#genetics #hypertrophic-cardiomyopathy #sarcomere #sudden-cardiac-death #MYBPC3 #gene-therapy #cardiomyopathy #DCM

MYBPC3 (Cardiac Myosin Binding Protein C)

Details

MYBPC3 encodes cardiac myosin-binding protein C (cMyBP-C), a thick-filament regulatory protein of the cardiac sarcomere that modulates crossbridge cycling, diastolic relaxation, and filament state transitions via phosphorylation-dependent binding switches. It is the most frequently mutated gene in HCM, accounting for 40–50% of all pathogenic HCM variants; >60% of mutations are truncating and produce haploinsufficiency through NMD/UPS/autophagy-mediated degradation of the truncated protein. MYBPC3 mutations also cause DCM (13% of genetic DCM cases), LVNC, and restrictive CMP, and bi-allelic truncating mutations cause uniformly fatal neonatal cardiomyopathy. A 25-bp South Asian founder deletion present in 4% of South Asians confers a 6.99-fold increased heart failure risk, making MYBPC3 among the most globally important cardiomyopathy genes.

Key Facts

Mutation Landscape

Frequency in HCM: >350 individual MYBPC3 mutations; 40–50% of all HCM mutations — the most frequently mutated HCM gene, followed by MYH7 (~25–40%). >60% are truncating (nonsense, indels, splice/branch-point), producing COOH-terminally truncated cMyBP-C lacking major myosin/titin-binding sites. Most heterozygous mutations associate with late onset and often benign progression. (sources/mybpc3-gene-2015, sources/HCM-VA-FCVMed-2022, rating: medium/high)
Bi-allelic truncating mutations: All 26 reported cases of homozygotes/compound heterozygotes with double truncating mutations presented with neonatal cardiomyopathy → heart failure and death within the first year of life; cardiac transplantation is the only curative option. Gene-dosage effect: 14% of childhood-onset HCM is caused by compound genetic variants. (sources/mybpc3-gene-2015)
MYBPC3 in DCM and LVNC: MYBPC3 mutations represented the second highest frequency of disease-causing mutations in a European multi-centre DCM cohort (38/294, 13%; Haas et al. 2014). MYBPC3 mutations also cause LVNC; both missense and truncating mutations occur across HCM, DCM, and LVNC. (sources/mybpc3-gene-2015)
South Asian founder variant: A 25-bp deletion in MYBPC3 intron 32 (delta25, frameshift) is present in 4% of the South Asian population and confers a 6.99-fold increased risk of heart failure (Dhandapany et al. 2009). Found in 13.8% of patients across HCM, DCM, and restrictive CMP in South Asian populations — clinically important for pre-test probability assessment in this group. (sources/mybpc3-gene-2015)

Founder Mutations by Population

All identified founder MYBPC3 mutations are truncating, lacking the M-motif phosphorylation sites and/or major binding domains: (sources/mybpc3-gene-2015, rating: medium)

Iceland c.927-2A>G (intron 11 splice, arose >550 years ago): 58% of Icelandic HCM
Veneto, Italy c.912_913delTT (exon 11): 19.5% of HCM probands
Netherlands c.2373_2374insG: 17% of Dutch HCM (plus 2 additional founder mutations at 2.6% and 1.6%)
Finland c.3183C>T / Gln1061X (exon 29): 17% of cases
Japan c.1775delT / Val592fs/8 (exon 18): 16% of HCM probands
Tuscany, Italy c.772G>A / Glu258Lys (exon 6): 14% of cases; used in Hamburg knock-in mouse model
Center-East France c.1898-2A>G (intron 20, arose ~10 centuries ago): 8.4% of cases
High founder prevalence increases compound heterozygote/homozygote likelihood and therefore the risk of severe pediatric cardiomyopathy in these populations.

