16 results on '"Turnbull, D."'
Search Results
2. Analysis of European mtDNAs for Recombination.
- Author
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Elson, J. L., Turnbull, D. M., Andrews, R. M., Chinnery, P. F., Lightowlers, R. N., and Howell, Neil
- Subjects
- *
GENETIC recombination , *GENETIC polymorphisms , *DNA , *HOMOPLASY , *STRUCTURE-activity relationships - Abstract
Focuses on a study which determined whether recombination has contributed to the distribution of human mitochondrial genome (mtDNA) polymorphisms in humans. Nucleotide sequences of mtDNA in the European population; Analysis of mtDNA linkage disequilibrium as a function of distance; Excess homoplasy test for recombination.
- Published
- 2001
- Full Text
- View/download PDF
3. Random Intracellular Drift Explains the Clonal Expansion of Mitochondrial DNA Mutations with Age.
- Author
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Elson, J. L., Samuels, D. C., Turnbull, D. M., and Chinnery, P. F.
- Subjects
- *
MITOCHONDRIAL DNA , *GENETIC mutation - Abstract
Presents information on a study which explained the clonal expansion of somatic mitochondrial DNA mutations with age. Role of random intracellular drift; Methodology; Results and discussion.
- Published
- 2001
- Full Text
- View/download PDF
4. Point Mutations of the mtDNA Control Region in Normal and Neurodegenerative Human Brains.
- Author
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Chinnery, P. F., Brown, D. T., Taylor, G. A., Howell, N., Parsons, T. J., and Turnbull, D. M.
- Subjects
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NEURODEGENERATION , *MITOCHONDRIAL DNA , *GENETICS of aging , *GENETIC mutation - Abstract
Studies the mitochondrial DNA control region in human brain tissues of normal elderly individuals and individuals with neurodegenerative disease to investigate the role of mitochondrial DNA mutations in aging. Position of the sequence changes seen in brain tissues of the individuals; Technique for the detection of low levels of mitochondrial DNA heteroplasmy; Possibilities for not detecting some of the mitochondrial DNA mutations.
- Published
- 2001
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5. S-acylation stabilizes ligand-induced receptor kinase complex formation during plant pattern-triggered immune signaling.
- Author
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Hurst CH, Turnbull D, Xhelilaj K, Myles S, Pflughaupt RL, Kopischke M, Davies P, Jones S, Robatzek S, Zipfel C, Gronnier J, and Hemsley PA
- Subjects
- Protein Kinases genetics, Protein Kinases metabolism, Ligands, Cysteine metabolism, Plants metabolism, Cell Membrane metabolism, Acylation, Plant Immunity, Arabidopsis metabolism, Arabidopsis Proteins metabolism
- Abstract
Plant receptor kinases are key transducers of extracellular stimuli, such as the presence of beneficial or pathogenic microbes or secreted signaling molecules. Receptor kinases are regulated by numerous post-translational modifications.
1 , 2 , 3 Here, using the immune receptor kinases FLS24 and EFR,5 we show that S-acylation at a cysteine conserved in all plant receptor kinases is crucial for function. S-acylation involves the addition of long-chain fatty acids to cysteine residues within proteins, altering their biochemical properties and behavior within the membrane environment.6 We observe S-acylation of FLS2 at C-terminal kinase domain cysteine residues within minutes following the perception of its ligand, flg22, in a BAK1 co-receptor and PUB12/13 ubiquitin ligase-dependent manner. We demonstrate that S-acylation is essential for FLS2-mediated immune signaling and resistance to bacterial infection. Similarly, mutating the corresponding conserved cysteine residue in EFR suppressed elf18-triggered signaling. Analysis of unstimulated and activated FLS2-containing complexes using microscopy, detergents, and native membrane DIBMA nanodiscs indicates that S-acylation stabilizes, and promotes retention of, activated receptor kinase complexes at the plasma membrane to increase signaling efficiency., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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6. Mutation-Independent Allele-Specific Editing by CRISPR-Cas9, a Novel Approach to Treat Autosomal Dominant Disease.
