2024
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder
Szot J, Cuny H, Martin E, Sheng D, Iyer K, Portelli S, Nguyen V, Gereis J, Alankarage D, Chitayat D, Chong K, Wentzensen I, Vincent-Delormé C, Lermine A, Burkitt-Wright E, Ji W, Jeffries L, Pais L, Tan T, Pitt J, Wise C, Wright H, Andrews I, Pruniski B, Grebe T, Corsten-Janssen N, Bouman K, Poulton C, Prakash S, Keren B, Brown N, Hunter M, Heath O, Lakhani S, McDermott J, Ascher D, Chapman G, Bozon K, Dunwoodie S. A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder. Journal Of Clinical Investigation 2024, 134: e174824. PMID: 38357931, PMCID: PMC10866660, DOI: 10.1172/jci174824.Peer-Reviewed Original ResearchConceptsCongenital NAD deficiency disorderNicotinamide adenine dinucleotideBiallelic loss-of-function variantsLoss-of-function variantsPrecursor supplementationNAD precursor supplementationStructures modelled in silicoNonredundant enzymesMetabolic signaturesNAD metabolomeNicotinamide adenine dinucleotide levelsDeficiency disordersPrevent adverse pregnancy outcomesSynthesis pathwayAdverse pregnancy outcomesModel in silicoNAD precursorsMetabolic blockEmbryonic developmentImproving clinical diagnosticsAdenine dinucleotideAbsence of malformationsPregnancy outcomesCongenital malformationsMalformations
2021
Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation
Tyler PM, Bucklin ML, Zhao M, Maher TJ, Rice AJ, Ji W, Warner N, Pan J, Morotti R, McCarthy P, Griffiths A, van Rossum AMC, Hollink IHIM, Dalm VASH, Catanzaro J, Lakhani SA, Muise AM, Lucas CL. Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation. Nature Immunology 2021, 22: 1118-1126. PMID: 34326534, PMCID: PMC8985851, DOI: 10.1038/s41590-021-00984-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalgranulin ADNA-Binding ProteinsFemaleGene Expression RegulationHereditary Autoinflammatory DiseasesHumansInflammatory Bowel DiseasesInterleukin 1 Receptor Antagonist ProteinLipocalin-2LipopolysaccharidesMacrophagesMaleMiceMice, Inbred C57BLMice, KnockoutTh17 CellsTranscription FactorsTranscription, GeneticTriggering Receptor Expressed on Myeloid Cells-1ConceptsInterleukin-1Inflammatory bowel disease (IBD) characteristicsInflammatory immune cellsHuman inflammatory disordersAnti-inflammatory genesTumor necrosis factorHuman autoinflammatory diseasesInnate stimuliHyperinflammatory responseMale patientsNeutrophil chemoattractantDisease characteristicsInflammatory disordersMucosal diseaseImmune cellsInflammation amplifierNecrosis factorUnrelated male patientsAutoinflammatory diseasesMouse modelBroad translational relevanceTranslational relevanceInflammationFunction variantsMouse macrophages
2020
Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome
Alharatani R, Ververi A, Beleza-Meireles A, Ji W, Mis E, Patterson QT, Griffin JN, Bhujel N, Chang CA, Dixit A, Konstantino M, Healy C, Hannan S, Neo N, Cash A, Li D, Bhoj E, Zackai EH, Cleaver R, Baralle D, McEntagart M, Newbury-Ecob R, Scott R, Hurst JA, Au PYB, Hosey MT, Khokha M, Marciano DK, Lakhani SA, Liu KJ. Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome. Human Molecular Genetics 2020, 29: 1900-1921. PMID: 32196547, PMCID: PMC7372553, DOI: 10.1093/hmg/ddaa050.Peer-Reviewed Original ResearchConceptsCell-cell junctionsNovel protein-truncating variantsP120-catenin proteinProtein-truncating variantsNext-generation sequencingTranscriptional signalingP120-cateninCRISPR/Epithelial-mesenchymal transitionSubset of phenotypesDevelopmental roleLimb dysmorphologiesAdditional phenotypesHuman diseasesCTNND1Conditional deletionDe novoTruncating mutationsBlepharocheilodontic syndromeEpithelial integrityNovel truncating mutationCraniofacial dysmorphismPhenotypeCleft palateNeurodevelopmental disorders
