41 results on '"Turnbull, Douglass M."'
Search Results
2. Mitochondrial DNA Mutations Are Established in Human Colonic Stem Cells, and Mutated Clones Expand by Crypt Fission
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Greaves, Laura C., Preston, Sean L., Tadrous, Paul J., Taylor, Robert W., Barron, Martin J., Oukrif, Dahmane, Leedham, Simon J., Deheragoda, Maesha, Sasieni, Peter, Novelli, Marco R., Jankowski, Janusz A. Z., Turnbull, Douglass M., Wright, Nicholas A., and McDonald, Stuart A. C.
- Published
- 2006
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3. Genetic and biochemical intricacy shapes mitochondrial cytopathies.
- Author
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Turnbull, Douglass M. and Rustin, Pierre
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MITOCHONDRIAL pathology , *GENETIC mutation , *GENOMES , *MITOCHONDRIAL DNA , *GENETICS , *THERAPEUTICS - Abstract
The major progress made in the identification of the molecular bases of mitochondrial disease has revealed the huge diversity of their origin. Today up to 300 mutations were identified in the mitochondrial genome and about 200 nuclear genes are possibly mutated. In this review, we highlight a number of features specific to mitochondria which possibly participate in the complexity of these diseases. These features include both the complexity of mitochondrial genetics and the multiplicity of the roles ensured by the organelles in numerous aspects of cell life and death. This spectacular complexity presumably accounts for the present lack of an efficient therapy in the vast majority of cases. [ABSTRACT FROM AUTHOR]
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- 2016
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4. Epilepsy in adults with mitochondrial disease: A cohort study.
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Whittaker, Roger G., Devine, Helen E., Gorman, Grainne S., Schaefer, Andrew M., Horvath, Rita, Ng, Yi, Nesbitt, Victoria, Lax, Nichola Z., McFarland, Robert, Cunningham, Mark O., Taylor, Robert W., and Turnbull, Douglass M.
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STROKE-related mortality ,AGE factors in disease ,DNA ,EPILEPSY ,LONGITUDINAL method ,MITOCHONDRIAL pathology ,GENETIC mutation ,RESEARCH funding ,STROKE ,DISEASE prevalence ,DISEASE progression ,DISEASE complications - Abstract
Objective: The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.Methods: We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7-year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death.Results: Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke-like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83).Interpretation: Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke-like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. [ABSTRACT FROM AUTHOR]- Published
- 2015
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5. Human stem cell aging: do mitochondrial DNA mutations have a causal role?
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Baines, Holly L., Turnbull, Douglass M., and Greaves, Laura C.
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STEM cells , *MITOCHONDRIAL DNA abnormalities , *GENETIC mutation , *REGENERATION (Biology) , *CELL populations , *DNA polymerases , *PHYSIOLOGY - Abstract
A decline in the replicative and regenerative capacity of adult stem cell populations is a major contributor to the aging process. Mitochondrial DNA (mt DNA) mutations clonally expand with age in human stem cell compartments including the colon, small intestine, and stomach, and result in respiratory chain deficiency. Studies in a mouse model with high levels of mt DNA mutations due to a defect in the proofreading domain of the mt DNA polymerase γ (mt DNA mutator mice) have established causal relationships between the accumulation of mt DNA point mutations, stem cell dysfunction, and premature aging. These mt DNA mutator mice have also highlighted that the consequences of mt DNA mutations upon stem cells vary depending on the tissue. In this review, we present evidence that these studies in mice are relevant to normal human stem cell aging and we explore different hypotheses to explain the tissue-specific consequences of mt DNA mutations. In addition, we emphasize the need for a comprehensive analysis of mt DNA mutations and their effects on cellular function in different aging human stem cell populations. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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6. Extraocular Muscle Atrophy and Central Nervous System Involvement in Chronic Progressive External Ophthalmoplegia.
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Yu-Wai-Man, Cynthia, Smith, Fiona E., Firbank, Michael J., Guthrie, Grant, Guthrie, Stuart, Gorman, Grainne S., Taylor, Robert W., Turnbull, Douglass M., Griffiths, Philip G., Blamire, Andrew M., Chinnery, Patrick F., and Yu-Wai-Man, Patrick
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MUSCULAR atrophy ,CENTRAL nervous system ,EYE paralysis ,MITOCHONDRIAL pathology ,BLEPHAROPTOSIS ,GENETIC mutation ,PROTON magnetic resonance spectroscopy - Abstract
Background: Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterised by bilateral progressive ptosis and ophthalmoplegia. These ocular features can develop either in isolation or in association with other prominent neurological deficits (CPEO+). Molecularly, CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction. Methods: Ten age-matched normal controls and twenty patients with CPEO were recruited nine patients with single, large-scale mtDNA deletions and eleven patients with multiple mtDNA deletions secondary to mutations in POLG, PEO1, OPA1, and RRM2B. All subjects underwent a standardised brain and orbital MRI protocol, together with proton magnetic resonance spectroscopy in two voxels located within the parietal white matter and the brainstem. Results: There was evidence of significant extraocular muscle atrophy in patients with single or multiple mtDNA deletions compared with controls. There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels. Volumetric brain measurements revealed marked cortical and cerebellar atrophy among patients with CPEO+ phenotypes. Conclusion: The results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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7. Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers†.
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Bates, Matthew G.D., Hollingsworth, Kieren G., Newman, Jane H., Jakovljevic, Djordje G., Blamire, Andrew M., MacGowan, Guy A., Keavney, Bernard D., Chinnery, Patrick F., Turnbull, Douglass M., Taylor, Robert W., Trenell, Michael I., and Gorman, Grainne S.
