1 Nature Reviews Genetics 2005 Vol: 6(5):389-402. DOI: 10.1038/nrg1606

Mitochondrial DNA mutations in human disease

The human mitochondrial genome is extremely small compared with the nuclear genome, and mitochondrial genetics presents unique clinical and experimental challenges. Despite the diminutive size of the mitochondrial genome, mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely.

Mentions
Figures
Figure 1: The role of the mitochondrial genome in energy generation.a | This highlights the importance of the mitochondrial genome in contributing polypeptide subunits to the five enzyme complexes that comprise the oxidative phosphorylation (OXPHOS) system within the inner mitochondrial membrane — the site of ATP synthesis. The reoxidation of reducing equivalents (NADH (reduced nicotinamide adenine dinucleotide) and FADH2 (reduced flavin adenine dinucleotide)) that are produced by the oxidation of carbohydrates (the tricarboxylic acid (TCA) cycle) and fatty acids (-oxidation) is coupled to the generation of an electrochemical gradient across the inner mitochondrial membrane, which is harnessed by the ATP synthase to drive the formation of ATP. b | A map of the human mitochondrial genome. The genes that encode the subunits of complex I (ND1–ND6 and ND4L) are shown in blue; cytochrome c oxidase (COI–COIII) is shown in red; cytochrome b of complex III is shown in green; and the subunits of the ATP synthase (ATPase 6 and 8) are shown in yellow. The two ribosomal RNAs (rRNAs; 12S and 16S, shown in purple) and 22 tRNAs, indicated by black lines and denoted by their single letter code, which are required for mitochondrial protein synthesis are also shown. The displacement loop (D-loop), or non-coding control region, contains sequences that are vital for the initiation of both mtDNA replication and transcription, including the proposed origin of heavy-strand replication (shown as OH). The origin of light-strand replication is shown as OL. Figure 2: Cytochrome c oxidase deficiency in mitochondrial DNA-associated disease and ageing.Transverse tissue sections that are reacted for both cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activities sequentially, with COX-positive cells shown in brown and COX-deficient cells shown in blue. a | Skeletal muscle from a patient with a heteroplasmic mitochondrial tRNA point mutation. The section shows a typical 'mosaic' pattern of COX activity, with many muscle fibres harbouring levels of mutated mtDNA that are above the crucial threshold to produce a functional enzyme complex. b | Cardiac tissue (left ventricle) from a patient with a homoplasmic tRNA mutation that causes hypertrophic cardiomyopathy, which demonstrates an absence of COX in most cells. c | A section of cerebellum from a patient with an mtDNA rearrangement that highlights the presence of COX-deficient neurons. d,e | Tissues that show COX deficiency that is due to clonal expansion of somatic mtDNA mutations within single cells — a phenomenon that is seen in both post-mitotic cells (d; extraocular muscles) and rapidly dividing cells (e; colonic crypt) in ageing humans. Figure 3: The mitochondrial genetic bottleneck.During the production of primary oocytes, a selected number of mitochondrial DNA (mtDNA) molecules are transferred into each oocyte. Oocyte maturation is associated with the rapid replication of this mtDNA population. This restriction-amplification event can lead to a random shift of mtDNA mutational load between generations and is responsible for the variable levels of mutated mtDNA observed in affected offspring from mothers with pathogenic mtDNA mutations. Mitochondria that contain mutated mtDNA are shown in red, those with normal mtDNA are shown in green. Figure 4: Nuclear transfer techniques.The prevention of mutated maternal mtDNA transmission could be achieved by nuclear transfer techniques. In theory, this could be carried out at the germinal vesicle stage (a), when clearly identifiable structures are visible. The germinal vesicle contains nuclear chromosomes and could be transferred to an oocyte that contains normal mtDNA (green). Alternatively, pronuclear transfer can be carried out at the fertilized oocyte stage (b); this involves removal of the male and female pronuclei from the oocyte that contains mutated mtDNA (red) and their subsequent transfer to an oocyte that has normal mtDNA (green).
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References
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    • . . . In addition, the clinical syndromes caused by mtDNA mutations have variable phenotypes and are often described by instantly forgettable eponyms or acronyms1 . . .
    • . . . Excellent reviews describe the defects that are due to mutations in nuclear genes that are involved in mitochondrial oxidative metabolism1, 14, 15 . . .
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    • . . . These views perhaps ignore the fact that the mitochondrial genome is central to the study of evolutionary genetics, has an important role in forensic medicine2 and that the human, bovine and mouse mitochondrial genomes were the first mammalian genomes to be completely sequenced3, 4, 5. . . .
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    • . . . The increasing ease with which the mitochondrial genome can be analysed, and the availability of a consensus human sequence6, have both helped to recognize mtDNA disorders as a frequent cause of genetic disease . . .
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    • . . . These estimates do not include the recent apparent association of mtDNA mutations and common clinical features (for example, hypertension)9, which indicate that the incidence could be higher still . . .
    • . . . Further difficulties in this area have been highlighted by a recent report that describes a clear association between members of a large family that harbour a homoplasmic mitochondrial tRNA mutation and a metabolic syndrome that is characterized by hypertension, hypomagnesaemia and hypercholesterolaemia9 . . .
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    • . . . In addition, there is increasing evidence from animal models10 and human studies11 that acquired mtDNA mutations and mitochondrial dysfunction are involved in ageing and age-related diseases such as diabetes12, 13 . . .
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    • . . . In addition, there is increasing evidence from animal models10 and human studies11 that acquired mtDNA mutations and mitochondrial dysfunction are involved in ageing and age-related diseases such as diabetes12, 13 . . .
