Browsing by Subject "hypertrophic cardiomyopathy"

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    Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation.
    (Frontiers in Physiology, 2017-01) Veltri, T; Landim-Vieira, M; Parvatiyar, MS; Gonzalez-Martinez, D; Dieseldorff Jones, KM; Michell, CA; Dweck, D; Landstrom, AP; Chase, PB; Pinto, JR
    Mutations in TNNC1-the gene encoding cardiac troponin C (cTnC)-that have been associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction may also affect Ca2+-regulation and function of slow skeletal muscle since the same gene is expressed in both cardiac and slow skeletal muscle. Therefore, we reconstituted rabbit soleus fibers and bovine masseter myofibrils with mutant cTnCs (A8V, C84Y, E134D, and D145E) associated with HCM to investigate their effects on contractile force and ATPase rates, respectively. Previously, we showed that these HCM cTnC mutants, except for E134D, increased the Ca2+ sensitivity of force development in cardiac preparations. In the current study, an increase in Ca2+ sensitivity of isometric force was only observed for the C84Y mutant when reconstituted in soleus fibers. Incorporation of cTnC C84Y in bovine masseter myofibrils reduced the ATPase activity at saturating [Ca2+], whereas, incorporation of cTnC D145E increased the ATPase activity at inhibiting and saturating [Ca2+]. We also tested whether reconstitution of cardiac fibers with troponin complexes containing the cTnC mutants and slow skeletal troponin I (ssTnI) could emulate the slow skeletal functional phenotype. Reconstitution of cardiac fibers with troponin complexes containing ssTnI attenuated the Ca2+ sensitization of isometric force when cTnC A8V and D145E were present; however, it was enhanced for C84Y. In summary, although the A8V and D145E mutants are present in both muscle types, their functional phenotype is more prominent in cardiac muscle than in slow skeletal muscle, which has implications for the protein-protein interactions within the troponin complex. The C84Y mutant warrants further investigation since it drastically alters the properties of both muscle types and may account for the earlier clinical onset in the proband.
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    Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.
    (JACC. Basic to translational science, 2017-02) Quick, AP; Landstrom, AP; Wang, Q; Beavers, DL; Reynolds, JO; Barreto-Torres, G; Tran, V; Showell, J; Philippen, LE; Morris, SA; Skapura, D; Bos, JM; Pedersen, SE; Pautler, RG; Ackerman, MJ; Wehrens, XHT
    BACKGROUND:Hypertrophic cardiomyopathy (HCM), defined as asymmetric left ventricular hypertrophy, is a leading cause of cardiac death in the young. Perturbations in calcium (Ca2+) handling proteins have been implicated in the pathogenesis of HCM. JPH2-encoded junctophilin 2 is a major component of the junctional membrane complex, the subcellular microdomain involved in excitation-contraction coupling. We hypothesized that a novel JPH2 mutation identified in patients with HCM is causally linked to HCM, and alters intracellular Ca2+ signaling in a pro-hypertrophic manner. OBJECTIVES:To determine using a transgenic mouse model whether a JPH2 mutation found in a HCM patient is responsible for disease development. METHODS:Genetic interrogation of a large cohort of HCM cases was conducted for all coding exons of JPH2. Pseudo-knock-in (PKI) mice containing a novel JPH2 variant were subjected to echocardiography, cardiac MRI, hemodynamic analysis, and histology. RESULTS:A novel JPH2 mutation, A405S, was identified in a genotype-negative proband with significant basal septal hypertrophy. Although initially underappreciated by traditional echocardiographic imaging, PKI mice with this JPH2 mutation (residue A399S in mice) were found to exhibit similar basal hypertrophy using a newly developed echo imaging plane, and this was confirmed using cardiac MRI. Histological analysis demonstrated cardiomyocyte hypertrophy and disarray consistent with HCM. CONCLUSIONS:Variant A405S is a novel HCM-associated mutation in JPH2 found in a proband negative for mutations in the canonical HCM-associated genes. Studies in the analogous mouse model demonstrated for the first time a causal link between a JPH2 defect and HCM. Moreover, novel imaging approaches identified subvalvular septal hypertrophy, specific findings also reported in the human JPH2 mutation carrier.
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    The clinical utility of pediatric cardiomyopathy genetic testing: From diagnosis to a precision medicine-based approach to care.
    (Progress in pediatric cardiology, 2021-09) Parker, Lauren E; Landstrom, Andrew P
    Pediatric-onset cardiomyopathies are rare yet cause significant morbidity and mortality in affected children. Genetic testing has a major role in the clinical evaluation of pediatric-onset cardiomyopathies, and identification of a variant in an associated gene can be used to confirm the clinical diagnosis and exclude syndromic causes that may warrant different treatment strategies. Further, risk-predictive testing of first-degree relatives can assess who is at-risk of disease and requires continued clinical follow-up. In this review, we seek to describe the current role of genetic testing in the clinical diagnosis and management of patients and families with the five major cardiomyopathies. Further, we highlight the ongoing development of precision-based approaches to diagnosis, prognosis, and treatment. Emerging application of genotype-phenotype correlations opens the door for genetics to guide a precision medicine-based approach to prognosis and potentially for therapies. Despite advances in our understanding of the genetic etiology of cardiomyopathy and increased accessibility of clinical genetic testing, not all pediatric cardiomyopathy patients have a clear genetic explanation for their disease. Expanded genomic studies are needed to understand the cause of disease in these patients, improve variant classification and genotype-driven prognostic predictions, and ultimately develop truly disease preventing treatment.