HGNC Approved Gene Symbol: MYBPC3
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,331,406-47,352,702 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Cardiomyopathy, dilated, 1MM | 615396 | Autosomal dominant | 3 |
| Cardiomyopathy, hypertrophic, 4 | 115197 | Autosomal dominant; Autosomal recessive | 3 | |
| Left ventricular noncompaction 10 | 615396 | Autosomal dominant | 3 |
Cardiac myosin-binding protein C (MYBPC3) is arrayed transversely in sarcomere A-bands and binds myosin heavy chain (see 160710) in thick filaments and titin (188840) in elastic filaments. Phosphorylation of this protein appears to modulate contraction.
Carrier et al. (1997) reported that the MYBPC3 gene spans more than 21 kb and contains 35 exons. Two exons are unusually small, 3 bp each.
Klaassen (2013) noted that the MYBPC3 gene contains a noncoding exon 1. Some authors (e.g., Probst et al., 2011) have used this noncoding exon in the numbering of the exons in the gene.
Using single-particle fluorescence imaging techniques, transgenic protein expression, proteomics, and modeling, Previs et al. (2012) found that cMyBP-C slows actomyosin motion generation in native cardiac thick filaments. This mechanical effect was localized to where cMyBP-C resides within the thick filament (i.e., the C-zones) and was modulated by phosphorylation and site-specific proteolytic degradation. Previs et al. (2012) concluded that their results provided molecular insight into why cMyBP-C should be considered a member of a tripartite complex with actin and myosin that allows fine tuning of cardiac muscle contraction.
Gautel et al. (1995) mapped the MYBPC3 gene to 11p11.2 by fluorescence in situ hybridization and proposed it as a candidate for the site of the mutation in familial hypertrophic cardiomyopathy-4 (CMH4; 115197), which maps to the same region.
Watkins et al. (1995) found that the MYBPC3 gene was linked to familial hypertrophic cardiomyopathy (CMH4; 115197) and demonstrated heterozygosity for a splice donor mutation (600958.0001) in 1 family and a duplication mutation (600958.0002) in a second. Incomplete penetrance was observed in both families. Both mutations were predicted to disrupt the high-affinity, C-terminal myosin-binding domain of cardiac MyBP-C. Again, findings demonstrated that as in the case of the 3 forms that had been defined in molecular terms previously, familial hypertrophic cardiomyopathy is a disease of the sarcomere.
In 2 unrelated French families with familial hypertrophic cardiomyopathy of the CMH4 type (as indicated by linkage), Bonne et al. (1995) identified a heterozygous mutation in a splice acceptor site of the MYBPC3 gene which caused skipping of the associated exon and was predicted to produce a truncated gene product. The 2 families shared a common haplotype in a region of 2 cM around the MYBPC gene, suggesting that they may be distantly related. Both families demonstrated incomplete penetrance.
Carrier et al. (1997) found 6 novel mutations in the CYBPC3 gene that were associated with familial hypertrophic cardiomyopathy in 7 unrelated French families. Four of these mutations were predicted to produce truncated cardiac myosin-binding protein C polypeptides (e.g., 600958.0007). The 2 others produced aberrant proteins, 1 truncated (600985.0005) and 1 mutated (600958.0006).
Mutations in the gene for cardiac myosin-binding protein C account for approximately 15% of cases of familial hypertrophic cardiomyopathy. Niimura et al. (1998) studied the spectrum of disease-causing mutations and the associated clinical features of these gene defects. Among 16 families studied, 12 novel mutations were identified: 4 missense mutations and 8 defects (insertions, deletions, and splice mutations) predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58% of adults under the age of 50 years who had a mutation in the MYBPC3 gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by mutations in other genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly.
In 46 young patients with dilated cardiomyopathy (CMD1MM; 615396), Daehmlow et al. (2002) performed mutation screening of 4 sarcomeric protein genes. They identified 2 mutations in the MYH7 gene (160760.0026-160760.0027) and 1 mutation in the MYBPC3 gene (asn948-to-thr; 600958.0013). Daehmlow et al. (2002) noted that they could not confirm the disease-causing nature of these variants because family members for the calculation of 2-point lod scores could not be obtained for further investigation.