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    • . . . In addition, there is increasing evidence from animal models10 and human studies11 that acquired mtDNA mutations and mitochondrial dysfunction are involved in ageing and age-related diseases such as diabetes12, 13 . . .
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    • . . . In addition, there is increasing evidence from animal models10 and human studies11 that acquired mtDNA mutations and mitochondrial dysfunction are involved in ageing and age-related diseases such as diabetes12, 13 . . .
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    • . . . Excellent reviews describe the defects that are due to mutations in nuclear genes that are involved in mitochondrial oxidative metabolism1, 14, 15 . . .
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    • . . . The differences between the two genetic systems that are in human cells are probably a relic of evolution16, but lead to some fascinating biology that dictates the functional consequences of mtDNA mutations. . . .
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    • . . . These include: the heterodimeric mtDNA polymerase , which consists of a catalytic subunit with proof-reading ability (PolgA) and a processivity subunit (PolgB)18, Twinkle, which has 5'–3' DNA helicase activity19, and a mitochondrial single-stranded binding protein . . .
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    • . . . These include: the heterodimeric mtDNA polymerase , which consists of a catalytic subunit with proof-reading ability (PolgA) and a processivity subunit (PolgB)18, Twinkle, which has 5'–3' DNA helicase activity19, and a mitochondrial single-stranded binding protein . . .
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    • . . . On the basis of ultrastructural and biochemical analyses, mtDNA replication had been considered to occur by a strand-displacement model20, in which replication of the leading (heavy (H)) strand occurs first, initiating at a specific site (called OH) in the non-coding control region (Fig. 1) . . .
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    • . . . Our understanding of the transcriptional machinery in mammalian mitochondria has improved, predominantly owing to the identification of specific proteins and the development of an in vitro system to dissect out the regulatory features28 . . .
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    • . . . Transcription from the mitochondrial promoters produces a POLYCISTRONIC precursor RNA that is then processed to produce individual tRNA and mRNA molecules29, 30 . . .
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    • . . . Transcription from the mitochondrial promoters produces a POLYCISTRONIC precursor RNA that is then processed to produce individual tRNA and mRNA molecules29, 30 . . .
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    • . . . To initiate transcription, the dedicated mitochondrial RNA polymerase (POLRMT) requires TFAM, and either mitochondrial transcription factor B1 (TFB1M) or B2 (TFB2M)31, 32 . . .
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    • . . . Mutations in mitochondrial tRNA or rRNA genes affect pathology by disrupting mitochondrial translation34 and recent research has concentrated on identifying nuclear factors, including mitochondrial ribosomal proteins (MRPs), that are essential for this process . . .
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    • . . . The first mutations in these nuclear genes, including MRPS16 (mitochondrial ribosomal protein S16)35 and EFG1 (officially known as GFM1; G elongation factor, mitochondrial 1)36 have recently been described in consanguineous families that have generalized mitochondrial translation defects. . . .
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    • . . . The first mutations in these nuclear genes, including MRPS16 (mitochondrial ribosomal protein S16)35 and EFG1 (officially known as GFM1; G elongation factor, mitochondrial 1)36 have recently been described in consanguineous families that have generalized mitochondrial translation defects. . . .
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    • . . . Numerous single-cell and TRANSMITOCHONDRIAL CYBRID CELL studies have shown that the mutated form is functionally recessive and that a biochemical phenotype is associated with high levels of mutation above a crucial threshold37. . . .
    • . . . These cells had identical characteristics to those found in patients with inherited mitochondrial disease37 . . .
    • . . . In addition, studies from patients showed that, in the presence of many mtDNA genomes within a cell, the mutation is functionally recessive and a threshold effect is observed37 . . .
  38. Coller, H. A. et al. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nature Genet. 28, 147-150 (2001) , .
    • . . . In most individuals there is no evidence of heteroplasmy, but all available evidence indicates that mtDNA is constantly undergoing mutation, with clonal expansion or loss of either point mutations or deletions38, 39 . . .
    • . . . How these mutations accumulate to high levels in individual tumours is still unclear, although both modelling and molecular studies indicate that they possibly accumulate without selection38, 39 . . .
  39. Taylor, R. W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351-1360 (2003) , .
    • . . . In most individuals there is no evidence of heteroplasmy, but all available evidence indicates that mtDNA is constantly undergoing mutation, with clonal expansion or loss of either point mutations or deletions38, 39 . . .
    • . . . More recently, mtDNA mutations were found to accumulate to high levels in dividing cells and presumably stem cells39, 146, and cause an observable biochemical defect39. . . .
    • . . . How these mutations accumulate to high levels in individual tumours is still unclear, although both modelling and molecular studies indicate that they possibly accumulate without selection38, 39 . . .
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    • . . . The standard model of mtDNA inheritance is that it is transmitted strictly through the maternal line40 and that mtDNA lineages are therefore clonal . . .
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    • . . . Low levels of paternal transmission of mtDNA have been observed in crosses between mouse species, but not within species41, although further studies showed that this paternal mtDNA was not transmitted to the subsequent generation42 . . .
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    • . . . Low levels of paternal transmission of mtDNA have been observed in crosses between mouse species, but not within species41, although further studies showed that this paternal mtDNA was not transmitted to the subsequent generation42 . . .
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    • . . . In addition, there is evidence that recombination has contributed to the distribution of mtDNA polymorphisms within the human population43 . . .
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    • . . . Although recombination might occur at the cellular level44, 45, the occurrence of recombination within the population is contentious46 . . .
    • . . . It has also been used to test rational, genetic therapies and more recently, to demonstrate the presence of heterologous mtDNA recombination in human cells44. . . .
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    • . . . Although recombination might occur at the cellular level44, 45, the occurrence of recombination within the population is contentious46 . . .
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    • . . . Although recombination might occur at the cellular level44, 45, the occurrence of recombination within the population is contentious46 . . .
