

    Article  PubMed  Google Scholar 

  2. Wallace DC, Singh G, Lott MT, et al.: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988, 242:1427–1430.

    Article  CAS  PubMed  Google Scholar 

  3. Holt IJ, Harding AE, Morgan-Hughes JA: Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988, 331:717–719.

    Article  CAS  PubMed  Google Scholar 

  4. DiMauro S, Schon EA: Mitochondrial DNA mutations in human disease. Am J Med Genet 2001, 106(1):18–26.

    Article  CAS  PubMed  Google Scholar 

  5. Elliott HR, Samuels DC, Eden JA, et al.: Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 2008, 83:254–260.

    Article  CAS  PubMed  Google Scholar 

  6. Bitner-Glindzicz M, Pembrey M, Duncan A, et al.: Prevalence of mitochondrial 1555A-- > G mutation in European children. N Engl J Med 2009, 360:640–642.

    Article  PubMed  Google Scholar 

  7. Vandebona H, Mitchell P, Manwaring N, et al.: Prevalence of mitochondrial 1555A-- > G mutation in adults of European descent. N Engl J Med 2009, 360:642–644.

    Article  CAS  PubMed  Google Scholar 

  8. Thorburn DR: Mitochondrial disorders: prevalence, myths and advances. J Inherit Metab Dis 2004, 27:349–362.

    Article  CAS  PubMed  Google Scholar 

  9. Lebon S, Chol M, Benit P, et al.: Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency. J Med Genet 2003, 40:896–899.

    Article  CAS  PubMed  Google Scholar 

  10. •• Kirby DM, Thorburn DR: Approaches to finding the molecular basis of mitochondrial oxidative phosphorylation disorders. Twin Res Hum Genet 2008, 11:395–411. This article gives an overview of mitochondrial disease genes discovered before those discussed in the present review.

  11. Smeitink JA, Zeviani M, Turnbull DM, Jacobs HT: Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metab 2006, 3:9–13.

    Article  CAS  PubMed  Google Scholar 

  12. Hakonen AH, Davidzon G, Salemi R, et al.: Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. Eur J Hum Genet 2007, 15:779–783.

    Article  CAS  PubMed  Google Scholar 

  13. Bourgeron T, Rustin P, Chretien D, et al.: Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995, 11:144–149.

    Article  CAS  PubMed  Google Scholar 

  14. Hoefs SJ, Dieteren CE, Distelmaier F, et al.: NDUFA2 complex I mutation leads to Leigh disease. Am J Hum Genet 2008, 82:1306–1315.

    Article  CAS  PubMed  Google Scholar 

  15. Barel O, Shorer Z, Flusser H, et al.: Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet 2008, 82:1211–1216.

    Article  CAS  PubMed  Google Scholar 

  16. Massa V, Fernandez-Vizarra E, Alshahwan S, et al.: Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet 2008, 82:1281–1289.

    Article  CAS  PubMed  Google Scholar 

  17. Shteyer E, Saada A, Shaag A, et al.: Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene. Am J Hum Genet 2009, 84:412–417.

    Article  CAS  PubMed  Google Scholar 

  18. • Sugiana C, Pagliarini DJ, McKenzie M, et al.: Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Am J Hum Genet 2008, 83:468–478. This article discusses a novel CI assembly factor with disease associations.

  19. •• Pagliarini DJ, Calvo SE, Chang B, et al.: A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008, 134:112–123. This article describes sophisticated prediction of mitochondrial genes that represent candidate disease genes, particularly those relevant to CI deficiency. It also contains the first report of C8orf38 mutations causing CI deficiency.

  20. • Saada A, Vogel RO, Hoefs SJ, et al.: Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Am J Hum Genet 2009, 84:718–727. The authors describe a novel CI assembly factor with disease associations.

  21. • Ghezzi D, Goffrini P, Uziel G, et al.: SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 2009, 41:654–656. This is the first report of a pathogenic mutation in a CII assembly factor.

