2023
Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Hong Y, Battle S, Shi W, Puiu D, Pillalamarri V, Xie J, Pankratz N, Lake N, Lek M, Rotter J, Rich S, Kooperberg C, Reiner A, Auer P, Heard-Costa N, Liu C, Lai M, Murabito J, Levy D, Grove M, Alonso A, Gibbs R, Dugan-Perez S, Gondek L, Guallar E, Arking D. Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality. Nature Communications 2023, 14: 6113. PMID: 37777527, PMCID: PMC10542802, DOI: 10.1038/s41467-023-41785-7.Peer-Reviewed Original ResearchConceptsSingle nucleotide variantsOwn circular genomeState of heteroplasmyAging-related diseasesNuclear genomeMitochondrial genomeCircular genomeMtDNA single nucleotide variantsMitochondrial DNASomatic cellsMitochondrial mutationsMtDNA heteroplasmyGenomeNucleotide variantsHeteroplasmyDNA moleculesFunctional roleMitochondriaUK BiobankCertain cancersVariantsDNAMutationsCopiesCellsMulti-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 signaturesEstimating the Prevalence of LAMA2 Congenital Muscular Dystrophy using Population Genetic Databases
Lake N, Phua J, Liu W, Moors T, Axon S, Lek M. Estimating the Prevalence of LAMA2 Congenital Muscular Dystrophy using Population Genetic Databases. Journal Of Neuromuscular Diseases 2023, 10: 381-387. PMID: 37005889, DOI: 10.3233/jnd-221552.Peer-Reviewed Original Research
2022
Neuromuscular disorders: finding the missing genetic diagnoses
Koczwara KE, Lake NJ, DeSimone AM, Lek M. Neuromuscular disorders: finding the missing genetic diagnoses. Trends In Genetics 2022, 38: 956-971. PMID: 35908999, DOI: 10.1016/j.tig.2022.07.001.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHigh-throughput functional screeningDiscovery of hundredsGenetic diagnosisNMD genesNext-generation sequencingFunctional screeningSequencing technologiesPathogenic variantsNeuromuscular disordersGroup of diseasesGenesSequencingFuture approachesLarge numberRecent advancementsDiscoveryVariantsYieldMitoVisualize: a resource for analysis of variants in human mitochondrial RNAs and DNA
Lake NJ, Zhou L, Xu J, Lek M. MitoVisualize: a resource for analysis of variants in human mitochondrial RNAs and DNA. Bioinformatics 2022, 38: 2967-2969. PMID: 35561159, DOI: 10.1093/bioinformatics/btac216.Peer-Reviewed Original ResearchConceptsRibosomal RNA secondary structuresHuman mitochondrial RNAMitochondrial transfer RNAsPost-transcriptional modificationsHuman mitochondrial DNADisease-associated variantsRNA secondary structureEffects of variantsMtDNA mapMitochondrial RNAMtDNA variationMitochondrial DNATransfer RNAAnalysis of variantsRNA structureSecondary structureVariant annotationLarge deletionsSupplementary dataVariant interpretationRNADNAVariantsGenesNew toolCenters for Mendelian Genomics: A decade of facilitating gene discovery
Baxter SM, Posey JE, Lake NJ, Sobreira N, Chong JX, Buyske S, Blue EE, Chadwick LH, Coban-Akdemir ZH, Doheny KF, Davis CP, Lek M, Wellington C, Jhangiani SN, Gerstein M, Gibbs RA, Lifton RP, MacArthur DG, Matise TC, Lupski JR, Valle D, Bamshad MJ, Hamosh A, Mane S, Nickerson DA, Consortium C, Adams M, Aguet F, Akay G, Anderson P, Antonescu C, Arachchi H, Atik M, Austin-Tse C, Babb L, Bacus T, Bahrambeigi V, Balasubramanian S, Bayram Y, Beaudet A, Beck C, Belmont J, Below J, Bilguvar K, Boehm