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    • . . . Studies of a patient with mitochondrial myopathy — who carried a novel, 2-bp pathogenic deletion in the NADH (reduced nicotinamide adenine dinucleotide) dehydrogenase subunit 2 (ND2) gene in his muscle mtDNA — have also challenged the maternal inheritance of mtDNA47 . . .
  48. Taylor, R. W. et al. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann. Neurol. 54, 521-524 (2003) , .
    • . . . Subsequent studies of other patients with mitochondrial myopathies have not shown any evidence of paternal transmission48, 49, 50, even when assisted reproduction techniques were applied51, 52. . . .
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    • . . . Subsequent studies of other patients with mitochondrial myopathies have not shown any evidence of paternal transmission48, 49, 50, even when assisted reproduction techniques were applied51, 52. . . .
  50. Schwartz, M. & Vissing, J. No evidence for paternal inheritance of mtDNA in patients with sporadic mtDNA mutations. J. Neurol. Sci. 218, 99-101 (2004) , .
    • . . . Subsequent studies of other patients with mitochondrial myopathies have not shown any evidence of paternal transmission48, 49, 50, even when assisted reproduction techniques were applied51, 52. . . .
  51. Danan, C. et al. Evaluation of parental mitochondrial inheritance in neonates born after intracytoplasmic sperm injection. Am. J. Hum. Genet. 65, 463-473 (1999) , .
    • . . . Subsequent studies of other patients with mitochondrial myopathies have not shown any evidence of paternal transmission48, 49, 50, even when assisted reproduction techniques were applied51, 52. . . .
  52. Marchington, D. R. et al. No evidence for paternal mtDNA transmission to offspring or extra-embryonic tissues after ICSI. Mol. Hum. Reprod. 8, 1046-1049 (2002) , .
    • . . . Subsequent studies of other patients with mitochondrial myopathies have not shown any evidence of paternal transmission48, 49, 50, even when assisted reproduction techniques were applied51, 52. . . .
  53. Chinnery, P. F. et al. Risk of developing a mitochondrial DNA deletion disorder. Lancet 364, 592-596 (2004) , .
    • . . . A recent analysis of a single, large-scale mtDNA deletion in 226 families, showed that the risk of recurrence in the offspring of an affected mother was 4.11% (Ref. 53) . . .
  54. Man, P. Y. et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am. J. Hum. Genet. 72, 333-339 (2003) , .
    • . . . Approximately 50% of males, but only 10% of females, develop impaired vision54, which certainly indicates that nuclear genetic factors are important in the expression of the disease . . .
  55. Prezant, T. R. et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4, 289-294 (1993) , .
    • . . . Another homoplasmic mtDNA mutation, the 1555A>G 12S ribosomal RNA (RNR1) mutation55, is an important cause of post-lingual deafness . . .
    • . . . Examples of such diseases include progressive external OPHTHALMOPLEGIA64, PEARSON SYNDROME65, LEIGH SYNDROME66, 67 (see also Online links box), exercise-induced muscle pain, fatigue and RHABDOMYOLYSIS68 (see also Online links box), and amino-glycoside-induced hearing loss55 . . .
  56. Battersby, B. J., Loredo-Osti, J. C. & Shoubridge, E. A. Nuclear genetic control of mitochondrial DNA segregation. Nature Genet. 33, 183-186 (2003) , .
    • . . . Nuclear genetic56 and environmental factors almost certainly affect expression of the disease phenotype . . .
  57. Brown, D. T., Samuels, D. C., Michael, E. M., Turnbull, D. M. & Chinnery, P. F. Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am. J. Hum. Genet. 68, 533-536 (2000) , .
    • . . . In addition, there is a GENETIC BOTTLENECK during development, and the amount of mutated mtDNA that is transmitted to the offspring is variable57 (Fig. 3) . . .
  58. Poulton, J. & Turnbull, D. M. 74th ENMC international workshop: mitochondrial diseases 19-20 November 1999, Naarden, the Netherlands. Neuromuscul. Disord. 10, 460-462 (2000) , .
    • . . . Because many of the clinical features depend on the relative proportions of mutated versus wild-type mtDNA, the outcome for each pregnancy remains difficult to predict58. . . .
  59. Taylor, R. W., Schaefer, A. M., Barron, M. J., McFarland, R. & Turnbull, D. M. The diagnosis of mitochondrial muscle disease. Neuromuscul. Disord. 14, 237-245 (2004) , .
    • . . . This includes histochemical and biochemical studies to determine the precise nature of the respiratory chain defect, analysis of the mitochondrial genome for common mutations and, finally, complete genome sequencing to look for rare or novel mutations59 . . .
  60. McFarland, R., Elson, J. L., Taylor, R. W., Howell, N. & Turnbull, D. M. Assigning pathogenicity to mitochondrial tRNA mutations: when 'definitely maybe' is not good enough. Trends Genet. 20, 591-596 (2004) , .
    • . . . The mitochondrial genome is highly variable and the ease of whole-genome sequencing does not resolve some diagnostic dilemmas because the interpretation of a novel sequence change can be difficult in relation to potential pathogenicity60 . . .
    • . . . The increasing recognition of mtDNA involvement in disease is partially due to the relative ease of sequencing the mitochondrial genome, although defining pathogenicity of specific base substitutions can be difficult60 . . .
  61. Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717-719 (1988).The first demonstration that heteroplasmic, large-scale rearrangements of the mitochondrial genome could cause human disease , .
    • . . . Genetic defects of the human mitochondrial genome were first described in 1988 (Refs 61,62) and arose from the investigation of two syndromes — Kearns–Sayre syndrome (KSS) and LHON . . .
