A5053767923- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- RNA modifications and cancer
- Genomics and Rare Diseases
- Genetic Neurodegenerative Diseases
- RNA and protein synthesis mechanisms
- Metalloenzymes and iron-sulfur proteins
- Genetics and Neurodevelopmental Disorders
- Neurological diseases and metabolism
- Neurogenetic and Muscular Disorders Research
- Cardiomyopathy and Myosin Studies
- Diet and metabolism studies
- RNA regulation and disease
- Ubiquitin and proteasome pathways
- Trace Elements in Health
- Neurological and metabolic disorders
- Biochemical and Molecular Research
- Cerebral Palsy and Movement Disorders
- Infectious Encephalopathies and Encephalitis
- Genetic factors in colorectal cancer
- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- Genomic variations and chromosomal abnormalities
- Neonatal Respiratory Health Research
Wellcome Centre for Mitochondrial Research
2016-2025
Newcastle University
2016-2025
Newcastle upon Tyne Hospitals NHS Foundation Trust
2010-2025
University of Newcastle Australia
2006-2024
NIHR Newcastle Biomedical Research Centre
2013-2024
University of Washington
2024
Royal Victoria Infirmary
2008-2023
Great North Children's Hospital
2022-2023
National Health Service
2021-2022
University College London
2010-2022
The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result clinical and genetic heterogeneity. phenotypic spectrum expanded significantly since the original reports that associated classic syndromes with DNA (mtDNA) rearrangements point mutations. revolution in technologies allowed interrogation nuclear genome manner dramatically improved diagnosis disorders. We comprehensively assessed all forms adult include pathogenic mutations both mtDNA.Adults...
Abstract Objective Diverse and variable clinical features, a loose genotype–phenotype relationship, presentation to different medical specialties have all hindered attempts gauge the epidemiological impact of mitochondrial DNA (mtDNA) disease. Nevertheless, clear understanding its prevalence remains an important goal, particularly about planning appropriate services. Consequently, aim this study was accurately define mtDNA disease (primary mutation occurs in mtDNA) working‐age population...
Additional neurological features have recently been described in seven families transmitting pathogenic mutations OPA1, the most common cause of autosomal dominant optic atrophy. However, frequency these syndromal 'dominant atrophy plus' variants and extent involvement not established. In this large multi-centre study 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular complications are OPA1 disease, affect up to 20% all mutational carriers. Bilateral...
Mutations in nuclear genes involved mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation multiple mtDNA deletions affected tissues. The majority families autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations encoding one three well-characterized proteins—polγ, Twinkle or Ant 1. Here we show that heterozygous mis-sense mutation OPA1 leads to skeletal muscle and mosaic defect cytochrome c oxidase...
Mutations in the gene coding for catalytic subunit of mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype their families. POLG1 was sequenced from different European diagnostic research centres to define phenotypic spectrum advance understanding recurrence risks. were identified 38 cases, majority being sporadic compound heterozygotes. Eighty-nine sequence...
<h3>Importance</h3> Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because massive number nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked human disease. <h3>Objective</h3> To determine basis multiple deficiencies. <h3>Design, Setting, and Participants</h3> We studied...
Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine 235, skeletal muscle 77) represents mutation load mitochondrial DNA (mtDNA) copy number most strongly burden progression. levels are correlated in blood, (R2 0.61-0.73). Blood heteroplasmy declines by ~2.3%/year; have extended previously...
<h3>Background</h3> Population-based studies suggest the m.3243A>G mutation in <i>MTTL1</i> is most common disease-causing mtDNA mutation, with a carrier rate of 1 400 people. The associated several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness diabetes (MIDD) progressive external ophthalmoplegia (PEO). Many patients affected by this exhibit phenotype that does not fall within accepted criteria for...
Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range complex human diseases, yet congenital disorders are rare.
Distinguishing pathogenic from polymorphic changes poses significant problems for geneticists and despite 30 years of postgenomic experience this remains the case in mitochondrial genetics. Base substitutions tRNA (mt-tRNA) genes are particularly difficult, but important, because they common causes pathology associated with high rates transmission. Providing accurate genetic advice to patients their families is paramount importance disease prevention, brings into sharp focus factors used...
Despite being a canonical presenting feature of mitochondrial disease, the genetic basis progressive external ophthalmoplegia remains unknown in large proportion patients. Here we show that mutations SPG7 are novel cause associated with multiple DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients either or without deletions skeletal muscle. Nine...
Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, the molecular etiology remains undiagnosed in majority of cases. Through whole-exome sequencing, we identified recessive nonsense splicing mutations FBXL4 segregating three unrelated consanguineous kindreds which affected children present with a fatal encephalopathy, lactic acidosis, severe mtDNA muscle. We show that is an F-box protein colocalizes mitochondria loss-of-function...
Identifying the genetic basis for mitochondrial diseases is technically challenging given size of proteome and heterogeneity disease presentations. Using next-generation exome sequencing, we identified in a patient with severe combined respiratory chain defects corresponding perturbation protein synthesis, homozygous p.Arg323Gln mutation TRIT1. This gene encodes human tRNA isopentenyltransferase, which responsible i6A37 modification anticodon loops small subset cytosolic tRNAs. Deficiency...
Abstract Background SURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report first natural history study deficiency. Methods conducted multi-centre case notes review 44 SURF1-deficient patients from ten different UK centres and two Australian centres. Survival data for LRPPRC-deficient LS nuclear-encoded complex I-deficient were obtained previous publications. The survival was compared with these...