- Author
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Christie KA, Robertson LJ, Conway C, Blighe K, DeDionisio LA, Chao-Shern C, Kowalczyk AM, Marshall J, Turnbull D, Nesbit MA, and Moore CBT
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- Amino Acid Sequence, Amino Acid Substitution, Cell Line, Genomics methods, Haplotypes, Humans, Polymorphism, Single Nucleotide, Precision Medicine, RNA, Guide, CRISPR-Cas Systems, Transforming Growth Factor beta1 genetics, Alleles, CRISPR-Cas Systems, Gene Editing, Genes, Dominant, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn therapy, Genetic Therapy, Mutation
- Abstract
CRISPR-Cas9 provides a tool to treat autosomal dominant disease by non-homologous end joining (NHEJ) gene disruption of the mutant allele. In order to discriminate between wild-type and mutant alleles, Streptococcus pyogenes Cas9 (SpCas9) must be able to detect a single nucleotide change. Allele-specific editing can be achieved by using either a guide-specific approach, in which the missense mutation is found within the guide sequence, or a protospacer-adjacent motif (PAM)-specific approach, in which the missense mutation generates a novel PAM. While both approaches have been shown to offer allele specificity in certain contexts, in cases where numerous missense mutations are associated with a particular disease, such as TGFBI (transforming growth factor β-induced) corneal dystrophies, it is neither possible nor realistic to target each mutation individually. In this study, we demonstrate allele-specific CRISPR gene editing independent of the disease-causing mutation that is capable of achieving complete allele discrimination, and we propose it as a targeting approach for autosomal dominant disease. Our approach utilizes natural variants in the target region that contain a PAM on one allele that lies in cis with the causative mutation, removing the constraints of a mutation-dependent approach. Our innovative patient-specific guide design approach takes into account the patient's individual genetic make-up, allowing on- and off-target activity to be assessed in a personalized manner., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2020
- Full Text
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7. The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England.
- Author
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Yu-Wai-Man P, Griffiths PG, Howell N, Turnbull DM, and Chinnery PF
- Published
- 2016
- Full Text
- View/download PDF
8. Oomycetes Seek Help from the Plant: Phytophthora infestans Effectors Target Host Susceptibility Factors.
- Author
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Boevink PC, McLellan H, Gilroy EM, Naqvi S, He Q, Yang L, Wang X, Turnbull D, Armstrong MR, Tian Z, and Birch PRJ
- Subjects
- Disease Susceptibility, Oomycetes metabolism, Oomycetes pathogenicity, Phytophthora infestans metabolism, Phytophthora infestans pathogenicity, Plant Diseases microbiology, Plants metabolism, Plants microbiology
- Published
- 2016
- Full Text
- View/download PDF
9. Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection.
- Author
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Elson JL, Turnbull DM, and Howell N
- Subjects
- Humans, DNA, Mitochondrial genetics, Evolution, Molecular, Genomics, Selection, Genetic
- Abstract
This article provides evidence that selection has been a significant force during the evolution of the human mitochondrial genome. Both gene-by-gene and whole-genome approaches were used here to assess selection in the 560 mitochondrial DNA (mtDNA) coding-region sequences that were used previously for reduced-median-network analysis. The results of the present analyses were complex, in that the action of selection was not indicated by all tests, but this is not surprising, in view of the characteristics and limitations of the different analytical methods. Despite these limitations, there is evidence for both gene-specific and lineage-specific variation in selection. Whole-genome sliding-window approaches indicated a lack of selection in large-scale segments of the coding region. In other tests, we analyzed the ratio of nonsynonymous-to-synonymous substitutions in the 13 protein-encoding mtDNA genes. The most straightforward interpretation of those results is that negative selection has acted on the mtDNA during evolution. Single-gene analyses indicated significant departures from neutrality in the CO1, ND4, and ND6 genes, although the data also suggested the possible operation of positive selection on the AT6 gene. Finally, our results and those of other investigators do not support a simple model in which climatic adaptation has been a major force during human mtDNA evolution.
- Published
- 2004
- Full Text
- View/download PDF
10. The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates.
- Author
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Howell N, Smejkal CB, Mackey DA, Chinnery PF, Turnbull DM, and Herrnstadt C
- Subjects
- Base Sequence, DNA, Mitochondrial chemistry, Female, Germ-Line Mutation, Humans, Locus Control Region genetics, Male, Models, Genetic, DNA, Mitochondrial genetics, Genetic Variation, Mutation, Optic Atrophy, Hereditary, Leber genetics, Pedigree, Phylogeny
- Abstract
We have extended our previous analysis of the pedigree rate of control-region divergence in the human mitochondrial genome. One new germline mutation in the mitochondrial DNA (mtDNA) control region was detected among 185 transmission events (generations) from five Leber hereditary optic neuropathy (LHON) pedigrees. Pooling the LHON pedigree analyses yields a control-region divergence rate of 1.0 mutation/bp/10(6) years (Myr). When the results from eight published studies that used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission events, a pedigree divergence rate of 0.95 mutations/bp/Myr for the control region was obtained with a 99.5% confidence interval of 0.53-1.57. Taken together, the cumulative results support the original conclusion that the pedigree divergence rate for the control region is approximately 10-fold higher than that obtained with phylogenetic analyses. There is no evidence that any one factor explains this discrepancy, and the possible roles of mutational hotspots (rate heterogeneity), selection, and random genetic drift and the limitations of phylogenetic approaches to deal with high levels of homoplasy are discussed. In addition, we have extended our pedigree analysis of divergence in the mtDNA coding region. Finally, divergence of complete mtDNA sequences was analyzed in two tissues, white blood cells and skeletal muscle, from each of 17 individuals. In three of these individuals, there were four instances in which an mtDNA mutation was found in one tissue but not in the other. These results are discussed in terms of the occurrence of somatic mtDNA mutations.