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STATISTICAL correlation ,DNA ,ENDOCARDIUM ,FISHER exact test ,GLOMERULAR filtration rate ,CARDIAC hypertrophy ,LEFT heart ventricle ,MAGNETIC resonance imaging ,MITOCHONDRIAL pathology ,GENETIC mutation ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,U-statistics ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Aims Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement. Methods and results Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = −0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE. Conclusion Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement. [ABSTRACT FROM PUBLISHER]
- Published
- 2013
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8. Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease.
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van der Walt, Elizna M, Smuts, Izelle, Taylor, Robert W, Elson, Joanna L, Turnbull, Douglass M, Louw, Roan, and van der Westhuizen, Francois H
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MITOCHONDRIAL pathology ,GENETIC mutation ,MITOCHONDRIAL DNA ,NUCLEIC acids ,NUCLEOTIDES - Abstract
Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81±26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup-defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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9. Maternally inherited mitochondrial DNA disease in consanguineous families.
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Alston, Charlotte L, He, Langping, Morris, Andrew A, Hughes, Imelda, Goede, Christian de, Turnbull, Douglass M, McFarland, Robert, and Taylor, Robert W
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MITOCHONDRIAL DNA abnormalities ,PREGNANCY complications ,INBORN errors of metabolism ,GENETIC mutation ,CONSANGUINITY - Abstract
Mitochondrial respiratory chain disease represents one of the most common inborn errors of metabolism and is genetically heterogeneous, with biochemical defects arising from mutations in the mitochondrial genome (mtDNA) or the nuclear genome. As such, inheritance of mitochondrial respiratory chain disease can either follow dominant or recessive autosomal (Mendelian) inheritance patterns, the strictly matrilineal inheritance observed with mtDNA point mutations or X-linked inheritance. Parental consanguinity in respiratory chain disease is often assumed to infer an autosomal recessive inheritance pattern, and the analysis of mtDNA may be overlooked in the pursuit of a presumed nuclear genetic defect. We report the histochemical, biochemical and molecular genetic investigations of two patients with suspected mitochondrial disease who, despite being born to consanguineous first-cousin parents, were found to harbour well-characterised pathogenic mtDNA mutations, both of which were maternally transmitted. Our findings highlight that any diagnostic algorithm for the investigation of mitochondrial respiratory chain disease must include a full and complete analysis of the entire coding sequence of the mitochondrial genome in a clinically relevant tissue. An autosomal basis for respiratory chain disease should not be assumed in consanguineous families and that 'maternally inherited consanguineous' mitochondrial disease may thus be going undiagnosed. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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10. Respiratory chain complex I deficiency caused by mitochondrial DNA mutations.
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Swalwell, Helen, Kirby, Denise M., Blakely, Emma L., Mitchell, Anna, Salemi, Renato, Sugiana, Canny, Compton, Alison G., Tucker, Elena J, Ke, Bi-Xia, Lamont, Phillipa J., Turnbull, Douglass M, McFarland, Robert, Taylor, Robert W., and Thorburn, David R.
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MITOCHONDRIAL DNA abnormalities ,RESPIRATORY diseases ,DNA ,GENETIC mutation ,GENETIC disorders in children ,GENOMES ,CELL fusion - Abstract
Defects of the mitochondrial respiratory chain are associated with a diverse spectrum of clinical phenotypes, and may be caused by mutations in either the nuclear or the mitochondrial genome (mitochondrial DNA (mtDNA)). Isolated complex I deficiency is the most common enzyme defect in mitochondrial disorders, particularly in children in whom family history is often consistent with sporadic or autosomal recessive inheritance, implicating a nuclear genetic cause. In contrast, although a number of recurrent, pathogenic mtDNA mutations have been described, historically, these have been perceived as rare causes of paediatric complex I deficiency. We reviewed the clinical and genetic findings in a large cohort of 109 paediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29 of 101 probands (29%), 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38 of 101 (38%) probands based on cell hybrid studies, mtDNA sequencing or mutation analysis (nuclear gene mutations were identified in 22 probands). Leigh or Leigh-like disease was the most common clinical presentation in both mtDNA and nuclear genetic defects. The median age at onset was higher in mtDNA patients (12 months) than in patients with a nuclear gene defect (3 months). However, considerable overlap existed, with onset varying from 0 to >60 months in both groups. Our findings confirm that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children. In the absence of parental consanguinity, we recommend whole mitochondrial genome sequencing as a key approach to elucidate the underlying molecular genetic abnormality. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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11. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease.
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Craven, Lyndsey, Tuppen, Helen A., Greggains, Gareth D., Harbottle, Stephen J., Murphy, Julie L., Cree, Lynsey M., Murdoch, Alison P., Chinnery, Patrick F., Taylor, Robert W., Lightowlers, Robert N., Herbert, Mary, and Turnbull, Douglass M.
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HUMAN embryos ,MITOCHONDRIAL DNA ,GENETIC mutation ,GENETIC disorders ,ZYGOTES ,BLASTOCYST ,MATERNALLY acquired immunity ,MATERNAL-fetal exchange ,MITOCHONDRIA - Abstract
Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births and at least 1 in 10,000 adults in the UK are affected by mtDNA disease. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans. [ABSTRACT FROM AUTHOR]
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- 2010
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12. A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation: are two mutations better than one?
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Swalwell, Helen, Blakely, Emma L., Sutton, Ruth, Tonska, Kasia, Elstner, Matthias, Langping He, Taivassalo, Tanja, Burns, Dennis K., Turnbull, Douglass M., Haller, Ronald G., Davidson, Mercy M., and Taylor, Robert W.
