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. 1999 Jul;36(7):505–510.

Mitochondrial DNA analysis: polymorphisms and pathogenicity

P Chinnery 1, N Howell 1, R Andrews 1, D Turnbull 1
PMCID: PMC1734403  PMID: 10424809

Abstract

The investigation of mtDNA disease can be relatively straightforward if a person has a recognisable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulties arise when no known mtDNA defect can be found, or when the clinical abnormalities are complex and not easily matched to those of the more common mitochondrial disorders. We will describe here the difficulties that can be encountered during the identification of pathogenic mtDNA mutations and the approaches that can be used to confirm, or eliminate, a likely pathogenic role, in either single gene diseases or in multifactorial disorders.


Keywords: mitochondrial DNA; phylogenetic analysis; Leber's hereditary optic neuropathy; Alzheimer's disease

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Selected References

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  1. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  2. Blume G., Pestronk A., Frank B., Johns D. R. Polymyositis with cytochrome oxidase negative muscle fibres. Early quadriceps weakness and poor response to immunosuppressive therapy. Brain. 1997 Jan;120(Pt 1):39–45. doi: 10.1093/brain/120.1.39. [DOI] [PubMed] [Google Scholar]
  3. Brierley E. J., Johnson M. A., Lightowlers R. N., James O. F., Turnbull D. M. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann Neurol. 1998 Feb;43(2):217–223. doi: 10.1002/ana.410430212. [DOI] [PubMed] [Google Scholar]
  4. Charlmers R. M., Harding A. E. A case-control study of Leber's hereditary optic neuropathy. Brain. 1996 Oct;119(Pt 5):1481–1486. doi: 10.1093/brain/119.5.1481. [DOI] [PubMed] [Google Scholar]
  5. Chinnery P. F., Johnson M. A., Taylor R. W., Durward W. F., Turnbull D. M. A novel mitochondrial tRNA isoleucine gene mutation causing chronic progressive external ophthalmoplegia. Neurology. 1997 Oct;49(4):1166–1168. doi: 10.1212/wnl.49.4.1166. [DOI] [PubMed] [Google Scholar]
  6. Chinnery P. F., Johnson M. A., Taylor R. W., Lightowlers R. N., Turnbull D. M. A novel mitochondrial tRNA phenylalanine mutation presenting with acute rhabdomyolysis. Ann Neurol. 1997 Mar;41(3):408–410. doi: 10.1002/ana.410410319. [DOI] [PubMed] [Google Scholar]
  7. Corral-Debrinski M., Horton T., Lott M. T., Shoffner J. M., Beal M. F., Wallace D. C. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 1992 Dec;2(4):324–329. doi: 10.1038/ng1292-324. [DOI] [PubMed] [Google Scholar]
  8. Corral-Debrinski M., Horton T., Lott M. T., Shoffner J. M., McKee A. C., Beal M. F., Graham B. H., Wallace D. C. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics. 1994 Sep 15;23(2):471–476. doi: 10.1006/geno.1994.1525. [DOI] [PubMed] [Google Scholar]
  9. Corral-Debrinski M., Shoffner J. M., Lott M. T., Wallace D. C. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res. 1992 Sep;275(3-6):169–180. doi: 10.1016/0921-8734(92)90021-g. [DOI] [PubMed] [Google Scholar]
  10. Davis R. E., Miller S., Herrnstadt C., Ghosh S. S., Fahy E., Shinobu L. A., Galasko D., Thal L. J., Beal M. F., Howell N. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4526–4531. doi: 10.1073/pnas.94.9.4526. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  11. Edland S. D., Silverman J. M., Peskind E. R., Tsuang D., Wijsman E., Morris J. C. Increased risk of dementia in mothers of Alzheimer's disease cases: evidence for maternal inheritance. Neurology. 1996 Jul;47(1):254–256. doi: 10.1212/wnl.47.1.254. [DOI] [PubMed] [Google Scholar]
  12. Farrer L. A., Myers R. H., Connor L., Cupples L. A., Growdon J. H. Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J Hum Genet. 1991 Jun;48(6):1026–1033. [PMC free article] [PubMed] [Google Scholar]