C, Boerwinkle E, Boone P, Bowne S, Brand H, Buckingham K, Byrne A, Calame D, Campbell I, Cao X, Carvalho C, Chander V, Chang J, Chao K, Chinn I, Clarke D, Collins R, Cummings B, Dardas Z, Dawood M, Delano K, DiTroia S, Doddapaneni H, Du H, Du R, Duan R, Eldomery M, Eng C, England E, Evangelista E, Everett S, Fatih J, Felsenfeld A, Francioli L, Frazar C, Fu J, Gamarra E, Gambin T, Gan W, Gandhi M, Ganesh V, Garimella K, Gauthier L, Giroux D, Gonzaga-Jauregui C, Goodrich J, Gordon W, Griffith S, Grochowski C, Gu S, Gudmundsson S, Hall S, Hansen A, Harel T, Harmanci A, Herman I, Hetrick K, Hijazi H, Horike-Pyne M, Hsu E, Hu J, Huang Y, Hurless J, Jahl S, Jarvik G, Jiang Y, Johanson E, Jolly A, Karaca E, Khayat M, Knight J, Kolar J, Kumar S, Lalani S, Laricchia K, Larkin K, Leal S, Lemire G, Lewis R, Li H, Ling H, Lipson R, Liu P, Lovgren A, López-Giráldez F, MacMillan M, Mangilog B, Mano S, Marafi D, Marosy B, Marshall J, Martin R, Marvin C, Mawhinney M, McGee S, McGoldrick D, Mehaffey M, Mekonnen B, Meng X, Mitani T, Miyake C, Mohr D, Morris S, Mullen T, Murdock D, Murugan M, Muzny D, Myers B, Neira J, Nguyen K, Nielsen P, Nudelman N, O’Heir E, O’Leary M, Ongaco C, Orange J, Osei-Owusu I, Paine I, Pais L, Paschall J, Patterson K, Pehlivan D, Pelle B, Penney S, Chavez J, Pierce-Hoffman E, Poli C, Punetha J, Radhakrishnan A, Richardson M, Rodrigues E, Roote G, Rosenfeld J, Ryke E, Sabo A, Sanchez A, Schrauwen I, Scott D, Sedlazeck F, Serrano J, Shaw C, Shelford T, Shively K, Singer-Berk M, Smith J, Snow H, Snyder G, Solomonson M, Son R, Song X, Stankiewicz P, Stephan T, Sutton V, Sveden A, Sánchez D, Tackett M, Talkowski M, Threlkeld M, Tiao G, Udler M, Vail L, Valivullah Z, Valkanas E, VanNoy G, Wang Q, Wang G, Wang L, Wangler M, Watts N, Weisburd B, Weiss J, Wheeler M, White J, Williamson C, Wilson M, Wiszniewski W, Withers M, Witmer D, Witzgall L, Wohler E, Wojcik M, Wong I, Wood J, Wu N, Xing J, Yang Y, Yi Q, Yuan B, Zeiger J, Zhang C, Zhang P, Zhang Y, Zhang X, Zhang Y, Zhang S, Zoghbi H, van den Veyver I, Rehm H, O’Donnell-Luria A. Centers for Mendelian Genomics: A decade of facilitating gene discovery. Genetics In Medicine 2022, 24: 784-797. PMID: 35148959, PMCID: PMC9119004, DOI: 10.1016/j.gim.2021.12.005.Peer-Reviewed Original ResearchConceptsGene discoveryMendelian GenomicsUnderstanding of genesGene-phenotype relationshipsGenome variationWorldwide data sharingCandidate genesMendelian phenotypesGenomic researchGenome sequencingMatchmaker ExchangeGenomicsGenesSequencingBiomedical researchMajor roleDiscoveryExomePhenotypeRoleGenotypesCommunityMitochondrial DNA variation across 56,434 individuals in gnomAD
Laricchia KM, Lake NJ, Watts NA, Shand M, Haessly A, Gauthier L, Benjamin D, Banks E, Soto J, Garimella K, Emery J, Consortium G, Rehm HL, MacArthur DG, Tiao G, Lek M, Mootha VK, Calvo SE. Mitochondrial DNA variation across 56,434 individuals in gnomAD. Genome Research 2022, 32: gr.276013.121. PMID: 35074858, PMCID: PMC8896463, DOI: 10.1101/gr.276013.121.Peer-Reviewed Original ResearchConceptsMtDNA variantsMitochondrial DNA variationPathogenic mtDNA variantsWhole genome sequencesUnique mtDNA variantsGenome Aggregation DatabasePopulation allele frequenciesAllele frequenciesMtDNA copy numberMitochondrial genomeNuclear sequencesVariant callsDNA variationIndividuals of EuropeanMtDNA genomeAncestral populationsMtDNA moleculesGenomic databasesHeteroplasmic variantsNuclear DNAHomoplasmic variantsMitochondrial originFalse positive variant callsMtDNA copiesMitochondrial haplogroups