cMyBP-C Protein Structure and Function

MYBPC3 is >21 kbp with 35 exons (34 coding) at chr11p11.2. cMyBP-C comprises 8 immunoglobulin-like (Ig) and 3 fibronectin-like (Fn3) domains. Cardiac-specific structural additions vs. skeletal isoforms: N-terminal C0 domain, multiple phosphorylation sites in the M motif (between C1 and C2), and a 28-aa insertion in the C5 domain — making cMyBP-C an ideal signalling platform. Located in the C-zone of the A-band, forming transverse stripes ~43 nm apart. (sources/mybpc3-gene-2015, rating: medium)
Crossbridge braking role: cMyBP-C tethers myosin S1 heads via the C1-M-C2 region binding to myosin S2 — constraining actin-myosin interaction and limiting loaded shortening velocity and power output. Loss of cMyBP-C (knockout mice) accelerates crossbridge cycling rates and increases force redevelopment. (sources/mybpc3-gene-2015)
Thin/thick filament coordination: The cMyBP-C N-terminus stabilises the ON state of thin filaments and the OFF state of thick filaments, coordinating both filament systems to control contractility (Kampourakis et al. 2014). (sources/mybpc3-gene-2015)
Diastolic relaxation: cMyBP-C prevents residual crossbridge cycling at low diastolic Ca²⁺; reduced/absent cMyBP-C impairs diastolic relaxation → diastolic dysfunction as an early consequence of MYBPC3 mutation, independent of hypertrophy. (sources/mybpc3-gene-2015)

Pathomechanisms

Haploinsufficiency (truncating mutations): Truncated cMyBP-Cs are undetectable in human myocardium and heterozygous knock-in mice — degraded by NMD (nonsense-mediated mRNA decay), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway. The result is a reduced total cMyBP-C level, not a stable toxic fragment. (sources/mybpc3-gene-2015, rating: medium)
Poison polypeptide (missense mutations): Stable mutant cMyBP-Cs may be incorporated into the sarcomere, disrupting sarcomeric structure/function. Homozygous c.772G>A knock-in mice produce three different mutant mRNAs/proteins at low levels — suggesting combined haploinsufficiency + polypeptide poisoning in the homozygous state. (sources/mybpc3-gene-2015)
Reduced cMyBP-C → increased myofilament Ca²⁺ sensitivity: Demonstrated across human HCM samples, heterozygous and homozygous knock-in mice, and engineered heart tissue (EHT) models. Mechanism linking haploinsufficiency to Ca²⁺ sensitivity is not fully elucidated; likely involves relief of the diastolic crossbridge-braking role. The Mybpc3-KI knock-in model (c.772G>A, exon 6) exhibits higher Ca²⁺ sensitivity, faster Ca²⁺ transient decay, and diastolic dysfunction — a confirmed proarrhythmic substrate. (sources/mybpc3-gene-2015, sources/HCM-VA-FCVMed-2022)
RyR2 interaction: MYBPC3 may interact directly with RyR2; MYBPC3 mutation or conformational change can disrupt intracellular Ca²⁺ homeostasis through this protein–protein interaction, contributing to spontaneous SR Ca²⁺ release and arrhythmogenic DADs. (sources/HCM-VA-FCVMed-2022)
UPS impairment: Neurohumoral stress or aging combined with Mybpc3 mutations impairs proteasomal activity in mice; proteasomal activities are also depressed in human HCM patient samples (Predmore et al. 2010). (sources/mybpc3-gene-2015)