  13. Gibbons A. Calibrating the mitochondrial clock. Science. 1998 Jan 2;279(5347):28–29. doi: 10.1126/science.279.5347.28. [DOI] [PubMed] [Google Scholar]
  14. Hegele R. A., Zinman B., Hanley A. J., Harris S., Connelly P. W. A common mtDNA polymorphism associated with variation in plasma triglyceride concentration. Am J Hum Genet. 1997 Jun;60(6):1552–1555. doi: 10.1016/S0002-9297(07)64252-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hirano M., Shtilbans A., Mayeux R., Davidson M. M., DiMauro S., Knowles J. A., Schon E. A. Apparent mtDNA heteroplasmy in Alzheimer's disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14894–14899. doi: 10.1073/pnas.94.26.14894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Howell N. Human mitochondrial diseases: answering questions and questioning answers. Int Rev Cytol. 1999;186:49–116. doi: 10.1016/s0074-7696(08)61051-7. [DOI] [PubMed] [Google Scholar]
  17. Howell N., Kubacka I., Halvorson S., Howell B., McCullough D. A., Mackey D. Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics. 1995 May;140(1):285–302. doi: 10.1093/genetics/140.1.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Howell N., Kubacka I., Mackey D. A. How rapidly does the human mitochondrial genome evolve? Am J Hum Genet. 1996 Sep;59(3):501–509. [PMC free article] [PubMed] [Google Scholar]
  19. Howell N. Leber hereditary optic neuropathy: how do mitochondrial DNA mutations cause degeneration of the optic nerve? J Bioenerg Biomembr. 1997 Apr;29(2):165–173. doi: 10.1023/a:1022690030664. [DOI] [PubMed] [Google Scholar]
  20. Howell N. Leber hereditary optic neuropathy: mitochondrial mutations and degeneration of the optic nerve. Vision Res. 1997 Dec;37(24):3495–3507. doi: 10.1016/S0042-6989(96)00167-8. [DOI] [PubMed] [Google Scholar]
  21. Hutchin T. P., Heath P. R., Pearson R. C., Sinclair A. J. Mitochondrial DNA mutations in Alzheimer's disease. Biochem Biophys Res Commun. 1997 Dec 18;241(2):221–225. doi: 10.1006/bbrc.1997.7793. [DOI] [PubMed] [Google Scholar]
  22. Hutchin T., Cortopassi G. A mitochondrial DNA clone is associated with increased risk for Alzheimer disease. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6892–6895. doi: 10.1073/pnas.92.15.6892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ivanov P. L., Wadhams M. J., Roby R. K., Holland M. M., Weedn V. W., Parsons T. J. Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II. Nat Genet. 1996 Apr;12(4):417–420. doi: 10.1038/ng0496-417. [DOI] [PubMed] [Google Scholar]
  24. Jazin E., Soodyall H., Jalonen P., Lindholm E., Stoneking M., Gyllensten U. Mitochondrial mutation rate revisited: hot spots and polymorphism. Nat Genet. 1998 Feb;18(2):109–110. doi: 10.1038/ng0298-109. [DOI] [PubMed] [Google Scholar]
  25. Johns D. R., Berman J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biochem Biophys Res Commun. 1991 Feb 14;174(3):1324–1330. doi: 10.1016/0006-291x(91)91567-v. [DOI] [PubMed] [Google Scholar]
  26. Johns D. R., Heher K. L., Miller N. R., Smith K. H. Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthalmol. 1993 Apr;111(4):495–498. doi: 10.1001/archopht.1993.01090040087038. [DOI] [PubMed] [Google Scholar]
  27. Jorde L. B., Bamshad M. J., Watkins W. S., Zenger R., Fraley A. E., Krakowiak P. A., Carpenter K. D., Soodyall H., Jenkins T., Rogers A. R. Origins and affinities of modern humans: a comparison of mitochondrial and nuclear genetic data. Am J Hum Genet. 1995 Sep;57(3):523–538. doi: 10.1002/ajmg.1320570340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lynch M., Jarrell P. E. A method for calibrating molecular clocks and its application to animal mitochondrial DNA. Genetics. 1993 Dec;135(4):1197–1208. doi: 10.1093/genetics/135.4.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mackey D. A., Oostra R. J., Rosenberg T., Nikoskelainen E., Bronte-Stewart J., Poulton J., Harding A. E., Govan G., Bolhuis P. A., Norby S. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. 1996 Aug;59(2):481–485. [PMC free article] [PubMed] [Google Scholar]