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GENETIC mutation ,HETEROGENEITY ,MITOCHONDRIAL DNA ,MUSCLE diseases ,DEAFNESS ,DIABETES - Abstract
Mutations in mitochondrial tRNA (mt-tRNA) genes are well recognized as a common cause of human disease, exhibiting a significant degree of clinical heterogeneity. While these differences are explicable, in part, by differences in the innate pathogenicity of the mutation, its distribution and abundance, other factors, including nuclear genetic background, mitochondrial DNA (mtDNA) haplotype and additional mtDNA mutations may influence the expression of mt-tRNA mutations. We describe the clinical, biochemical and molecular findings in a family with progressive myopathy, deafness and diabetes and striking respiratory chain abnormalities due to a well-characterized heteroplasmic mt-tRNA mutation in the mt-tRNA
Ser(UCN) (MTTS1) gene. In addition to the m.7472Cins mutation, all individuals were homoplasmic for another variant, m.7472A>C, affecting the adjacent nucleotide in the mt-tRNASer(UCN) structure. In addition to available patient tissues, we have analysed transmitochondrial cybrid clones harbouring homoplasmic levels of m.7472A>C and varying levels of the m.7472Cins mutation in an attempt to clarify the precise role of the m.7472A>C transversion in the underlying respiratory chain abnormality. Evidence from both in vivo and in vitro studies demonstrate that the m.7472A>C is able to modify the expression of the m.7472Cins mutation and would suggest that it is not a neutral variant but appears to cause a biochemical defect by itself, confirming that homoplasmic mtDNA variants can modulate the phenotypic expression of pathogenic, heteroplasmic mtDNA mutations.European Journal of Human Genetics (2008) 16, 1265–1274; doi:10.1038/ejhg.2008.65; published online 9 April 2008 [ABSTRACT FROM AUTHOR]- Published
- 2008
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13. Mitochondrial DNA Mutations and Aging.
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KRISHNAN, KIM J., GREAVES, LAURA C., REEVE, AMY K., and TURNBULL, DOUGLASS M.
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MITOCHONDRIAL DNA ,GENETIC mutation ,AGING ,DNA ,MITOCHONDRIA ,REACTIVE oxygen species - Abstract
Mitochondria have been hypothesized to play a role in both aging and neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. Many studies have shown the accumulation of mitochondrial DNA (mtDNA) mutations in post-mitotic tissues and more recent data have shown this also to be a feature of aging mitotic tissues. Much of this data has been correlative, until recently with the development of polymerase gamma deficient mice which accumulate high levels of mtDNA mutations and show a premature aging phenotype, that a more causative role has been proposed. This article focuses on recent developments in aging research into the role that mtDNA mutations play in the aging process. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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14. A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast.
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Blakely, Emma L., Mitchell, Anna L., Fisher, Nicholas, Meunier, Brigitte, Nijtmans, Leo G., Schaefer, Andrew M., Jackson, Margaret J., Turnbull, Douglass M., and Taylor, Robert W.
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CYTOCHROME b ,CYTOCHROMES ,GENETIC mutation ,ENZYMES ,MITOCHONDRIAL DNA ,AMINO acids - Abstract
Whereas the majority of disease-related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene ( MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical presentation involving exercise intolerance. Recent studies have shown that a small number of MTCYB mutations are associated with a combined enzyme complex defect involving both complexes I and III, on account of the fact that an absence of assembled complex III results in a dramatic loss of complex I, confirming a structural dependence between these two complexes. We present the biochemical and molecular genetic studies of a patient with both muscle and brain involvement and a severe reduction in the activities of both complexes I and III in skeletal muscle due to a novel mutation in the MTCYB gene that predicts the substitution (Arg318Pro) of a highly conserved amino acid. Consistent with the dramatic biochemical defect, Western blotting and BN-PAGE experiments demonstrated loss of assembled complex I and III subunits. Biochemical studies of the equivalent amino-acid substitution (Lys319Pro) in the yeast enzyme showed a loss of enzyme activity and decrease in the steady-state level of bc
1 complex in the mutant confirming pathogenicity. [ABSTRACT FROM AUTHOR]- Published
- 2005
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15. LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation.
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Blakely, Emma L., de Silva, Rajith, King, Andrew, Schwarzer, Verena, Harrower, Tim, Dawidek, Gervase, Turnbull, Douglass M., and Taylor, Robert W.
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MITOCHONDRIAL DNA ,GENETIC mutation ,GENES ,SYNDROMES ,NEUROPATHY ,MITOCHONDRIAL pathology - Abstract
Pathogenic point mutations in the mitochondrial MTND1 gene have previously been described in association with two distinct clinical phenotypes-Leber hereditary optic neuropathy (LHON) and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Here we report the first heteroplasmic mitochondrial DNA (mtDNA) point mutation (3376G>A) in the MTND1 gene associated with an overlap syndrome comprising the clinical features of both LHON and MELAS. Muscle histochemistry revealed subtle mitochondrial abnormalities, while biochemical analysis showed an isolated complex I deficiency. Our findings serve to highlight the growing importance of mutations in mitochondrial complex I structural genes in MELAS and its associated overlap syndromes.European Journal of Human Genetics (2005) 13, 623-627. doi:10.1038/sj.ejhg.5201363 Published online 12 January 2005 [ABSTRACT FROM AUTHOR]
- Published
- 2005
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16. Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells.