2014
Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA
Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY, Taniguchi T, Shadel GS, Chen ZJ, Iwasaki A, Flavell RA. Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA. Cell 2014, 159: 1563-1577. PMID: 25525875, PMCID: PMC4272443, DOI: 10.1016/j.cell.2014.11.037.Peer-Reviewed Original ResearchConceptsMitochondrial outer membrane permeabilizationCell deathOuter membrane permeabilizationType I interferonDNA-dependent activationCaspase-dependent mannerI interferonCGAS/STING pathwayMitochondrial DNAApoptotic caspasesMembrane permeabilizationActive caspasesProapoptotic caspasesMitochondriaCaspasesSTING pathwayIFN responseAntiviral immunityCentral roleDual controlPathwayProinflammatory typeInductionCellsActivation
2012
JNK Expression by Macrophages Promotes Obesity-Induced Insulin Resistance and Inflammation
Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, Flavell RA, Davis RJ. JNK Expression by Macrophages Promotes Obesity-Induced Insulin Resistance and Inflammation. Science 2012, 339: 218-222. PMID: 23223452, PMCID: PMC3835653, DOI: 10.1126/science.1227568.Peer-Reviewed Original ResearchConceptsInsulin resistanceObesity-induced insulin resistancePro-inflammatory macrophage polarizationProtection of miceHigh-fat dietJNK-deficient miceMacrophage polarizationSimilar obesityTissue infiltrationInflammationMacrophagesMiceJNK deficiencyJNK expressionMetabolic responseRole of JNKObesityTerminal kinaseJNK
2007
Endoplasmic Reticulum Stress-induced Death of Mouse Embryonic Fibroblasts Requires the Intrinsic Pathway of Apoptosis*
Masud A, Mohapatra A, Lakhani SA, Ferrandino A, Hakem R, Flavell RA. Endoplasmic Reticulum Stress-induced Death of Mouse Embryonic Fibroblasts Requires the Intrinsic Pathway of Apoptosis*. Journal Of Biological Chemistry 2007, 282: 14132-14139. PMID: 17371867, DOI: 10.1074/jbc.m700077200.Peer-Reviewed Original Research
2006
Caspases 3 and 7: Key Mediators of Mitochondrial Events of Apoptosis
Lakhani SA, Masud A, Kuida K, Porter GA, Booth CJ, Mehal WZ, Inayat I, Flavell RA. Caspases 3 and 7: Key Mediators of Mitochondrial Events of Apoptosis. Science 2006, 311: 847-851. PMID: 16469926, PMCID: PMC3738210, DOI: 10.1126/science.1115035.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisApoptosis Inducing FactorBcl-2-Associated X ProteinCaspase 3Caspase 7CaspasesCell NucleusCell ShapeCell SurvivalCells, CulturedCytochromes cDNA FragmentationFemaleFibroblastsHeartHeart Defects, CongenitalMaleMiceMice, Inbred C57BLMice, KnockoutMitochondriaMitochondrial MembranesPermeabilityT-LymphocytesConceptsApoptosis-inducing factorMitochondrial eventsDownstream effector caspasesDeath receptor-mediated apoptosisCytochrome c releaseCaspase-3Receptor-mediated apoptosisDefective nuclear translocationEarly apoptotic eventsMitochondrial membrane potentialEffector caspasesBax translocationC releaseCardiac developmentApoptotic eventsCaspase-7Upstream signalsNuclear translocationApoptosisMembrane potentialCritical mediatorKey mediatorTranslocationCaspasesEffectors