  30. Mizuno Y., Ikebe S., Hattori N., Nakagawa-Hattori Y., Mochizuki H., Tanaka M., Ozawa T. Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. Biochim Biophys Acta. 1995 May 24;1271(1):265–274. doi: 10.1016/0925-4439(95)00038-6. [DOI] [PubMed] [Google Scholar]
  31. Molina J. A., de Bustos F., Jiménez-Jiménez F. J., Benito-León J., Gasalla T., Ortí-Pareja M., Vela L., Bermejo F., Martín M. A., Campos Y. Respiratory chain enzyme activities in isolated mitochondria of lymphocytes from patients with Alzheimer's disease. Neurology. 1997 Mar;48(3):636–638. doi: 10.1212/wnl.48.3.636. [DOI] [PubMed] [Google Scholar]
  32. Mutisya E. M., Bowling A. C., Beal M. F. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem. 1994 Dec;63(6):2179–2184. doi: 10.1046/j.1471-4159.1994.63062179.x. [DOI] [PubMed] [Google Scholar]
  33. Ozawa T., Katsumata K., Hayakawa M., Yoneda M., Tanaka M., Sugiyama S. Mitochondrial DNA mutations and survival rate. Lancet. 1995 Jan 21;345(8943):189–189. doi: 10.1016/s0140-6736(95)90191-4. [DOI] [PubMed] [Google Scholar]
  34. Parsons T. J., Muniec D. S., Sullivan K., Woodyatt N., Alliston-Greiner R., Wilson M. R., Berry D. L., Holland K. A., Weedn V. W., Gill P. A high observed substitution rate in the human mitochondrial DNA control region. Nat Genet. 1997 Apr;15(4):363–368. doi: 10.1038/ng0497-363. [DOI] [PubMed] [Google Scholar]
  35. Pegoraro E., Carelli V., Zeviani M., Cortelli P., Montagna P., Barboni P., Angelini C., Hoffman E. P. X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant. Am J Med Genet. 1996 Feb 2;61(4):356–362. doi: 10.1002/(SICI)1096-8628(19960202)61:4<356::AID-AJMG10>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  36. Petruzzella V., Moraes C. T., Sano M. C., Bonilla E., DiMauro S., Schon E. A. Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. Hum Mol Genet. 1994 Mar;3(3):449–454. doi: 10.1093/hmg/3.3.449. [DOI] [PubMed] [Google Scholar]
  37. Prezant T. R., Agapian J. V., Bohlman M. C., Bu X., Oztas S., Qiu W. Q., Arnos K. S., Cortopassi G. A., Jaber L., Rotter J. I. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet. 1993 Jul;4(3):289–294. doi: 10.1038/ng0793-289. [DOI] [PubMed] [Google Scholar]
  38. Riordan-Eva P., Sanders M. D., Govan G. G., Sweeney M. G., Da Costa J., Harding A. E. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995 Apr;118(Pt 2):319–337. doi: 10.1093/brain/118.2.319. [DOI] [PubMed] [Google Scholar]
  39. Santorelli F. M., Sciacco M., Tanji K., Shanske S., Vu T. H., Golzi V., Griggs R. C., Mendell J. R., Hays A. P., Bertorini T. E. Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients. Ann Neurol. 1996 Jun;39(6):789–795. doi: 10.1002/ana.410390615. [DOI] [PubMed] [Google Scholar]
  40. Schon E. A., Bonilla E., DiMauro S. Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr. 1997 Apr;29(2):131–149. doi: 10.1023/a:1022685929755. [DOI] [PubMed] [Google Scholar]
  41. Schon E. A., Shoubridge E. A., Moraes C. T. Cybrids in Alzheimer's disease: a cellular model of the disease? Neurology. 1998 Jul;51(1):326–327. doi: 10.1212/wnl.51.1.326. [DOI] [PubMed] [Google Scholar]
  42. Shoffner J. M., Brown M. D., Torroni A., Lott M. T., Cabell M. F., Mirra S. S., Beal M. F., Yang C. C., Gearing M., Salvo R. Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics. 1993 Jul;17(1):171–184. doi: 10.1006/geno.1993.1299. [DOI] [PubMed] [Google Scholar]
  43. Shults C. W., Haas R. H., Passov D., Beal M. F. Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Ann Neurol. 1997 Aug;42(2):261–264. doi: 10.1002/ana.410420221. [DOI] [PubMed] [Google Scholar]
  44. Simonian N. A., Hyman B. T. Functional alterations in Alzheimer's disease: diminution of cytochrome oxidase in the hippocampal formation. J Neuropathol Exp Neurol. 1993 Nov;52(6):580–585. [PubMed] [Google Scholar]
