Dataset Information

Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

ABSTRACT: RATIONALE:High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. OBJECTIVE:To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND RESULTS:Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. CONCLUSIONS:High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

SUBMITTER: Sequeira V

PROVIDER: S-EPMC3675884 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

Sequeira Vasco V Wijnker Paul J M PJ Nijenkamp Louise L A M LL Kuster Diederik W D DW Najafi Aref A Witjas-Paalberends E Rosalie ER Regan Jessica A JA Boontje Nicky N Ten Cate Folkert J FJ Germans Tjeerd T Carrier Lucie L Sadayappan Sakthivel S van Slegtenhorst Marjon A MA Zaremba Ruud R Foster D Brian DB Murphy Anne M AM Poggesi Corrado C Dos Remedios Cris C Stienen Ger J M GJ Ho Carolyn Y CY Michels Michelle M van der Velden Jolanda J

Circulation research 20130318 11

<h4>Rationale</h4>High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.<h4>Objective</h4>To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM wi ...[more]

PMID: 23508784

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Project description:Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM.

Dataset Information

Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

Publications

Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

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