  62. Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427-1430 (1988).This paper describes the first example of a single-nucleotide change in the mitochondrial genome (11778G>A) as the cause of a maternally inherited, neurological disorder in multiple families , .
    • . . . Genetic defects of the human mitochondrial genome were first described in 1988 (Refs 61,62) and arose from the investigation of two syndromes — Kearns–Sayre syndrome (KSS) and LHON . . .
  63. Brandon, M. C. et al. MITOMAP: a human mitochondrial genome database - 2004 update. Nucleic Acids Res. 33, D611-D613 (2005) , .
    • . . . Since 1988, several mutations63 of the mitochondrial genome have been identified and associated with disease (Table 2). . . .
    • . . . Because several mtDNA mutations cause diabetes63 it is clearly impractical and uneconomical to screen all patients with diabetes for causative mutations . . .
  64. Moraes, C. T. et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N. Engl. J. Med. 320, 1293-1299 (1989) , .
    • . . . Examples of such diseases include progressive external OPHTHALMOPLEGIA64, PEARSON SYNDROME65, LEIGH SYNDROME66, 67 (see also Online links box), exercise-induced muscle pain, fatigue and RHABDOMYOLYSIS68 (see also Online links box), and amino-glycoside-induced hearing loss55 . . .
    • . . . In many heteroplasmic mtDNA64, 122 disorders there are marked tissue-specific differences in the level of heteroplasmy, and therefore a reasonable concern is whether a prenatal sample will reflect the likely outcome for the fetus . . .
  65. Rotig, A., Cormier, V., Blanche, S., Bonnefont, J. -P. & Ledeist, F. Pearson's marrow pancreas syndrome. A multisystem mitochondrial disorder of infancy. J. Clin. Invest. 86, 1601-1608 (1990) , .
    • . . . Examples of such diseases include progressive external OPHTHALMOPLEGIA64, PEARSON SYNDROME65, LEIGH SYNDROME66, 67 (see also Online links box), exercise-induced muscle pain, fatigue and RHABDOMYOLYSIS68 (see also Online links box), and amino-glycoside-induced hearing loss55 . . .
  66. McFarland, R. et al. De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann. Neurol. 55, 58-64 (2004) , .
    • . . . Examples of such diseases include progressive external OPHTHALMOPLEGIA64, PEARSON SYNDROME65, LEIGH SYNDROME66, 67 (see also Online links box), exercise-induced muscle pain, fatigue and RHABDOMYOLYSIS68 (see also Online links box), and amino-glycoside-induced hearing loss55 . . .
  67. de Vries, D. D., van Engelen, B. G., Gabreels, F. J., Ruitenbeek, W. & van Oost, B. A. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann. Neurol. 34, 410-412 (1993) , .
    • . . . Examples of such diseases include progressive external OPHTHALMOPLEGIA64, PEARSON SYNDROME65, LEIGH SYNDROME66, 67 (see also Online links box), exercise-induced muscle pain, fatigue and RHABDOMYOLYSIS68 (see also Online links box), and amino-glycoside-induced hearing loss55 . . .
  68. Andreu, A. L. et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. 341, 1037-1044 (1999) , .
    • . . . Examples of such diseases include progressive external OPHTHALMOPLEGIA64, PEARSON SYNDROME65, LEIGH SYNDROME66, 67 (see also Online links box), exercise-induced muscle pain, fatigue and RHABDOMYOLYSIS68 (see also Online links box), and amino-glycoside-induced hearing loss55 . . .
  69. Lowell, B. B. & Shulman, G. I. Mitochondrial dysfunction and type 2 diabetes. Science 307, 384-387 (2005) , .
    • . . . A good example of a common condition in which mtDNA is a potential cause is diabetes, the most common metabolic disease to affect humans69. mtDNA disease certainly is associated with diabetes, but these patients represent a tiny proportion of those affected with diabetes70, 71, 72 . . .
  70. Maassen, J. A. et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 53 (Suppl. 1), 103-109 (2004) , .
    • . . . A good example of a common condition in which mtDNA is a potential cause is diabetes, the most common metabolic disease to affect humans69. mtDNA disease certainly is associated with diabetes, but these patients represent a tiny proportion of those affected with diabetes70, 71, 72 . . .
    • . . . Other factors that make the diagnosis of mtDNA difficult include the specific combination of clinical symptoms (Box 2); for example, mitochondrial diabetes is often accompanied by deafness70, and stroke-like episodes are usually associated with migraine-like symptoms . . .
  71. Saker, P. J. et al. UKPDS 21: low prevalence of the mitochondrial transfer RNA gene (tRNALeu(UUR)) mutation at position 3243bp in UK Caucasian type 2 diabetic patients. Diabet. Med. 14, 42-45 (1997) , .
    • . . . A good example of a common condition in which mtDNA is a potential cause is diabetes, the most common metabolic disease to affect humans69. mtDNA disease certainly is associated with diabetes, but these patients represent a tiny proportion of those affected with diabetes70, 71, 72 . . .
  72. Ohkubo, K. et al. Mitochondrial gene mutations in the tRNALeu(UUR) region and diabetes: prevalence and clinical phenotypes in Japan. Clin. Chem. 47, 1641-1648 (2001) , .
    • . . . A good example of a common condition in which mtDNA is a potential cause is diabetes, the most common metabolic disease to affect humans69. mtDNA disease certainly is associated with diabetes, but these patients represent a tiny proportion of those affected with diabetes70, 71, 72 . . .
  73. Kearney, P. M. et al. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217-223 (2005) , .
    • . . . Because conditions such as hypertension and hypercholesterolaemia affect many individuals73, the number of patients with mtDNA disease is potentially very high . . .