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Mcdonnell, Martina T., Schaefer, Andrew M., Blakely, Emma L., McFarland, Robert, Chinnery, Patrick F., Turnbull, Douglass M., and Taylor, Robert W.
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MITOCHONDRIAL DNA ,DNA ,GENETIC mutation ,EPITHELIAL cells ,URINARY organs ,NONINVASIVE diagnostic tests ,GENETICS ,HUMAN genetics - Abstract
The 3243A>G mutation is one of the most frequently observed mutations of mitochondrial DNA (mtDNA), and is associated with numerous clinical presentations including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), progressive external ophthalmoplegia (PEO) and diabetes and deafness. The routine diagnosis of the 3243A>G mutation in blood is difficult as mutation levels are known to decrease in this tissue over time, while in some patients it may be absent. We have directly compared the levels of the 3243A>G mutation in skeletal muscle, blood and urinary epithelial cells in 18 patients and observed a striking correlation between the mutation load in postmitotic muscle and urinary epithelium, a mitotic tissue. These data strongly support the use of urinary epithelial cells as the tissue of choice in the noninvasive diagnosis of the 3243A>G mutation.European Journal of Human Genetics (2004) 12, 778-781. doi:10.1038/sj.ejhg.5201216 Published online 16 June 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2004
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17. Leigh disease associated with a novel mitochondrial DNA ND5 mutation.
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Taylor, Robert W., Morris, Andrew A.M., Hutchinson, Michael, and Turnbull, Douglass M.
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NEURODEGENERATION ,MITOCHONDRIAL DNA ,GENETIC mutation - Abstract
Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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18. Clinical features, investigation, and management of patients with defects of mitochondrial DNA.
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CHINNERY, PATRICK F., TURNBULL, DOUGLASS M., Chinnery, P F, and Turnbull, D M
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THERAPEUTIC use of vitamin C ,THERAPEUTIC use of vitamin E ,DNA ,MUSCLE diseases ,GENETIC mutation ,MITOCHONDRIAL myopathy - Published
- 1997
19. Nuclear genes and mitochondrial translation: a new class of genetic disease
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Jacobs, Howard T. and Turnbull, Douglass M.
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MITOCHONDRIA , *GENETIC mutation , *PEPTIDE hormones , *MITOCHONDRIAL DNA , *GENES , *GENETIC disorders - Abstract
Mitochondria contain a separate protein-synthesis machinery to produce the polypeptides encoded in mitochondrial DNA (mtDNA), and many mtDNA disease mutations affect this machinery. In humans, the mitochondrial rRNAs and tRNAs are encoded by mtDNA, whereas all proteins involved in mitochondrial translation are encoded by nuclear genes. Recently, several articles have discussed the identification of pathological mutations in nuclear genes encoding components of this protein-synthesis machinery, suggesting that these types of mutation are a frequent cause of human genetic diseases. [Copyright &y& Elsevier]
- Published
- 2005
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20. Diabetes and Deafness.
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Whittaker, Roger G., Schaefer, Andrew M., McFarland, Robert, Taylor, Robert W., Walker, Mark, and Turnbull, Douglass M.
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MITOCHONDRIAL DNA ,GENETIC mutation ,DIAGNOSIS ,PEOPLE with diabetes ,DEAFNESS ,DIABETES ,URINALYSIS - Abstract
The article focuses on a study which assessed whether the m.3243A>G mitochondrial DNA mutation is a suitable screening strategy for patients with deafness and diabetes. Definition of diabetes according to the World Health Organization criteria and the clinical definition of deafness are given. It recommends that patients with the combination of deafness and diabetes be screened for the m.3243A>G mutation. Urine screening is preferred compared to buccal mucosa or blood screening.
- Published
- 2007
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21. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation.
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McFarland, Robert, Clark, Kim M., Morris, Andrew A.M., Taylor, Robert W., Macphail, Sheila, Lightowlers, Robert N., and Turnbull, Douglass M.
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GENETIC mutation ,INFANT death ,MITOCHONDRIAL DNA - Abstract
Mutations of mitochondrial DNA (mtDNA) are an important cause of genetic disease. We describe a family with an unusual homoplasmic mutation that resulted in six neonatal deaths and one surviving child with Leigh syndrome. The mother is clinically normal, but a severe biochemical and molecular genetic defect was present in both a fatally affected child and the mother. This family highlights the role of homoplasmic mt-tRNA mutations in genetic disease. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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22. A novel mitochondrial tRNAGlu (MTTE) gene mutation causing chronic progressive external ophthalmoplegia at low levels of heteroplasmy in muscle
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Alston, Charlotte L., Lowe, James, Turnbull, Douglass M., Maddison, Paul, and Taylor, Robert W.