- Published
- 2003
- Full Text
- View/download PDF
11. The epidemiology of Leber hereditary optic neuropathy in the North East of England.
- Author
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Yu-Wai-Man P, Griffiths PG, Brown DT, Howell N, Turnbull DM, and Chinnery PF
- Subjects
- Adult, Age of Onset, DNA, Mitochondrial blood, DNA, Mitochondrial genetics, England epidemiology, Female, Founder Effect, Genetic Linkage, Humans, Male, Middle Aged, Mutation, Optic Atrophy, Hereditary, Leber diagnosis, Optic Atrophy, Hereditary, Leber etiology, Optic Atrophy, Hereditary, Leber physiopathology, Pedigree, Penetrance, Prevalence, Prospective Studies, Sex Factors, Optic Atrophy, Hereditary, Leber epidemiology
- Abstract
We performed the first population-based clinical and molecular genetic study of Leber hereditary optic neuropathy (LHON) in a population of 2,173,800 individuals in the North East of England. We identified 16 genealogically unrelated families who harbor one of the three primary mitochondrial DNA (mtDNA) mutations that cause LHON. Two of these families were found to be linked genetically to a common maternal founder. A de novo mtDNA mutation (G3460A) was identified in one family. The minimum point prevalence of visual failure due to LHON within this population was 3.22 per 100,000 (95% CI 2.47-3.97 per 100,000), and the minimum point prevalence for mtDNA LHON mutations was 11.82 per 100,000 (95% CI 10.38-13.27 per 100,000). These results indicate that LHON is not rare but has a population prevalence similar to autosomally inherited neurological disorders. The majority of individuals harbored only mutant mtDNA (homoplasmy), but heteroplasmy was detected in approximately 12% of individuals. Overall, however, approximately 33% of families with LHON had at least one heteroplasmic individual. The high incidence of heteroplasmy in pedigrees with LHON raises the possibility that a closely related maternal relative of an index case may not harbor the mtDNA mutation, highlighting the importance of molecular genetic testing for each maternal family member seeking advice about their risks of visual failure.
- Published
- 2003
- Full Text
- View/download PDF
12. An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy.
- Author
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Clark KM, Taylor RW, Johnson MA, Chinnery PF, Chrzanowska-Lightowlers ZM, Andrews RM, Nelson IP, Wood NW, Lamont PJ, Hanna MG, Lightowlers RN, and Turnbull DM
- Subjects
- Adult, Electron Transport Complex IV metabolism, Female, Humans, Male, Middle Aged, Mitochondrial Encephalomyopathies enzymology, Protein Biosynthesis, RNA, Messenger analysis, RNA, Transfer, Asp genetics, RNA, Transfer, Ser genetics, Codon, Initiator genetics, DNA, Mitochondrial genetics, Electron Transport Complex IV genetics, Mitochondrial Encephalomyopathies genetics, Point Mutation genetics
- Abstract
A novel heteroplasmic 7587T-->C mutation in the mitochondrial genome which changes the initiation codon of the gene encoding cytochrome c oxidase subunit II (COX II), was found in a family with mitochondrial disease. This T-->C transition is predicted to change the initiating methionine to threonine. The mutation load was present at 67% in muscle from the index case and at 91% in muscle from the patient's clinically affected son. Muscle biopsy samples revealed isolated COX deficiency and mitochondrial proliferation. Single-muscle-fiber analysis revealed that the 7587C copy was at much higher load in COX-negative fibers than in COX-positive fibers. After microphotometric enzyme analysis, the mutation was shown to cause a decrease in COX activity when the mutant load was >55%-65%. In fibroblasts from one family member, which contained >95% mutated mtDNA, there was no detectable synthesis or any steady-state level of COX II. This new mutation constitutes a new mechanism by which mtDNA mutations can cause disease-defective initiation of translation.
- Published
- 1999
- Full Text
- View/download PDF
13. Genetic counseling and prenatal diagnosis for mtDNA disease.
- Author
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Chinnery PF, Howell N, Lightowlers RN, and Turnbull DM
- Subjects
- DNA, Mitochondrial blood, Female, Humans, Pregnancy, DNA, Mitochondrial genetics, Genetic Counseling, Mutation, Prenatal Diagnosis
- Published
- 1998
- Full Text
- View/download PDF
14. Specification of mouse telencephalic and mid-hindbrain progenitors following heterotopic ultrasound-guided embryonic transplantation.