  74. Chinnery, P. F. et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann. Neurol. 48, 188-193 (2000) , .
    • . . . In epidemiological surveys of populations74, the incidence of mtDNA mutations within a specific disease phenotype75 is small . . .
  75. Choo-Kang, A. T. et al. Defining the importance of mitochondrial gene defects in maternally inherited diabetes by sequencing the entire mitochondrial genome. Diabetes 51, 2317-2320 (2002) , .
    • . . . In epidemiological surveys of populations74, the incidence of mtDNA mutations within a specific disease phenotype75 is small . . .
  76. Wallace, D. C. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628-632 (1992) , .
    • . . . There has been considerable interest in the possibility that mtDNA variants might predispose to common diseases; for example, diabetes, Alzheimer disease (AD) and Parkinson disease (PD)76 . . .
  77. Herrnstadt, C. et al. Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am. J. Hum. Genet. 70, 1152-1171 (2002) , .
    • . . . Unfortunately, interpreting the results is limited by the relatively small number of individual mtDNA sequences in each group and by the high mutation rate of mtDNA, which results in a high frequency of rare variants or private polymorphisms77 . . .
  78. Khogali, S. S. et al. A common mitochondrial DNA variant associated with susceptibility to dilated cardiomyopathy in two different populations. Lancet 357, 1265-1267 (2001) , .
    • . . . For example, the 16189 variant, a variable length polycytosine tract in the non-coding control region, has been associated with several late-onset, multifactorial disorders, including susceptibility to cardiomyopathy78 and type 2 diabetes79, and has been proposed to affect mtDNA replication79 . . .
  79. Poulton, J. et al. Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. Hum. Mol. Genet. 11, 1581-1583 (2002) , .
    • . . . For example, the 16189 variant, a variable length polycytosine tract in the non-coding control region, has been associated with several late-onset, multifactorial disorders, including susceptibility to cardiomyopathy78 and type 2 diabetes79, and has been proposed to affect mtDNA replication79 . . .
  80. Torroni, A. et al. Classification of European mtDNAs from an analysis of three European populations. Genetics 144, 1835-1850 (1996) , .
    • . . . Human populations can be divided into several mtDNA haplogroups that are based on specific SNPs, reflecting mutations accumulated by a discrete maternal lineage80 . . .
  81. Chagnon, P. et al. Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population. Am. J. Med. Genet. 85, 20-30 (1999) , .
    • . . . Various results have been reported for both AD and PD81, 82, 83, 84 . . .
  82. van der Walt, J. M. et al. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci. Lett. 365, 28-32 (2004) , .
    • . . . Various results have been reported for both AD and PD81, 82, 83, 84 . . .
  83. Ross, O. A. et al. mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish. Exp. Gerontol. 38, 397-405 (2003) , .
    • . . . Various results have been reported for both AD and PD81, 82, 83, 84 . . .
  84. van der Walt, J. M. et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am. J. Hum. Genet. 72, 804-811 (2003) , .
    • . . . Various results have been reported for both AD and PD81, 82, 83, 84 . . .
  85. Helgason, A., Yngvadóttir, B., Hrafnkelsson, B., Gulcher, J. & Stefánsson, K. An Icelandic example of the impact of population structure on association studies. Nature Genet. 37, 90-95 (2005) , .
    • . . . It is difficult to 'match' groups, even when one tries to control nationality and ethnicity85. . . .
  86. King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500-503 (1989).This paper highlights the technology that has made transmitochondrial cybrids - which are generated by fusing human cell lines that lack mtDNA to enucleated cytoplasts from patients' cells that harbour mtDNA mutations and then growing them under selection - such an elegant cell culture system to study the bioenergetic and cellular consequences of pathogenic mtDNA mutations , .
    • . . . As ° cells have no functional respiratory chain and are dependent on pyruvate and uridine for growth, the loss of either of these two metabolic requirements can be used to select for transformants that harbour complementing (exogenous) mtDNA86 . . .
  87. Chomyn, A. et al. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl Acad. Sci. USA 89, 4221-4225 (1992) , .
    • . . . This elegant system allows the functional and physiological consequences of different levels of heteroplasmy of certain mtDNA mutations to be tested87, 88 . . .
  88. Hayashi, J. et al. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 88, 10614-10618 (1991) , .
    • . . . This elegant system allows the functional and physiological consequences of different levels of heteroplasmy of certain mtDNA mutations to be tested87, 88 . . .
  89. Tiranti, V. et al. Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. Hum. Mol. Genet. 4, 1421-1427 (1995) , .
    • . . . In addition, it has also proved useful in determining the genetic origin of certain mitochondrial disorders89, 90, the effect of nuclear background on the segregation of pathogenic mtDNA mutations91 and in identifying the first tRNA suppressor mutation in human mitochondria92 . . .
  90. Taanman, J. W. et al. Molecular mechanisms in mitochondrial DNA depletion syndrome. Hum. Mol. Genet. 6, 935-942 (1997) , .
    • . . . In addition, it has also proved useful in determining the genetic origin of certain mitochondrial disorders89, 90, the effect of nuclear background on the segregation of pathogenic mtDNA mutations91 and in identifying the first tRNA suppressor mutation in human mitochondria92 . . .
  91. Dunbar, D. R., Moonie, P. A., Jacobs, H. T. & Holt, I. J. Different cellular backgrounds confer a marked advantage to either mutant or wild-type mitochondrial genomes. Proc. Natl Acad. Sci. USA 92, 6562-6566 (1995) , .
    • . . . In addition, it has also proved useful in determining the genetic origin of certain mitochondrial disorders89, 90, the effect of nuclear background on the segregation of pathogenic mtDNA mutations91 and in identifying the first tRNA suppressor mutation in human mitochondria92 . . .