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
Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases
Liu W, Pajusalu S, Lake NJ, Zhou G, Ioannidis N, Mittal P, Johnson NE, Weihl CC, Williams BA, Albrecht DE, Rufibach LE, Lek M. Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases. Genetics In Medicine 2019, 21: 2512-2520. PMID: 31105274, DOI: 10.1038/s41436-019-0544-8.Peer-Reviewed Original ResearchConceptsMuscular dystrophyLimb-girdle muscular dystrophyClinical trialsGene-level mechanismsLower incidencePossible underdiagnosisGeneral populationEpidemiological studiesEpidemiology dataPrevalence estimatesGenetic subtypesMuscle diseaseLGMD subtypesDisease prevalencePrevalenceRecessive diseaseSubtypesPublic sequencing databasesDiseaseTrialsLGMDDystrophyHeterogeneous categorySequencing databasesA 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 diagnosisLeigh syndrome caused by mutations in MTFMT is associated with a better prognosis
Hayhurst H, de Coo I, Piekutowska‐Abramczuk D, Alston C, Sharma S, Thompson K, Rius R, He L, Hopton S, Ploski R, Ciara E, Lake N, Compton A, Delatycki M, Verrips A, Bonnen P, Jones S, Morris A, Shakespeare D, Christodoulou J, Wesol‐Kucharska D, Rokicki D, Smeets H, Pronicka E, Thorburn D, Gorman G, McFarland R, Taylor R, Ng Y. Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis. Annals Of Clinical And Translational Neurology 2019, 6: 515-524. PMID: 30911575, PMCID: PMC6414492, DOI: 10.1002/acn3.725.Peer-Reviewed Original ResearchConceptsPathogenic variantsLeigh syndromeSubcortical white matter abnormalitiesNew casesFrequent initial manifestationLast clinical reviewRetrospective cohort studyBasal ganglia changesWhite matter abnormalitiesRespiratory chain deficiencyBi-allelic pathogenic variantsMitochondrial methionyl-tRNA formyltransferaseMolecular genetic findingsMilder clinical phenotypeInitial manifestationBrainstem lesionsCohort studyMedian ageBetter prognosisChain deficiencyMotor symptomsClinical reviewDisease progressionMultiple respiratory chain deficiencyMuscle biopsy
2017
Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome
Lake N, Webb B, Stroud D, Richman T, Ruzzenente B, Compton A, Mountford H, Pulman J, Zangarelli C, Rio M, Boddaert N, Assouline Z, Sherpa M, Schadt E, Houten S, Byrnes J, McCormick E, Zolkipli-Cunningham Z, Haude K, Zhang Z, Retterer K, Bai R, Calvo S, Mootha V, Christodoulou J, Rötig A, Filipovska A, Cristian I, Falk M, Metodiev M, Thorburn D. Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. American Journal Of Human Genetics 2017, 101: 239-254. PMID: 28777931, PMCID: PMC5544391, DOI: 10.1016/j.ajhg.2017.07.005.Peer-Reviewed Original ResearchConceptsSmall mitoribosomal subunitMitoribosomal subunitHuman oxidative phosphorylation (OXPHOS) systemMitochondrial protein translationOxidative phosphorylation systemMitochondrial translation defectQuantitative proteomic analysisSpecific cellular pathwaysLeigh syndromeLentiviral-mediated expressionMitoribosomal proteinsMitochondrial ribosomesOXPHOS subunitsMitochondrial translationOXPHOS defectsProtein translationMitochondrial DNATranslation defectsUnrelated familiesProteomic analysisPhosphorylation systemQuantitative proteomicsCellular pathwaysProtein subunitsSubunit proteinsTRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis
