Disease relevance of MYBPC3

• MYH7 mutations caused HCM at younger age, more frequent syncope and ECG abnormalities compared with MYBPC3 mutations [1].
• The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC) [2].
• OBJECTIVES: We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent [3].
• Patients with MYBPC3 mutations did not differ significantly from patients with thick filament-HCM, thin filament-HCM, or genotype-negative HCM with respect to age at diagnosis, degree of hypertrophy, incidence of myectomy, or family history of HCM or sudden death [4].
• The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M) [5].

High impact information on MYBPC3

• Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments [6].
• Two further FHC loci have been mapped to chromosomes 11p13-q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11p11.2 and proposed as a candidate FHC gene [6].
• Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins [7].
• Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere [7].
• The gene coding for cardiac MyBP-C has been assigned to the chromosomal location 11p11.2 in humans, and is therefore in a region of physical linkage to subsets of familial hypertrophic cardiomyopathy (FHC) [8].

Biological context of MYBPC3

• Cosegregation with the HCM phenotype could be demonstrated for 13 mutations (eight mutations in MYBPC3 and five mutations in MYH7) [9].
• In MYBPC3 we found one missense mutation (Asn948Thr) in a male patient [10].
• These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11p and reaffirm that FHC is a disease of the sarcomere [6].
• BACKGROUND: Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene [11].
• The MYBPC3 gene comprises > 21,000 base pairs and contains 35 exons [2].

Anatomical context of MYBPC3

• Cardiac myosin binding protein-C (cardiac MyBP-C, cardiac C protein) belongs to a family of proteins implicated in both regulatory and structural functions of striated muscle [8].
• Both FHC and NM mutant alpha-Tm proteins incorporated normally into the adult muscle sarcomere, similar to normal Tm but exerted differential "dominant-negative" effects on the contractile function of the muscle cell [12].
• For this characterization, cDNA constructs (rat alpha-MyHC, full-length and truncated human cardiac MyBP-C) were transiently expressed singly or in pairwise combination in COS cells [13].
• Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells [14].

Associations of MYBPC3 with chemical compounds

• Triton skinned fibers were tested for maximal isometric force, Ca(2+)/force relation, rigor force, and stiffness in the absence and presence of the recombinant cardiac MyBP-C motif [15].
• In order to determine the consequences of these mutations on myosin filament organization, we have characterized the effect of a 52-kDa NH2-terminal peptide of human cardiac MyBP-C on the alpha-myosin heavy chain (alpha-MyHC) filament organization [13].

Other interactions of MYBPC3

• These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM [1].
• Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy [2].
• The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing [2].
• Partial amino acid sequences proved that the 15- and 14-kDa fragments are located at the C termini of cardiac MyBP-C and skeletal MyBP-H, respectively [16].

Analytical, diagnostic and therapeutic context of MYBPC3

• METHODS: Using deoxyribonucleic acid from 389 unrelated patients with HCM, each protein coding exon of MYBPC3 was analyzed for mutations by polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing [4].
• Site-directed mutagenesis identifies a LAGGGRRIS loop in the N-terminal region of cardiac MyBP-C as the key substrate site for phosphorylation by both PKA and a calmodulin-dependent protein kinase associated with the native protein [8].

References