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MITOCHONDRIA , *TRANSFER RNA , *GENE expression , *GENETIC mutation , *MITOCHONDRIAL DNA , *EYE paralysis , *PHENOTYPES , *MUSCLES - Abstract
Abstract: Mitochondrial respiratory chain defects are associated with diverse clinical phenotypes in both adults and children, and may be caused by mutations in either nuclear or mitochondrial DNA (mtDNA). We report the molecular genetic investigations of a patient with chronic progressive external ophthalmoplegia (CPEO) and myopathy where muscle biopsies taken 11years apart revealed a progressive increase in the proportion of cytochrome c oxidase (COX)-deficient fibres. Mitochondrial genetic analysis of the early biopsy had seemingly excluded both mtDNA rearrangements and mtDNA point mutations. Sequencing mtDNA from individual COX-deficient muscle fibres in the second biopsy, however, identified an unreported m.14723T>C substitution within the mitochondrial tRNAGlu (MTTE) gene, which fulfilled all canonical criteria for pathogenicity. The m.14723T>C mutation was absent from several tissues, including muscle, from maternal relatives suggesting a de novo event, whilst quantitative analysis of the first muscle biopsy confirmed a very low level of the mutation (7% mutated mtDNA), highlighting a potential problem whereby pathogenic mtDNA mutations may remain undetected using established screening methodologies. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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23. A neurological perspective on mitochondrial disease
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McFarland, Robert, Taylor, Robert W, and Turnbull, Douglass M
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MITOCHONDRIAL pathology , *MITOCHONDRIAL DNA abnormalities , *NEUROLOGY , *GENETIC mutation , *NEUROLOGICAL disorders , *DISEASE management - Abstract
Summary: Disruption of the most fundamental cellular energy process, the mitochondrial respiratory chain, results in a diverse and variable group of multisystem disorders known collectively as mitochondrial disease. The frequent involvement of the brain, nerves, and muscles, often in the same patient, places neurologists at the forefront of the interesting and challenging process of diagnosing and caring for these patients. Mitochondrial diseases are among the most frequently inherited neurological disorders, and can be caused by mutations in mitochondrial or nuclear DNA. Substantial progress has been made over the past decade in understanding the genetic basis of these disorders, with important implications for the general neurologist in terms of the diagnosis, investigation, and multidisciplinary management of these patients. [Copyright &y& Elsevier]
- Published
- 2010
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24. Mitochondrial DNA mutations and human disease
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Tuppen, Helen A.L., Blakely, Emma L., Turnbull, Douglass M., and Taylor, Robert W.
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MITOCHONDRIAL DNA , *GENETIC mutation , *MITOCHONDRIAL pathology , *PHENOTYPES , *TWO-dimensional electrophoresis , *MITOCHONDRIAL membranes , *PARKINSON'S disease , *PHOSPHORYLATION - Abstract
Abstract: Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of mitochondrial genetics, an inability to manipulate the mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of mitochondrial genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
25. Do organellar genomes function as long-term redox damage sensors?
- Author
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Wright, Alan F., Murphy, Michael P., and Turnbull, Douglass M.
- Subjects
- *
GENOMES , *OXIDATION-reduction reaction , *GENETIC mutation , *BIOENERGETICS , *BIOSENSORS , *CELLULAR signal transduction - Abstract
A small group of proteins that form core components of electron transfer complexes are consistently encoded by organellar genomes in multicellular organisms, suggesting functional constraint. These genomes are costly to maintain and vulnerable to mutation. We propose that they provide cell lineages with sensors of long-term redox damage, and of bioenergetic and genomic competence. This proposed adaptive function sets tonic retrograde signalling to the nucleus and anterograde responses influencing protective and cell death pathways. The nature of the proposed gain-of-function signalling mechanisms is unclear but could involve defective complex assembly. Organellar proteomes therefore provide cumulative feedback on bioenergetic and genomic status within cell lineages, selection of the energetically ‘fittest’ cells and a means of removing cells that compromise survival of the organism. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
26. Distal weakness with respiratory insufficiency caused by the m.8344A>G “MERRF” mutation.
- Author
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Blakely, Emma L., Alston, Charlotte L., Lecky, Bryan, Chakrabarti, Biswajit, Falkous, Gavin, Turnbull, Douglass M., Taylor, Robert W., and Gorman, Grainne S.
- Subjects
- *
ASTHENIA , *RESPIRATORY insufficiency , *MERRF syndrome , *GENETIC mutation , *TRANSFER RNA , *EPILEPSY , *ATAXIA , *MYOCLONUS , *PHENOTYPES - Abstract
Abstract: The m.8344A>G mutation in the mt-tRNALys gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A>G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A>G ‘MERRF’ mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non-invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A>G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A>G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb-girdle muscular dystrophy in which screening of the common genes prove negative. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
27. Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load
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Hollingsworth, Kieren G., Gorman, Grainne S., Trenell, Michael I., McFarland, Robert, Taylor, Robert W., Turnbull, Douglass M., MacGowan, Guy A., Blamire, Andrew M., and Chinnery, Patrick F.
- Subjects
- *
CARDIOMYOPATHIES , *MITOCHONDRIAL DNA , *GENETIC mutation , *NEUROMUSCULAR diseases , *HEART failure patients , *CARDIAC magnetic resonance imaging - Abstract
Abstract: Although neuromuscular clinical features often dominate the clinical presentation of mitochondrial disease due to the m.3243A>G mitochondrial DNA (mtDNA) mutation, many patients develop cardiac failure, which is often overlooked until it reaches an advanced stage. We set out to determine whether cardiac complications are sufficiently common to warrant prospective screening in all mutation carriers. Routine clinical echocardiography and 3 Tesla cardiac MRI were performed on ten m.3243A>G mutation carriers and compared to age and gender matched controls, with contemporaneous quadriceps muscle biopsies to measure respiratory chain activity and mtDNA mutation levels. Despite normal echocardiography, all ten m.3243A>G mutation carriers had evidence of abnormal cardiac function on MRI. The degree of cardiac dysfunction correlated with the percentage level of mutant mtDNA in skeletal muscle. Sub-clinical cardiac dysfunction was a universal finding in this study, adding weight to the importance of screening for cardiac complications in patients with m.3243A>G. The early detection of cardiac dysfunction with MRI opens up opportunities to prevent heart failure in these patients through early intervention. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
28. A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits
- Author
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Craig, Kate, Young, Matthew J., Blakely, Emma L., Longley, Matthew J., Turnbull, Douglass M., Copeland, William C., and Taylor, Robert W.