  92. El Meziane, A. et al. A tRNA supressor mutation in human mitochondria. Nature Genet. 18, 350-353 (1998) , .
    • . . . In addition, it has also proved useful in determining the genetic origin of certain mitochondrial disorders89, 90, the effect of nuclear background on the segregation of pathogenic mtDNA mutations91 and in identifying the first tRNA suppressor mutation in human mitochondria92 . . .
  93. Jenuth, J., Peterson, A. C., Fu, K. & Shoubridge, E. A. Random genetic drift in the female germ line explains the rapid segregation of mammalian mitochondrial DNA. Nature Genet. 14, 146-151 (1996).By generating heteroplasmic mice for two (neutral) mtDNA genotypes, the authors demonstrated that random genetic drift in early oogenesis was the reason for the observed rapid segregation of mtDNA sequence variants that occurs between generations , .
    • . . . Heteroplasmic mice were first generated by fusing zygotes that carried one mtDNA haplotype with enucleated embryos that carried a different haplotype93, 94, although these mice (BALB and NZB) harboured only neutral mtDNA variants . . .
  94. Jenuth, J. P., Peterson, A. C. & Shoubridge, E. A. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nature Genet. 16, 93-95 (1997) , .
    • . . . Heteroplasmic mice were first generated by fusing zygotes that carried one mtDNA haplotype with enucleated embryos that carried a different haplotype93, 94, although these mice (BALB and NZB) harboured only neutral mtDNA variants . . .
    • . . . The present evidence indicates that this should not be a problem94, 123 . . .
  95. Marchington, D. R., Barlow, D. & Poulton, J. Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: developing the first mouse model of mitochondrial DNA disease. Nature Med. 5, 957-960 (1999) , .
    • . . . Further advances were made with the generation of chimeric, heteroplasmic chloramphenicol resistant (CAPR) mice, which could transmit mtDNA mutations to subsequent generations and showed signs of mitochondrial dysfunction95, 96 . . .
  96. Sligh, J. E. et al. Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proc. Natl Acad. Sci. USA 97, 14461-14466 (2000) , .
    • . . . Further advances were made with the generation of chimeric, heteroplasmic chloramphenicol resistant (CAPR) mice, which could transmit mtDNA mutations to subsequent generations and showed signs of mitochondrial dysfunction95, 96 . . .
  97. Inoue, K. et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nature Genet. 26, 176-181 (2000).By isolating mouse cybrid clones with high levels of a somatic mtDNA rearrangement and fusing these with fertilized mouse eggs, these authors generated the first mouse model of a pathogenic mtDNA mutation (mtDNA deletion or duplication), which was transmitted from mother to offspring , .
    • . . . By fusing CYTOPLASTS that harbour high levels of a somatic mtDNA rearrangement to one-cell embryos, Hayashi and colleagues generated a model that has a pathogenic deletion or duplication97 of the mitochondrial genome, which was transmitted through the germ line . . .
  98. Nakada, K. et al. Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nature Med. 7, 934-940 (2001) , .
    • . . . Although subsequent studies that use this mouse model have improved our understanding of mitochondrial segregation and disease pathogenesis98, no reported studies specifically address the development of potential therapies. . . .
  99. Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet. 18, 231-236 (1998).The first Tfam knockout mouse model that demonstrates a role for the TFAM nuclear protein in maintaining mtDNA copy number , .
    • . . . The generation of mouse models that target nuclear genes involved in mtDNA maintenance or replication, such as the Tfam knockout mouse, has proved to be a more successful approach99, 100, 101, 102, 103 . . .
  100. Silva, J. P. et al. Impaired insulin secretion and -cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nature Genet. 26, 336-340 (2000) , .
    • . . . The generation of mouse models that target nuclear genes involved in mtDNA maintenance or replication, such as the Tfam knockout mouse, has proved to be a more successful approach99, 100, 101, 102, 103 . . .
  101. Sorensen, L. et al. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21, 8082-8090 (2001) , .
    • . . . The generation of mouse models that target nuclear genes involved in mtDNA maintenance or replication, such as the Tfam knockout mouse, has proved to be a more successful approach99, 100, 101, 102, 103 . . .
    • . . . For example, the mice generated by the postnatal disruption of Tfam in neurons of the hippocampus and neocortex develop a late-onset neurodegeneration, but there is minimal cell loss until the mice developed seizures101 . . .
  102. Wredenberg, A. et al. Increased mitochondrial mass in mitochondrial myopathy mice. Proc. Natl Acad. Sci. USA 99, 15066-15071 (2002) , .
    • . . . The generation of mouse models that target nuclear genes involved in mtDNA maintenance or replication, such as the Tfam knockout mouse, has proved to be a more successful approach99, 100, 101, 102, 103 . . .
  103. Wang, J. et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nature Genet. 21, 133-137 (1999) , .
    • . . . The generation of mouse models that target nuclear genes involved in mtDNA maintenance or replication, such as the Tfam knockout mouse, has proved to be a more successful approach99, 100, 101, 102, 103 . . .
  104. Chinnery, P. F. & Bindoff, L. A. 116th ENMC international workshop: the treatment of mitochondrial disorders, 14th-16th March 2003, Naarden, The Netherlands. Neuromuscul. Disord. 13, 757-764 (2003) , .
    • . . . However, there are important issues associated with the clinical management of patients and many of these issues have recently been discussed104 . . .
  105. Taivassalo, T. et al. Gene shifting: a novel therapy for mitochondrial myopathy. Hum. Mol. Genet. 8, 1047-1052 (1999) , .
    • . . . Resistance training or muscle necrosis stimulates the incorporation of SATELLITE CELLS into existing muscle fibres105, 106 . . .
    • . . . However, there are concerns that mutated mtDNA might be preferentially amplified, and that this increase might become clinically relevant after deconditioning105, 108 . . .