  22. Hao HX, Khalimonchuk O, Schraders M, et al.: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 2009, 325:1139–1142.

    Article  CAS  PubMed  Google Scholar 

  23. • Weraarpachai W, Antonicka H, Sasarman F, et al.: Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet 2009, 41:833–837. The authors describe a novel gene involved in mtDNA translation and associated with CIV deficiency.

  24. • Ghezzi D, Saada A, D’Adamo P, et al.: FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet 2008, 83:415–423. This article discusses a novel gene required for CIV activity.

  25. • Cizkova A, Stranecky V, Mayr JA, et al.: TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet 2008, 40:1288–1290. This article describes a novel CV assembly factor with disease associations that also may be a common cause of CV deficiency.

  26. Gerards M, Sluiter W, van den Bosch BJ, et al.: Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome. J Med Genet 2009 Jun 18 (Epub ahead of print).

  27. Tiranti V, Viscomi C, Hildebrandt T, et al.: Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 2009, 15:200–205.

    Article  CAS  PubMed  Google Scholar 

  28. Wortmann SB, Rodenburg RJ, Jonckheere A, et al.: Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain 2009, 132:136–146.

    Article  PubMed  Google Scholar 

  29. Houstek J, Kmoch S, Zeman J: TMEM70 protein—a novel ancillary factor of mammalian ATP synthase. Biochim Biophys Acta 2009, 1787:529–532.

    Article  CAS  PubMed  Google Scholar 

  30. • Duncan AJ, Bitner-Glindzicz M, Meunier B, et al.: A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet 2009, 84:558–566. The authors describe a novel disease gene with potential for treatment.

  31. Zeharia A, Shaag A, Pappo O, et al.: Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 2009, 85:401–407.

    Article  CAS  PubMed  Google Scholar 

  32. Calvo S, Jain M, Xie X, et al.: Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet 2006, 38:576–582.

    Article  CAS  PubMed  Google Scholar 

  33. Metzker ML: Sequencing technologies—the next generation. Nat Rev Genet 2010, 11:31–46.

    Article  CAS  PubMed  Google Scholar 

  34. Choi M, Scholl UI, Ji W, et al.: Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A 2009, 106:19096–19101.

    Article  CAS  PubMed  Google Scholar 

  35. • Ng SB, Buckingham KJ, Lee C, et al.: Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 2010, 42:30–35. This article provides a demonstration of high-throughput sequencing in the identification and diagnosis of disease genes (for an unrelated disorder).

  36. Taylor RW, Taylor GA, Morris CM, et al.: Diagnosis of mitochondrial disease: assessment of mitochondrial DNA heteroplasmy in blood. Biochem Biophys Res Commun 1998, 251:883–887.

    Article  CAS  PubMed  Google Scholar 

  37. • Vasta V, Ng SB, Turner EH, et al.: Next generation sequence analysis for mitochondrial disorders. Genome Med 2009, 1:100. This article discusses the validation of high-throughput sequencing for the detection of mitochondrial disease mutations.

  38. Tarpey PS, Smith R, Pleasance E, et al.: A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 2009, 41:535–543.

    Article  CAS  PubMed  Google Scholar 

  39. Nelson DL, Gibbs RA: X-cess of variants in XLMR. Nat Genet 2009, 41:510–512.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors’ research was supported by grants from the National Health and Medical Research Council (NHMRC), the Muscular Dystrophy Association, an NHMRC Principal Research Fellowship to Dr. Thorburn, and an Australian Postgraduate Award to Ms. Tucker.

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No potential conflicts of interest relevant to this article were reported.

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Correspondence to Elena J. Tucker.

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Tucker, E.J., Compton, A.G. & Thorburn, D.R. Recent Advances in the Genetics of Mitochondrial Encephalopathies. Curr Neurol Neurosci Rep 10, 277–285 (2010). https://doi.org/10.1007/s11910-010-0112-8

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  • DOI: https://doi.org/10.1007/s11910-010-0112-8

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