- Subjects
- *
GENETIC mutation , *MITOCHONDRIAL DNA , *DELETION mutation , *DNA polymerases , *DNA replication , *GENETIC code , *ENZYME inhibitors - Abstract
Abstract: Human mitochondrial DNA (mtDNA) polymerase γ (pol γ) is the sole enzyme required to replicate and maintain the integrity of the mitochondrial genome. It comprises two subunits, a catalytic p140 subunit and a smaller p55 accessory subunit encoded by the POLG2 gene. We describe the molecular characterization of a potential dominant POLG2 mutation (p.R369G) in a patient with adPEO and multiple mtDNA deletions. Biochemical studies of the recombinant mutant p55 protein showed a reduced affinity to the pol γ p140 subunit, leading to impaired processivity of the holoenzyme complex but did not show sensitivity to N-ethylmalaimide (NEM) inhibition, inferring a novel disease mechanism. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
29. Long-term survival of neonatal mitochondrial complex III deficiency associated with a novel BCS1L gene mutation
- Author
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Tuppen, Helen A.L., Fehmi, Janev, Czermin, Birgit, Goffrini, Paola, Meloni, Francesca, Ferrero, Iliana, He, Langping, Blakely, Emma L., McFarland, Robert, Horvath, Rita, Turnbull, Douglass M., and Taylor, Robert W.
- Subjects
- *
MITOCHONDRIAL pathology , *GENETIC mutation , *DIAGNOSIS of diseases in women , *YEAST , *COMPLEMENTATION (Genetics) , *BIOPSY - Abstract
Abstract: Mutations of the BCS1L gene are a recognised cause of isolated respiratory chain complex III deficiency and underlie several fatal, neonatal mitochondrial diseases. Here we describe a 20-year-old Kenyan woman who initially presented as a floppy infant but whose condition progressed during childhood and adolescence with increasing muscle weakness, focal motor seizures and optic atrophy. Muscle biopsy demonstrated complex III deficiency and the pathogenicity of a novel, homozygous BCS1L mutation was confirmed by yeast complementation studies. Our data indicate that BCS1L mutations can cause a variable, neurological course which is not always fatal in childhood. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
30. The investigation and diagnosis of pathogenic mitochondrial DNA mutations in human urothelial cells
- Author
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Blackwood, John K., Whittaker, Roger G., Blakely, Emma L., Alston, Charlotte L., Turnbull, Douglass M., and Taylor, Robert W.
- Subjects
- *
GENETIC mutation , *MITOCHONDRIAL DNA abnormalities , *URINARY organ diseases , *EPITHELIUM , *PHENOTYPES , *TRANSFER RNA , *PHYSIOLOGY - Abstract
Abstract: Patients with mitochondrial DNA disease are amongst the most challenging to diagnose and manage given the striking phenotypic and genetic heterogeneity, which characterise these conditions. Recently, we and others have demonstrated the m.3243A>G mutation, one of the most common mitochondrial DNA pathogenic mutations, is present at clinically relevant levels in urinary epithelium, thus providing a practical, non-invasive test for diagnosis and mutation screening. In this study we further evaluate the use of these cells in detecting the m.3243A>G mutation, other mtDNA tRNA gene point mutations including the m.8344A>G mutation and single large-scale mtDNA deletions. We observe a robust relationship between m.3243A>G levels in urothelial cells and clinically affected tissues that does not change with time. Conversely, single large-scale mtDNA deletions can be detected in urothelial cells, with higher levels present in younger patients with more severe disease, but generally mtDNA deletion levels are not representative of those seen in a clinically affected tissue. Our results have implications for the diagnosis, management and counselling of families with mtDNA disease. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
31. Neuromuscular disease presentation with three genetic defects involving two genomes
- Author
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Al-Dosary, Mazhor, Whittaker, Roger G., Haughton, Joanna, McFarland, Robert, Goodship, Judith, Turnbull, Douglass M., and Taylor, Robert W.
- Subjects
- *
NEUROMUSCULAR diseases , *GENOMES , *MITOCHONDRIAL DNA , *TRANSFER RNA , *GENETIC mutation , *NEUROPATHY , *ACUTE kidney failure , *GENETICS - Abstract
Abstract: An extensive range of molecular defects have been identified in the human mitochondrial genome (mtDNA), many associated with well-characterised, progressive neurological syndromes. We describe a patient who presented to a mitochondrial clinic with progressive bilateral ptosis, external opthalmoplegia and increasing difficulty with walking. He had previously been diagnosed with a dominant, demyelinating polyneuropathy due to PMP22 gene duplication and had also developed gout, presenting in acute renal failure, due to an X-linked recessive HPRT gene mutation. Muscle biopsy revealed many COX-deficient fibres which we show contain high levels of a third genetic defect – a novel, mitochondrial tRNALeu(CUN) (MTTL2) gene mutation. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
32. Novel mutations in the TK2 gene associated with fatal mitochondrial DNA depletion myopathy
- Author
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Blakely, Emma, He, Langping, Gardner, Julie L., Hudson, Gavin, Walter, John, Hughes, Imelda, Turnbull, Douglass M., and Taylor, Robert W.