  106. Clark, K. M. et al. Reversal of a mitochondrial DNA defect in human skeletal muscle. Nature Genet. 16, 222-224 (1997) , .
    • . . . Resistance training or muscle necrosis stimulates the incorporation of SATELLITE CELLS into existing muscle fibres105, 106 . . .
    • . . . It is postulated that for sporadic mutations, resistance training might lead to an overall reduction in the proportion of mutated mtDNA versus wild-type, as satellite cells contain a low or negligible amount of mutated mtDNA106, 107 . . .
  107. Fu, K. et al. A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Hum. Mol. Genet. 5, 1835-1840 (1996) , .
    • . . . It is postulated that for sporadic mutations, resistance training might lead to an overall reduction in the proportion of mutated mtDNA versus wild-type, as satellite cells contain a low or negligible amount of mutated mtDNA106, 107 . . .
  108. Taivassalo, T. et al. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann. Neurol. 50, 133-141 (2001) , .
    • . . . However, there are concerns that mutated mtDNA might be preferentially amplified, and that this increase might become clinically relevant after deconditioning105, 108 . . .
  109. Manfredi, G. et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nature Genet. 30, 394-399 (2002) , .
    • . . . Using this approach, it was possible to express the wild-type ATPase 6 protein allotopically from nucleus-transfected constructs in transmitochondrial cybrid cells that were homoplasmic for the 8993T>G MTATP6 (subunit 6 of mitochondrial ATP synthase) mutation (which causes neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome) and demonstrate a partial rescue of the biochemical defect109 . . .
  110. Guy, J. et al. Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann. Neurol. 52, 534-542 (2002) , .
    • . . . A similar strategy has been used to express a modified NADH dehydrogenase subunit 4 (ND4) gene to complement the 11778G>A mutation that causes LHON110 . . .
  111. Kolesnikova, O. A. et al. Suppression of mutations in mitochondrial DNA by tRNAs imported from the cytoplasm. Science 289, 1931-1933 (2000) , .
    • . . . Yeast cytosolic tRNALysCUU (tK1) and similar derivatives can be imported into isolated human mitochondria if the tRNA is amino-acylated and supplied with soluble factors, including lysl-tRNA synthetases111 . . .
  112. Kolesnikova, O. A. et al. Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells. Hum. Mol. Genet. 13, 2519-2534 (2004) , .
    • . . . Using transmitochondrial cybrid cells and primary human fibroblasts that carry the 8344A>G TRNK (a tRNA gene) mutation, which causes myoclonic epilepsy and ragged-red fibres (MERRF) syndrome, it has recently been shown that the imported tRNALys is correctly amino-acylated and able to participate in mitochondrial translation, partially rescuing mitochondrial function112. . . .
  113. Taylor, R. W., Chinnery, P. F., Turnbull, D. M. & Lightowlers, R. N. Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nature Genet. 15, 212-215 (1997) , .
    • . . . The selective inhibition of mutated mtDNA replication by antigenomic agents has been applied to manipulate mtDNA heteroplasmy113 . . .
  114. Tanaka, M. et al. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci. 9, 534-541 (2002) , .
    • . . . Another strategy involves targeting the organelle with restriction endonucleases that, by differentiating between mtDNA genotypes, can cause the preferential elimination of the mutated genotype and propagation of the wild-type genotype114, 115 . . .
  115. Srivastava, S. & Moraes, C. T. Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum. Mol. Genet. 10, 3093-3099 (2001) , .
    • . . . Another strategy involves targeting the organelle with restriction endonucleases that, by differentiating between mtDNA genotypes, can cause the preferential elimination of the mutated genotype and propagation of the wild-type genotype114, 115 . . .
  116. Manfredi, G. et al. Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. J. Biol. Chem. 274, 9386-9381 (1999) , .
    • . . . Oligomycin, an irreversible inhibitor of mitochondrial ATP synthase, has been used to increase the fraction of wild-type molecules in cells that harbour the 8933T>G MTATP6 mutation under culture conditions (using galactose as the sole carbon source) that specifically select for the wild-type molecule116 . . .
  117. Santra, S., Gilkerson, R. W., Davidson, M. & Schon, E. A. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Ann. Neurol. 56, 662-669 (2004) , .
    • . . . In this case, a ketogenic medium has been used to shift the heteroplasmy of cells that contain a mixture of wild-type and partially deleted mtDNAs117 . . .
  118. Feuermann, M. et al. The yeast counterparts of human 'MELAS' mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF-Tu. EMBO Rep. 4, 53-58 (2003) , .
    • . . . Finally, the revelation that overexpressing mitochondrial Tu translation elongation factor, TUFM, in yeast mutant counterparts of TRNL1 (a tRNA gene) MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) mutations facilitates the rescue of the respiratory defect might have implications for human disease-related mutations118. . . .
  119. Harding, A. E., Holt, I. J., Sweeney, M. G., Brockington, M. & Davis, M. B. Prenatal diagnosis of mitochondrial DNA 8993T>G disease. Am. J. Hum. Genet. 50, 629-633 (1992) , .
    • . . . Chorionic villus biopsy has been used in some families that have heteroplasmic mtDNA disorders, where the results have influenced the clinical management119, 120, 121 . . .
  120. Leshinsky-Silver, E. et al. Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA. Prenat. Diagn. 23, 31-33 (2003) , .
    • . . . Chorionic villus biopsy has been used in some families that have heteroplasmic mtDNA disorders, where the results have influenced the clinical management119, 120, 121 . . .
  121. Jacobs, L. J. et al. Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation. Mol. Hum. Reprod. 11, 223-228 (2005) , .