Lake N, Taylor R, Trahair H, Harikrishnan K, Curran J, Almeida M, Kulkarni H, Mukhamedova N, Hoang A, Low H, Murphy A, Johnson M, Dyer T, Mahaney M, Göring H, Moses E, Sviridov D, Blangero J, Jowett J, Bozaoglu K. TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis. European Heart Journal 2017, 38: 3579-3587. PMID: 28655204, PMCID: PMC6251650, DOI: 10.1093/eurheartj/ehx315.Peer-Reviewed Original ResearchConceptsNovel regulatorLiver X receptorHDL biogenesisCholesterol effluxTranscription of ABCA1ABCA1 expressionSan Antonio Family Heart StudyAbsence of ABCA1Novel associationsSiRNA-mediated knockdownTrafficking proteinsTranscriptomic dataABCA1 promoterMolecular basisTRAK2RegulatorKnockdownBiogenesisHuman macrophagesMember 1Protein expressionEfflux pathwayX receptorHDL metabolismFamily Heart StudyATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism
Desai R, Frazier A, Durigon R, Patel H, Jones A, Rosa I, Lake N, Compton A, Mountford H, Tucker E, Mitchell A, Jackson D, Sesay A, Di Re M, van den Heuvel L, Burke D, Francis D, Lunke S, McGillivray G, Mandelstam S, Mochel F, Keren B, Jardel C, Turner A, Andrews P, Smeitink J, Spelbrink J, Heales S, Kohda M, Ohtake A, Murayama K, Okazaki Y, Lombès A, Holt I, Thorburn D, Spinazzola A. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain 2017, 140: 1595-1610. PMID: 28549128, PMCID: PMC5445257, DOI: 10.1093/brain/awx094.Peer-Reviewed Original ResearchConceptsATAD3A geneHigh-throughput sequencing technologyIntegration of mitochondriaMitochondrial DNA organizationCholesterol homeostasisCellular cholesterol homeostasisSingle nucleotide polymorphism arrayMitochondrial DNA abnormalitiesNiemann-Pick type C diseaseNucleotide polymorphism arrayWhole-exome sequencing dataDNA organizationExome sequencing dataMitochondrial DNACausal genesCholesterol metabolismGenomic analysisGenomic rearrangementsSequencing technologiesHigh homologySequencing dataType C diseaseDrug-induced perturbationsGene cluster deletionsGenes
2015
Leigh syndrome: One disorder, more than 75 monogenic causes
Lake N, Compton A, Rahman S, Thorburn D. Leigh syndrome: One disorder, more than 75 monogenic causes. Annals Of Neurology 2015, 79: 190-203. PMID: 26506407, DOI: 10.1002/ana.24551.Peer-Reviewed Original ResearchLeigh Syndrome
Lake N, Bird M, Isohanni P, Paetau A. Leigh Syndrome. Journal Of Neuropathology & Experimental Neurology 2015, 74: 482-492. PMID: 25978847, DOI: 10.1097/nen.0000000000000195.Peer-Reviewed Original ResearchConceptsLeigh syndromeAnimal modelsHypoxic-ischemic encephalopathyBilateral symmetrical lesionsCommon pediatric presentationMolecular mechanismsSevere ATP depletionNeuronal preservationPediatric presentationProgressive encephalopathySymmetrical lesionsBasal gangliaCapillary proliferationCerebrospinal fluidUnique pathologyPathogenic mechanismsLesion developmentPatient samplesReactive oxygen speciesGliosisHyperlacticacidemiaEncephalopathyATP depletionSyndromePathology