Phosphorylation of cMyBP-C

M-motif sites: Ser273, Ser282, Ser302 (mouse numbering). Ser282 is a hierarchical switch — its phosphorylation renders Ser273 and Ser302 more accessible. Kinases: PKA (beta-adrenergic/cAMP, most important), CaMKII, RSK, PKD, PKC. GSK3beta phosphorylates Ser131/133 at the actin-binding site outside the M-domain. (sources/mybpc3-gene-2015, rating: medium)
Functional switch: Dephosphorylated cMyBP-C binds myosin S2 → brakes crossbridges (diastolic state). Phosphorylation by PKA via beta-adrenergic stimulation shifts binding to actin → accelerates crossbridge cycling, enhances force development, and promotes relaxation. Phosphorylation is required for normal cardiac function and the inotropic/lusitropic response to adrenergic stimulation.
Disease state: cMyBP-C phosphorylation is reduced in human and experimental heart failure — loss of the protective phosphorylation state. Transgenic phosphomimetic cMyBP-C protected hearts from ischaemia-reperfusion injury and reduced calpain-mediated proteolysis (40-kDa fragment). Preserving phosphorylation is therapeutically beneficial. (sources/mybpc3-gene-2015)

Arrhythmia and Electrophysiology

Arrhythmia risk in HCM: Japanese HCM studies found MYBPC3 mutation carriers have a higher incidence of ventricular arrhythmia and syncope compared to carriers of other sarcomere mutations. (sources/HCM-VA-FCVMed-2022, rating: high)
K⁺ current finding (mouse only): Mybpc3-KI mice show reduced K⁺ currents as the dominant proarrhythmic mechanism. This was NOT replicated in human MYBPC3-homozygous EHT or LV septum samples from HCM patients at myectomy — illustrating a critical species translational gap. See Contradictions. (sources/HCM-VA-FCVMed-2022)
Atrial fibrosis substrate: MYBPC3 variant–positive HCM patients undergoing AF ablation have significantly more LA low-voltage areas than gene-negative HCM controls (normal voltage 85.6% vs. 94.3%; intermediate scar 7.12% vs. 3.07%; dense scar 7.31% vs. 2.61%), despite similar LA pressures — supporting primary atrial myopathy driven by the MYBPC3 variant, independent of haemodynamic loading. (sources/MYBPC3-MYH7-JACCEP-2024, rating: medium)
Greater LV mass in MYBPC3 vs. MYH7 carriers: MYBPC3 variant–positive patients had significantly greater LV mass index (145.7 ± 48.4 vs. 86.6 ± 27.3 g/m² in MYH7; P=0.04), contributing to thicker LA walls, higher rates of non-transmural ablation lesions, and pulmonary vein reconnection. (sources/MYBPC3-MYH7-JACCEP-2024)
AF ablation outcomes: Freedom from AF at 12 months in MYBPC3-positive HCM (66.7%) was similar to controls (73.3%; P=0.92) but required more procedures on average; all gene-positive patients remained on AADs post-ablation. (sources/MYBPC3-MYH7-JACCEP-2024)

Penetrance and Clinical Genetics

Incomplete penetrance and variable expressivity: MYBPC3 mutations show highly variable penetrance; a genotype-positive first-degree relative of an HCM proband may never develop phenotypic disease. MYBPC3 is a primary target for cascade family screening — genotype-positive/phenotype-negative relatives require longitudinal surveillance but not pre-emptive ICD. (sources/HCM-VA-FCVMed-2022, rating: high)
Genotype-phenotype complexity: Incomplete penetrance predictors are lacking, meaning genotype-positive individuals carry a labelled diagnosis with uncertain individual risk — with implications for insurance, employment, and psychological wellbeing. (sources/HCM-VA-FCVMed-2022)