  45. Swerdlow R. H., Parks J. K., Cassarino D. S., Maguire D. J., Maguire R. S., Bennett J. P., Jr, Davis R. E., Parker W. D., Jr Cybrids in Alzheimer's disease: a cellular model of the disease? Neurology. 1997 Oct;49(4):918–925. doi: 10.1212/wnl.49.4.918. [DOI] [PubMed] [Google Scholar]
  46. Swerdlow R. H., Parks J. K., Miller S. W., Tuttle J. B., Trimmer P. A., Sheehan J. P., Bennett J. P., Jr, Davis R. E., Parker W. D., Jr Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol. 1996 Oct;40(4):663–671. doi: 10.1002/ana.410400417. [DOI] [PubMed] [Google Scholar]
  47. Tanaka M., Gong J. S., Zhang J., Yoneda M., Yagi K. Mitochondrial genotype associated with longevity. Lancet. 1998 Jan 17;351(9097):185–186. doi: 10.1016/S0140-6736(05)78211-8. [DOI] [PubMed] [Google Scholar]
  48. Taylor R. W., Chinnery P. F., Bates M. J., Jackson M. J., Johnson M. A., Andrews R. M., Turnbull D. M. A novel mitochondrial DNA point mutation in the tRNA(Ile) gene: studies in a patient presenting with chronic progressive external ophthalmoplegia and multiple sclerosis. Biochem Biophys Res Commun. 1998 Feb 4;243(1):47–51. doi: 10.1006/bbrc.1997.8055. [DOI] [PubMed] [Google Scholar]
  49. Torroni A., Petrozzi M., D'Urbano L., Sellitto D., Zeviani M., Carrara F., Carducci C., Leuzzi V., Carelli V., Barboni P. Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am J Hum Genet. 1997 May;60(5):1107–1121. [PMC free article] [PubMed] [Google Scholar]
  50. Torroni A., Wallace D. C. Mitochondrial DNA variation in human populations and implications for detection of mitochondrial DNA mutations of pathological significance. J Bioenerg Biomembr. 1994 Jun;26(3):261–271. doi: 10.1007/BF00763098. [DOI] [PubMed] [Google Scholar]
  51. Vilarinho L., Santorelli F. M., Rosas M. J., Tavares C., Melo-Pires M., DiMauro S. The mitochondrial A3243G mutation presenting as severe cardiomyopathy. J Med Genet. 1997 Jul;34(7):607–609. doi: 10.1136/jmg.34.7.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wallace D. C. 1994 William Allan Award Address. Mitochondrial DNA variation in human evolution, degenerative disease, and aging. Am J Hum Genet. 1995 Aug;57(2):201–223. [PMC free article] [PubMed] [Google Scholar]
  53. Wallace D. C., Stugard C., Murdock D., Schurr T., Brown M. D. Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14900–14905. doi: 10.1073/pnas.94.26.14900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wallace D. C., Torroni A. American Indian prehistory as written in the mitochondrial DNA: a review. Hum Biol. 1992 Jun;64(3):403–416. [PubMed] [Google Scholar]
  55. Watson E., Forster P., Richards M., Bandelt H. J. Mitochondrial footprints of human expansions in Africa. Am J Hum Genet. 1997 Sep;61(3):691–704. doi: 10.1086/515503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wise C. A., Sraml M., Rubinsztein D. C., Easteal S. Comparative nuclear and mitochondrial genome diversity in humans and chimpanzees. Mol Biol Evol. 1997 Jul;14(7):707–716. doi: 10.1093/oxfordjournals.molbev.a025810. [DOI] [PubMed] [Google Scholar]
  57. Wooten G. F., Currie L. J., Bennett J. P., Harrison M. B., Trugman J. M., Parker W. D., Jr Maternal inheritance in Parkinson's disease. Ann Neurol. 1997 Feb;41(2):265–268. doi: 10.1002/ana.410410218. [DOI] [PubMed] [Google Scholar]
  58. van Holst Pellekaan S., Frommer M., Sved J., Boettcher B. Mitochondrial control-region sequence variation in aboriginal Australians. Am J Hum Genet. 1998 Feb;62(2):435–449. doi: 10.1086/301710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. van den Ouweland J. M., Lemkes H. H., Ruitenbeek W., Sandkuijl L. A., de Vijlder M. F., Struyvenberg P. A., van de Kamp J. J., Maassen J. A. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992 Aug;1(5):368–371. doi: 10.1038/ng0892-368. [DOI] [PubMed] [Google Scholar]

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