Dataset Information

Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

ABSTRACT:

Background

Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.

Methods

Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro.

Results

Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5'-3' quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, P<0.001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ?90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type.

Conclusions

Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.

SUBMITTER: Helms AS

PROVIDER: S-EPMC7676622 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Spatial and Functional Distribution of <i>MYBPC3</i> Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

Helms Adam S AS Thompson Andrea D AD Glazier Amelia A AA Hafeez Neha N Kabani Samat S Rodriguez Juliani J Yob Jaime M JM Woolcock Helen H Mazzarotto Francesco F Lakdawala Neal K NK Wittekind Samuel G SG Pereira Alexandre C AC Jacoby Daniel L DL Colan Steven D SD Ashley Euan A EA Saberi Sara S Ware James S JS Ingles Jodie J Semsarian Christopher C Michels Michelle M Olivotto Iacopo I Ho Carolyn Y CY Day Sharlene M SM

Circulation. Genomic and precision medicine 20200825 5

<h4>Background</h4>Pathogenic variants in <i>MYBPC3</i>, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique <i>MYBPC3</i> variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.<h4>Methods</h4>Patients with hypertrophic cardiomyopathy and <i>MYBPC3</i> variants were identified from the Sarcomeric Human Cardiomyopathy Registry. V ...[more]

PMID: 32841044

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Project description:RATIONALE:Truncation mutations in the MYBPC3 gene, encoding for cardiac myosin-binding protein C (MyBP-C), are the leading cause of hypertrophic cardiomyopathy (HCM). Whole heart, fiber and molecular studies demonstrate that MyBP-C is a potent modulator of cardiac contractility, but how these mutations contribute to HCM is unresolved. OBJECTIVES:To readdress whether MYBPC3 truncation mutations result in loss of MyBP-C content and/or the expression of truncated MyBP-C from the mutant allele and determine how these mutations effect myofilament sliding in human myocardium. METHODS AND RESULTS:Septal wall tissue samples were obtained from HCM patients undergoing myectomy (n = 18) and donor controls (n = 8). The HCM samples contained 40% less MyBP-C and reduced levels of MyBP-C phosphorylation, when compared to the donor control samples using quantitative mass spectrometry. These differences occurred in the absence of changes in the stoichiometry of other myofilament proteins or production of truncated MyBP-C from the mutant MYBPC3 allele. The functional impact of MYBPC3 truncation mutations on myofilament sliding was determined using a total internal reflection microscopy (TIRFM) single particle assay. Myosin-thick filaments containing their native complement of MyBP-C, and actin-thin filaments decorated with the troponin/tropomyosin calcium regulatory proteins, were isolated from a subgroup of the HCM (n = 4) and donor (n = 5) heart samples. The maximal sliding velocity of native thin filaments was enhanced within the C-zones of the native thick filaments isolated from the HCM samples, when compared to velocity within the C-zones of thick filaments isolated from the donor samples. Analytical modeling demonstrated that the 40% reduction in MyBP-C content was sufficient to enhance the myofilament sliding velocity, as observed in the TIRFM assay. CONCLUSIONS:HCM-causing MYBPC3 truncation mutations result in a loss of MyBP-C content that enhances maximal myofilament sliding velocities, only where MyBP-C is localized within the C-zone. These findings support therapeutic rationale for restoring normal levels of MyBP-C and/or dampening maximal contractile velocities for the treatment of human HCM.