- Subjects
- *
MITOCHONDRIAL DNA , *ENZYMES , *GENES , *MUSCLE diseases , *GENETIC mutation , *NEUROLOGICAL disorders , *JUVENILE diseases , *RESPIRATORY insufficiency - Abstract
Abstract: Mitochondrial DNA depletion syndromes are a heterogeneous group of childhood neurological disorders characterised by a quantitative abnormality of mitochondrial DNA. We describe two siblings who presented at 8 months and 14 months with myopathy, which rapidly progressed and resulted in death by respiratory failure at age 14 and 18 months, respectively. Muscle biopsy revealed marked respiratory chain defects, with real-time PCR confirming a dramatic depletion of mitochondrial DNA. Sequencing of the thymidine kinase 2 (TK2) gene revealed two, novel heterozygous mutations (p.Q87X and p.N100S) with parental DNA analysis confirming the transmission of mutated alleles. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
33. mtDNA mutations and common neurodegenerative disorders
- Author
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Howell, Neil, Elson, Joanna L., Chinnery, Patrick F., and Turnbull, Douglass M.
- Subjects
- *
GENETIC mutation , *DNA , *PARKINSON'S disease , *ALZHEIMER'S disease , *NEURODEGENERATION - Abstract
The incidence and prevalence of Alzheimer''s disease (AD) and Parkinson''s disease (PD) are increasing as the population ages. Both disorders have been associated with oxidative stress and mitochondrial dysfunction, and it has been proposed that mutations in the mitochondrial genome have a key role in neurodegeneration in AD and PD patients. Two recent publications propose that heteroplasmic mtDNA mutations are involved in AD and PD. However, when these new studies are considered in relation to the sum of previous evidence, the role of mtDNA mutations in the development of either AD or PD still remains to be established. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
34. Assigning pathogenicity to mitochondrial tRNA mutations: when ‘definitely maybe’ is not good enough
- Author
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McFarland, Robert, Elson, Joanna L., Taylor, Robert W., Howell, Neil, and Turnbull, Douglass M.
- Subjects
- *
MITOCHONDRIA , *TRANSFER RNA , *GENETIC mutation , *MOLECULES - Abstract
Some mutations in mitochondrial tRNA (mt-tRNA) genes cause devastating disease, whereas others have no clinical consequences. We understand little of the factors determining the pathogenicity of specific mt-tRNA mutations, making prediction of clinical outcome extremely difficult. Using extensive sequence databases, we compared the characteristics of neutral variations with those of pathogenic mutations. We recommend that the location of the proposed mutation within the secondary structure of the mt-tRNA molecule and the disruption it causes to Watson-Crick base pairing should be considered when assessing the pathological significance of a novel mt-tRNA mutation. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
35. Childhood neurological presentation of a novel mitochondrial tRNAVal gene mutation
- Author
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Blakely, Emma L., Poulton, Joanna, Pike, Michael, Wojnarowska, Fenella, Turnbull, Douglass M., McFarland, Robert, and Taylor, Robert W.
- Subjects
- *
GENETIC mutation , *MITOCHONDRIA , *TRANSFER RNA , *MOVEMENT disorders in children - Abstract
We describe a young girl with a novel 1659T>C mutation in the tRNAVal gene of mitochondrial DNA (mtDNA) who presented with learning difficulties, hemiplegia, and a movement disorder, together with a raised cerebrospinal fluid (CSF) lactate. The mutation, which was present at high levels of heteroplasmy in patient tissues, interrupts a conserved Watson–Crick basepair in the TΨC stem and has not previously been described in controls. This report further confirms the frequent association of mitochondrial tRNA mutation with neurological presentations, even in paediatric cases. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
36. Risk of developing a mitochondrial DNA deletion disorder.
- Author
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Chinnery, Patrick F., DiMauro, Salvatore, Shanske, Sara, Schon, Eric A., Zeviani, Massimo, Mariotti, Caterina, Carrara, Fanco, Lombes, Anne, Laforet, Pascal, Ogier, Helène, Jaksch, Michaela, Lochmüller, Hanns, Horvath, Rita, Deschauer, Marcus, Thorburn, David R., Bindoff, Laurence A., Poulton, Joanna, Taylor, Robert W., Matthews, John N. S., and Turnbull, Douglass M.
- Subjects
- *
MITOCHONDRIAL DNA , *EYE paralysis , *MATERNAL-fetal exchange , *GENETIC disorders , *FAMILIAL diseases , *GENETIC research , *GENETIC mutation , *DISEASE risk factors - Abstract
Background Pathogenic mitochondrial DNA (mtDNA) mutations are found in at least one in 8000 individuals. No effective treatment for mtDNA disorders is available, making disease prevention important. Many patients with mtDNA disease harbour a single pathogenic mtDNA deletion, but the risk factors for new cases and disease recurrence are not known. Methods We did a multicentre study of 226 families in which a single mtDNA deletion had been identified in the proband, including patients with chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, or Pearson's syndrome. We studied the relation between maternal age and the risk of unaffected mothers having an affected child, and determined the recurrence risks among the siblings and offspring of affected individuals. Findings We noted no relation between maternal age and the risk of unaffected mothers having children with an mtDNA deletion disorder. None of the 251 siblings of the index cases developed clinical features of mtDNA disease. Risk of recurrence among the offspring of affected women was 4.11% (95% CI 0.86-11.54, or one in 117 to one in nine births). Only one of the mothers who had an affected child had a duplication of mtDNA in skeletal muscle. Interpretation Unlike nuclear chromosomal rearrangements, incidence of mtDNA deletion disorders does not increase with maternal age, and unaffected mothers are unlikely to have more than one affected child. Affected women were previously thought to have a negligible chance of having clinically affected offspring, but the actual risk is, on average, about one in 24 births. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
