Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants
Halder S, Rynkiewicz M, Kim L, Barry M, Zied A, Sewanan L, Kirk J, Moore J, Lehman W, Campbell S. Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants. Journal Of Clinical Investigation 2024 PMID: 39436707, DOI: 10.1172/jci179135.Peer-Reviewed Original ResearchTPM1 mutationActin thin filamentsDilated cardiomyopathyE54KPhenotypic diversityMyosin activityStem cell-derived cardiomyocytesGene expressionHuman engineered heart tissueIncreased calcium sensitivitySarcomeric proteinsCell-derived cardiomyocytesThin filamentsK mutationMolecular eventsTPM1MutationsClinical phenotypePhenotypeAllosteric interactionsGenesMuscle contractilityCalcium sensitivityInherited disorderAssociation rateClassifying pathogenicity of TPM1 variants of unknown significance using in vitro and in silico approaches
Campbell S, Creso J, Firlar I, Halder S, Lehman W, Rynkiewicz M, Moore J. Classifying pathogenicity of TPM1 variants of unknown significance using in vitro and in silico approaches. Journal Of Cardiac Failure 2024, 30: s3. DOI: 10.1016/j.cardfail.2023.11.005.Peer-Reviewed Original ResearchHypertrophic cardiomyopathyUnknown significanceContractile forceOngoing clinical challengeFirst-degree relativesGenetic testing yieldSlowing of relaxationViral exposureContractile weaknessClinical challengeHypercontractile phenotypeHCM mutationsMyofilament activityHeart tissueMild phenotypeFurther studiesContractile behaviorSignificant increaseHEHTTesting yieldDCM mutationsMinimal effectVUSPathogenicityPhenotype