    • . . . Chorionic villus biopsy has been used in some families that have heteroplasmic mtDNA disorders, where the results have influenced the clinical management119, 120, 121 . . .
  122. Weber, K. et al. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am. J. Hum. Genet. 60, 373-380 (1997) , .
    • . . . In many heteroplasmic mtDNA64, 122 disorders there are marked tissue-specific differences in the level of heteroplasmy, and therefore a reasonable concern is whether a prenatal sample will reflect the likely outcome for the fetus . . .
  123. White, S. L. et al. Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. Prenat. Diagn. 19, 1165-1168 (1999) , .
    • . . . The present evidence indicates that this should not be a problem94, 123 . . .
  124. Lin, D. P. et al. Comparison of mitochondrial DNA contents in human embryos with good or poor morphology at the 8-cell stage. Fertil. Steril. 81, 73-79 (2004) , .
    • . . . The high number of mitochondrial genomes within oocytes124 indicates that PGD should be feasible for mtDNA disease . . .
  125. Dean, N. L. et al. Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol. Hum. Reprod. 9, 631-638 (2003) , .
    • . . . Experiments in heteroplasmic mice have shown the levels of heteroplasmy to be virtually identical between the ooplasm and polar body of the mature oocyte and also between blastomeres of each of the 2-, 4-, and 6–8-cell embryo125. . . .
  126. Kagawa, Y. & Hayashi, J. I. Gene therapy of mitochondrial diseases using human cytoplasts. Gene Ther. 4, 6-10 (1997) , .
    • . . . Cytoplasmic transfer involves the transfer of normal mitochondria into the abnormal oocyte to dilute the effect of any mtDNA defect126 . . .
  127. Cohen, J., Scott, R., Schimmel, T., Levron, J. & Willadsen, S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs. Lancet 350, 186-187 (1997) , .
    • . . . Cytoplasmic transfer between human oocytes has been carried out to improve the outcome of assisted reproduction methods127 . . .
  128. Hawes, S. M., Sapienza, C. & Latham, K. E. Ooplasmic donation in humans: the potential for epigenic modifications. Hum. Reprod. 17, 850-852 (2002) , .
    • . . . The effectiveness of this procedure is uncertain128, but some of the children born were heteroplasmic with low levels of mtDNA from the donor oocyte129 . . .
  129. Brenner, C. A., Barritt, J. A., Willadsen, S. & Cohen, J. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil. Steril. 74, 573-578 (2000) , .
    • . . . The effectiveness of this procedure is uncertain128, but some of the children born were heteroplasmic with low levels of mtDNA from the donor oocyte129 . . .
  130. Thorburn, D. R. & Dahl, H. H. M. Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am. J. Med. Genet. 106, 102-114 (2001) , .
    • . . . However, despite the observation that changes in heteroplasmy can occur, it is likely that this technique will have limited value for patients with mtDNA disease, as mouse experiments indicate that the amount of mtDNA that can be transferred is relatively small130. . . .
  131. Roberts, R. M. Prevention of human mitochondrial (mtDNA) disease by nucleus transplantation into an enucleated donor oocyte. Am. J. Med. Genet. 87, 265-266 (1999).This paper describes the possibility of preventing transmission of mitochondrial DNA disease , .
    • . . . Alternatively, nuclear chromosomes from an oocyte that contains mutated mtDNA could be transferred to an enucleated oocyte from a normal female131 . . .
  132. Liu, H., Wang, C. W., Grifo, J. A., Krey, L. C. & Zhang, J. Reconstruction of mouse oocytes by germinal vesicle transfer: maturity of host oocyte cytoplasm determines meiosis. Hum. Reprod. 14, 2357-2361 (1999) , .
    • . . . However, although maturation and fertilization of normal germinal-vesicle-stage oocytes has been achieved with both mouse132, 133, 134 and human oocytes135, 136, these methods are very inefficient . . .
  133. Liu, H., Zhang, J., Krey, L. C. & Grifo, J. A. In-vitro development of mouse zygotes following reconstruction by sequential transfer of germinal vesicles and haploid pronuclei. Hum. Reprod. 15, 1997-2002 (2000) , .
    • . . . However, although maturation and fertilization of normal germinal-vesicle-stage oocytes has been achieved with both mouse132, 133, 134 and human oocytes135, 136, these methods are very inefficient . . .
  134. Takeuchi, T., Ergun, B., Huang, T. H., Rosenwaks, Z. & Palermo, G. D. A reliable technique of nuclear transplantation for immature mammalian oocytes. Hum. Reprod. 14, 1312-1317 (1999) , .
    • . . . However, although maturation and fertilization of normal germinal-vesicle-stage oocytes has been achieved with both mouse132, 133, 134 and human oocytes135, 136, these methods are very inefficient . . .
  135. Barnes, F. L. et al. Blastocyst development and birth after in-vitro maturation of human primary oocytes, intracytoplasmic sperm injection and assisted hatching. Hum. Reprod. 10, 3243-3247 (1995) , .
    • . . . However, although maturation and fertilization of normal germinal-vesicle-stage oocytes has been achieved with both mouse132, 133, 134 and human oocytes135, 136, these methods are very inefficient . . .
  136. Goud, P. T. et al. In-vitro maturation of human germinal vesicle stage oocytes: role of cumulus cells and epidermal growth factor in the culture medium. Hum. Reprod. 13, 1638-1644 (1998) , .
    • . . . However, although maturation and fertilization of normal germinal-vesicle-stage oocytes has been achieved with both mouse132, 133, 134 and human oocytes135, 136, these methods are very inefficient . . .
  137. Kattera, S. & Chen, C. Normal birth after microsurgical enucleation of tripronuclear human zygotes: case report. Hum. Reprod. 18, 1319-1322 (2003) , .
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