Gene Therapy

Exon skipping (AON/AAV9): AONs targeting exons 5 and 6 packaged under the U7 promoter in AAV9 induce an in-frame deletion → expression of an alternatively spliced Mybpc3 variant. Systemic administration to newborn Mybpc3 knock-in mice prevented systolic dysfunction and LV hypertrophy (Gedicke-Hornung et al. 2013). For human MYBPC3, 6 single or 5 double exon skips would preserve functionally important phosphorylation and binding sites, addressing ~50% of mutations including 35 within exon 25. (sources/mybpc3-gene-2015, rating: medium)
RNA trans-splicing: Two pre-trans-splicing molecules (targeting 5' and 3' of MYBPC3 pre-mRNA) produce repaired full-length mRNA. Feasibility demonstrated in cells and in vivo, but efficiency was too low to prevent the disease phenotype in homozygous knock-in mice (Mearini et al. 2013). Theoretically the most powerful approach — only 2 molecules bypass all MYBPC3 mutations — but requires substantial efficiency improvement. (sources/mybpc3-gene-2015)
Gene replacement (AAV-mediated): Full-length Mybpc3 transfer dose-dependently prevented cardiac hypertrophy and dysfunction over 34 weeks in homozygous knock-in mice (Mearini et al. 2014). Unexpectedly, exogenous Mybpc3 expression down-regulated endogenous mutant Mybpc3, likely through sarcomeric protein competition. Proof-of-concept established for larger animal models (HCM cat model) and pediatric translation for bi-allelic mutations. (sources/mybpc3-gene-2015)
CRISPR/Cas9: Not evaluated for MYBPC3 at time of the 2015 review; under investigation in iPSC lines at that stage. Applicable per-founder mutation. For updated CRISPR cardiac data, see sources/gene-therapy-arrhythmia-2025. (sources/mybpc3-gene-2015)

Contradictions / Open Questions

K⁺ current reduction — mouse finding not replicated in human: Mybpc3 knock-in mice show reduced K⁺ currents as the dominant proarrhythmic mechanism in HCM. This finding was NOT replicated in human MYBPC3-homozygous engineered heart tissue (EHT) or LV septum samples from HCM patients undergoing surgical myectomy. The translational gap undermines using mouse Mybpc3 models to guide antiarrhythmic drug development for human HCM. (sources/HCM-VA-FCVMed-2022)
Incomplete penetrance — no validated predictors: MYBPC3 mutations show variable expressivity and incomplete penetrance. A genotype-positive relative may never develop phenotypic disease; current guidelines recommend surveillance but not pre-emptive ICD. No validated tool exists to predict individual penetrance — genotype-positive individuals carry a labelled diagnosis with uncertain personal risk, with implications for insurance, employment, and psychological wellbeing. (sources/HCM-VA-FCVMed-2022)
Haploinsufficiency vs. dominant-negative — therapeutically critical but unresolved per variant: Most truncating variants produce haploinsufficiency (truncated protein absent by Western blot, degraded via NMD/UPS/autophagy). Some missense variants likely produce stable dominant-negative poison polypeptides incorporated into the sarcomere. The therapeutic implications differ — gene replacement addresses haploinsufficiency; gene silencing or exon skipping is needed for dominant-negative. Distinguishing the mechanism for individual variants is not routinely performed in clinical practice. (sources/HCM-VA-FCVMed-2022, sources/mybpc3-gene-2015)
Opposing PTM effects on cMyBP-C — net disease fingerprint unknown: Phosphorylation at the M-motif (PKA/CaMKII) is broadly protective — reduced in heart failure, phosphomimetic cardioprotective. However, S-glutathiolation increases myofilament Ca²⁺ sensitivity (potentially pathological), and acetylation may promote calpain-mediated proteolysis. The net PTM fingerprint under disease conditions and the question of which modifications to target therapeutically have not been systematically established. (sources/mybpc3-gene-2015)

Connections

Related to entities/HCM
Related to entities/DCM
Related to entities/MYH7
Related to entities/RYR2
Related to concepts/Calcium-Homeostasis-in-HCM
Related to concepts/Ion-Channel-Remodeling-in-HCM
Related to concepts/HCM-Risk-SCD
Related to concepts/Atrial-Myopathy-in-HCM
Related to concepts/Catheter-Ablation-AF
Related to concepts/AAV-Gene-Delivery
Related to concepts/Sarcomere-Biology
Related to concepts/Cascade-Family-Screening
Related to sources/HCM-VA-FCVMed-2022
Related to sources/MYBPC3-MYH7-JACCEP-2024
Related to sources/mybpc3-gene-2015
Related to sources/gene-therapy-arrhythmia-2025