37. Mitochondrial DNA mutations in human colonic crypt stem cells.
- Author
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Taylor, Robert W., Barron, Martin J., Borthwick, Gillian M., Gospel, Amy, Chinnery, Patrick F., Samuels, David C., Taylor, Geoffrey A., Plusa, Stelan M., Needham, Stephanie J., Greaves, Laura C., Kirkwood, Thomas B. L., Turnbull, Douglass M., and Plusa, Stefan M
- Subjects
- *
STEM cells , *GENOMES , *MITOCHONDRIA , *DNA , *GENETIC polymorphisms , *GENE therapy , *BIOLOGICAL models , *COLON (Anatomy) , *COMPARATIVE studies , *ELECTRON transport , *MATHEMATICS , *RESEARCH methodology , *MEDICAL cooperation , *GENETIC mutation , *RESEARCH , *EVALUATION research - Abstract
The mitochondrial genome encodes 13 essential subunits of the respiratory chain and has remarkable genetics based on uniparental inheritance. Within human populations, the mitochondrial genome has a high rate of sequence divergence with multiple polymorphic variants and thus has played a major role in examining the evolutionary history of our species. In recent years it has also become apparent that parhogenic mitochondrial DNA (mtDNA) mutations play an important role in neurological and other diseases. Patients harbor many different mtDNA mutations, some of which are mtDNA mutations, some of which are inherited, but others that seem to be sporadic. It has also been suggested that mtDNA mutations play a role in aging and cancer, but the evidence for a causative role in these conditions is less clear. The accumulated data would suggest, however, that mtDNA mutations occur on a frequent basis. In this article we describe a new phenomenon: the accumulation of mtDNA mutations in human colonic crypt stem cells that result in a significant biochemical defect in their progeny. These studies have important consequences not only for understanding of the finding of mtDNA mutations in aging tissues and tumors, but also for determining the frequency of mtDNA mutations within a cell. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
38. Bridging PNAs can bind preferentially to a deleted mitochondrial DNA template but replication by mitochondrial DNA polymerase γ in vitro is not impaired
- Author
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McGregor, Alistair, Smith, Paul M., Ross, Günther F., Taylor, Robert W., Turnbull, Douglass M., and Lightowlers, Robert N.
- Subjects
- *
MITOCHONDRIAL DNA , *GENETIC mutation , *PATHOLOGY , *PEPTIDES - Abstract
Mutations in mitochondrial DNA (mtDNA) are an important cause of neurological and other human pathologies. In the vast majority of cases, supportive care only is available. Mutated and wild-type mtDNAs often coexist in the same cell. A strategy for treatment has been proposed whereby replication of mutated mtDNA is inhibited by selective hybridisation of a nucleic acid derivative, allowing propagation of the wild-type genome and correction of the associated respiratory chain defect. Peptide nucleic acid molecules (PNAs) can be designed to selectively target pathogenic mtDNA with single point mutations. Molecules harbouring deletions present a complex problem. Deletions often occur between two short repeat sequences (4–13 residues), one of which is retained in the deleted molecule. With the more common large repeats, it is therefore difficult to design an antigenomic molecule that will bind selectively under physiological conditions. Following limited success with antigenomic oligodeoxynucleotides (ODNs), we have repeated these studies with a series of bridging PNAs. Molecules complementary to the sequence flanking either side of the 13 bp ‘common deletion’ were synthesised. The PNAs demonstrated markedly greater affinity for the delete than to the wild-type template. In runoff assays using Klenow fragment, these PNAs selectively inhibited replication of the delete template. However, no selective inhibition was observed when a polymerase γ-containing mitochondrial fraction was used. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
39. A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia
- Author
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Deschauer, Marcus, Kiefer, Reinhard, Blakely, Emma L., He, Langping, Zierz, Stephan, Turnbull, Douglass M., and Taylor, Robert W.
- Subjects
- *
CONJUNCTIVA diseases , *GENETIC mutation , *MITOCHONDRIAL DNA - Abstract
Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
40. A splice junction mutation in muscle carnitine palmitoyltransferase II deficiency
- Author
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Deschauer, Marcus, Chrzanowska-Lightowlers, Zofia M.A., Biekmann, Eckhard, Pourfarzam, Morteza, Taylor, Robert W., Turnbull, Douglass M., and Zierz, Stephan
- Subjects
- *
GENETIC mutation , *MYALGIA - Abstract
We report the first splice junction mutation to be described in the carnitine palmitoyltransferase (CPT) 2 gene in a patient with the muscle form of CPT II deficiency. The patient, a 25-year-old man, suffered from attacks of myalgia and muscle weakness in early adult life. There was biochemical evidence of CPT II deficiency. Molecular genetic analysis revealed the common S113L mutation on one allele whilst a novel mutation at the splice donor junction in intron 3 was identified on the other allele. Sequencing of reverse transcription polymerase chain reaction (RT-PCR) products clearly demonstrated that this mutation causes the skipping of exon 3, thus establishing its pathogenic role. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
41. The prevalence of mitochondrial disease in the adult population.
- Author
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Yu-Wai-Man, Patrick, Gorman, Grainne S., Schaefer, Andrew M., Grady, John P., Ng, Yi, Chinnery, Patrick F., Taylor, Robert W., McFarland, Robert, and Turnbull, Douglass M.
- Subjects
- *
MITOCHONDRIAL pathology , *MITOCHONDRIAL DNA , *FERTILIZATION in vitro , *DISEASE prevalence , *GENETIC mutation , *GENETICS ,DISEASES in adults - Published
- 2015
- Full Text
- View/download PDF
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