2023
Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease
Amarasekera S, Hock D, Lake N, Calvo S, Grønborg S, Krzesinski E, Amor D, Fahey M, Simons C, Wibrand F, Mootha V, Lek M, Lunke S, Stark Z, Østergaard E, Christodoulou J, Thorburn D, Stroud D, Compton A. Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. Human Molecular Genetics 2023, 32: 2441-2454. PMID: 37133451, PMCID: PMC10360397, DOI: 10.1093/hmg/ddad069.Peer-Reviewed Original ResearchConceptsQuantitative proteomicsMitochondrial oxidative phosphorylation systemProtein complex assemblySmall mitoribosomal subunitExome sequencingOxidative phosphorylation systemMitochondrial deoxyribonucleic acidMitochondrial ribosomesMitoribosomal subunitDeoxyribonucleic acidGene-disease associationsLarge subunitOXPHOS disordersSmall subunitComplex assemblyPhosphorylation systemProteomic dataComplex abundanceFunctional validationDisease genesGenome sequencingMitochondrial diseaseCryptic exonGene matchingProtein signatures
2020
Fatal Perinatal Mitochondrial Cardiac Failure Caused by Recurrent De Novo Duplications in the ATAD3 Locus
Frazier A, Compton A, Kishita Y, Hock D, Welch A, Amarasekera S, Rius R, Formosa L, Imai-Okazaki A, Francis D, Wang M, Lake N, Tregoning S, Jabbari J, Lucattini A, Nitta K, Ohtake A, Murayama K, Amor D, McGillivray G, Wong F, van der Knaap M, Vermeulen R, Wiltshire E, Fletcher J, Lewis B, Baynam G, Ellaway C, Balasubramaniam S, Bhattacharya K, Freckmann M, Arbuckle S, Rodriguez M, Taft R, Sadedin S, Cowley M, Minoche A, Calvo S, Mootha V, Ryan M, Okazaki Y, Stroud D, Simons C, Christodoulou J, Thorburn D. Fatal Perinatal Mitochondrial Cardiac Failure Caused by Recurrent De Novo Duplications in the ATAD3 Locus. Med 2020, 2: 49-73.e10. PMID: 33575671, PMCID: PMC7875323, DOI: 10.1016/j.medj.2020.06.004.Peer-Reviewed Original ResearchConceptsMitochondrial diseasePediatric mitochondrial diseaseMitochondrial oxidative phosphorylation complexes IOxidative phosphorylation complexes IDominant-negative mannerStudy of RNADNA sequencing techniquesSegmental duplicationsGenomic strategiesQuantitative proteomicsWhole genomeGenomic investigationsGene locusRepetitive regionsSequencing techniquesGenomeComplex IRecessive deletionsLociWhole exomeDuplicationMonogenic diseasesDe novo duplicationExome sequencingPontocerebellar hypoplasia
2019
A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant
Lake N, Formosa L, Stroud D, Ryan M, Calvo S, Mootha V, Morar B, Procopis P, Christodoulou J, Compton A, Thorburn D. A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant. Human Mutation 2019, 40: 893-898. PMID: 30981218, PMCID: PMC6661004, DOI: 10.1002/humu.23753.Peer-Reviewed Original ResearchConceptsProtein-truncating variantsCI assemblyC-terminusLeigh syndromeMutant proteinsKnockout cellsDisease genesUncharacterized variantsHypomorphic effectPathogenic variantsLeigh-like syndromeMitochondrial diseaseWhole-exome sequencingGenomic criteriaFunctional studiesAmino acidsGenesTIMMDC1Homozygous nonsense variantPatient's clinical phenotypeClinical phenotypeExome sequencingNonsense variantMedical GeneticsDual diagnosis
2016
Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder
Nafisinia M, Guo Y, Dang X, Li J, Chen Y, Zhang J, Lake N, Gold W, Riley L, Thorburn D, Keating B, Xu X, Hakonarson H, Christodoulou J. Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder. JIMD Reports 2016, 32: 117-124. PMID: 27344648, PMCID: PMC5362551, DOI: 10.1007/8904_2016_541.Peer-Reviewed Original ResearchLeigh syndromeCompound heterozygous mutationsLate-onset Leigh syndromeWhole-exome sequencingWhole exome sequencing identifiesAmino acid substitution p.Putaminal abnormalitiesSpongiform lesionsCapillary proliferationMitochondrial respiratory chain functionLactate peakExome sequencing identifiesPatientsBrain tissuePatient muscleSyndromeBrain MRSHeterozygous mutationsExome sequencingPathogenic effectsProtein expressionRespiratory chain functionLaboratory evaluationSubstitution p.Significant reduction