- Author
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Olsson M, Campbell K, and Turnbull DH
- Subjects
- Animals, Brain Tissue Transplantation methods, Cell Differentiation, Fetal Tissue Transplantation methods, Mice, Mice, Inbred Strains, Mice, Transgenic, Neurons cytology, Neurons physiology, Neurons transplantation, Prosencephalon diagnostic imaging, Rhombencephalon cytology, Rhombencephalon transplantation, Stem Cells cytology, Telencephalon cytology, Telencephalon transplantation, Transplantation, Heterotopic methods, Transplantation, Heterotopic physiology, Ultrasonography methods, beta-Galactosidase biosynthesis, Brain Tissue Transplantation physiology, Fetal Tissue Transplantation physiology, Prosencephalon physiology, Rhombencephalon physiology, Stem Cells physiology, Telencephalon physiology
- Abstract
We have demonstrated the utility of ultrasound backscatter microscopy for targeted intraparenchymal injections into embryonic day (E) 13.5 mouse embryos. This system has been used to test the degree of commitment present in neural progenitors from the embryonic ventral telencephalon and mid-hindbrain region. Many E13.5 ventral telencephalic progenitors were observed to integrate and adopt local phenotypes following heterotopic transplantation into telencephalic or mid-hindbrain targets, whereas mid-hindbrain cells of the same stage were unable to integrate and change fate in the telencephalon. In contrast, many mid-hindbrain cells from an earlier developmental stage (E10.5) were capable of integrating and adopting a forebrain phenotype after grafting into the telencephalon, suggesting that mouse mid-hindbrain progenitors become restricted in their developmental potential between E10.5 and E13.5.
- Published
- 1997
- Full Text
- View/download PDF
15. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.
- Author
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Weber K, Wilson JN, Taylor L, Brierley E, Johnson MA, Turnbull DM, and Bindoff LA
- Subjects
- Base Sequence, Cells, Cultured, Cytochromes metabolism, Electron Transport Complex IV metabolism, Female, Glutamic Acid metabolism, Humans, Middle Aged, Mitochondria, Muscle metabolism, Mitochondrial Myopathies metabolism, Molecular Sequence Data, Muscle Fibers, Skeletal metabolism, Nucleic Acid Conformation, RNA, Transfer, Amino Acyl chemistry, Succinates metabolism, Succinic Acid, DNA, Mitochondrial genetics, Mitochondrial Myopathies genetics, Muscle, Skeletal metabolism, Point Mutation, RNA, Transfer, Amino Acyl genetics
- Abstract
We have identified a new mutation in mtDNA, involving tRNALeu(CUN) in a patient manifesting an isolated skeletal myopathy. This heteroplasmic A-->G transition at position 12320 affects the T psi C loop at a conserved site and was not found in 120 controls. Analysis of cultured fibroblasts, white blood cells/platelets, and skeletal muscle showed that only skeletal muscle contained the mutation and that only this tissue demonstrated a biochemical defect of respiratory-chain activity. In a series of four muscle-biopsy specimens taken over a 12-year period, there was a gradual increase, from 70% to 90%, in the overall level of mutation, as well as a marked clinical deterioration. Single-fiber PCR confirmed that the proportion of mutant mtDNA was highest in cytochrome c oxidase-negative fibers. This study, which reports a mutation involving tRNALeu(CUN), demonstrates clearly that mtDNA point mutations can accumulate over time and may be restricted in their tissue distribution. Furthermore, clinical deterioration seemed to follow the increase in the level of mutation, although, interestingly, the appearance of fibers deficient in respiratory-chain activity showed a lag period.
- Published
- 1997
16. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
- Author
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Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, Taylor L, and Turnbull DM
- Subjects
- Amino Acid Sequence, Cloning, Molecular, Female, Humans, Male, Molecular Sequence Data, NADH, NADPH Oxidoreductases genetics, Pedigree, Mitochondria, Mutation, NAD(P)H Dehydrogenase (Quinone) genetics, Optic Atrophies, Hereditary genetics
- Abstract
Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to determine the mitochondrial genetic etiology of their disease. Biochemical assays of mitochondrial electron transport in organelles isolated from the platelet/white-blood-cell fraction have established that the members of this family have a substantial and specific lowering of flux through complex I (NADH-ubiquinone oxidoreductase). To determine the site of the primary mitochondrial gene mutation in this pedigree, all seven mitochondrial complex I genes were sequenced, in their entirety, from two family members. The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein. This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue. This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree. The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation. The ND1/A52T mutation at nucleotide 3460 was found in five of these 11 pedigrees. In contrast, this sequence change was not found in any of the 47 non-LHON controls. The possible role of secondary complex I mutations in the etiology of LHON is also addressed in these studies.
- Published
- 1991
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