Konno et al. (2003) analyzed the MYBPC3 gene in 250 unrelated probands with CMH and 90 with CMD and identified a missense mutation (R820Q; 600958.0015) in 16 individuals from families with CMH and in a 71-year-old man with a clinical diagnosis of CMD. The authors suggested that the patient diagnosed with CMD may actually have been in the 'burnt-out' phase of hypertrophic cardiomyopathy.
Lekanne Deprez et al. (2006) reported 2 unrelated Dutch infants with severe hypertrophic cardiomyopathy in whom they identified compound heterozygosity for truncating mutations in the MYBPC3 gene (see, e.g., 600958.0023). The infants died at 5 and 6 weeks of age. The nonconsanguineous asymptomatic parents were heterozygous carriers of 1 of the mutations in each case; 1 of the fathers was found to have mild hypertrophic cardiomyopathy on cardiac MRI.
Wang et al. (2005) observed that patients with hypertrophic cardiomyopathy carrying identical mutations can have different left ventricular thicknesses, suggesting the presence of modifying variants. They genotyped 226 patients with CMH and 226 age- and sex-matched controls for 3 MYBPC3 polymorphisms, and found that the GG genotype at nucleotide 18443 in exon 30 was associated with a significantly thicker left ventricular wall in patients, compared to the AA and AG genotypes (p less than 0.001). GG was not associated with left ventricular wall thickness in normal controls, and there was no difference in genotype distribution between patients and controls. Wang et al. (2005) concluded that the MYBPC3 polymorphism is a modifier for expression of cardiac hypertrophy in patients with CMH.
In a 12-month-old girl with restrictive cardiomyopathy (RCM3; 612422), Peddy et al. (2006) performed direct sequencing of the 8 genes most commonly implicated in hypertrophic cardiomyopathy and identified a de novo 3-bp deletion in the TNNT2 gene (191045.0011). The girl also carried a known MYBPC3 (600958) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC.
In 23 Old Order Amish infants with severe neonatal hypertrophic cardiomyopathy, Xin et al. (2007) identified homozygosity for a splice site mutation in the MYBPC3 gene (3330+2T-G; 600958.0020). Noting the many reports of cardiac symptoms, including sudden death, among these probands' parents and relatives, and the close similarity between this mutation and the 3330+5G-C mutation (600958.0001) previously documented by Watkins et al. (1995) as the cause of CMH in heterozygous carriers, Xin et al. (2007) suggested that heterozygotes for the 3330+2T-G mutation may also be at risk for CMH.
Frank-Hansen et al. (2008) used SSCP analysis and sequence confirmation in 250 unrelated patients with CMH to determine whether intronic variation flanking the 3 microexons in the MYBPC3 gene is disease-causing. Functional studies and segregation analysis indicated that 4 of the 7 mutations they identified are associated with CMH (see, e.g., 600958.0016 and 600958.0017): all 4 mutations result in premature termination codons, suggesting that haploinsufficiency is a pathogenic mechanism of this type of mutation. In 1 family, a second mutation in the MYBPC3 gene was also identified (V1125M; 600958.0018).
Ehlermann et al. (2008) screened the MYBPC3 gene in 87 patients with hypertrophic cardiomyopathy and 71 patients with CMD and identified heterozygous mutations in 16 (18.4%) of the CMH patients and in 2 (2.8%) of the CMD patients. However, in the first CMD family, 3 additional carriers of the MYBPC3 missense mutation had no certain pathologic findings, and the authors noted that in the index patient, hypertensive heart disease could not be ruled out as the cause of his CMD phenotype. In the second CMD family, the 2 oldest carriers of the splice site mutation displayed CMD, whereas 4 younger mutation carriers showed CMH; the authors stated that it was mostly likely that the 2 older patients suffered from end-stage CMH with progression to a CMD phenotype. Screening the cohort for variation in 5 additional cardiomyopathy-associated genes (MYH7, 160760; TNNT2, 191045; TNNI3, 191044; ACTC1, 102540; and TPM1, 191010) revealed no further mutations. Of a total of 45 affected individuals, from 12 families and 6 sporadic patients, 23 (51%) suffered an adverse event such as progression to severe heart failure, transient ischemic attack, stroke, or sudden death.
Waldmuller et al. (2003) identified a 25-bp deletion in intron 32 of the MYBPC3 gene (600958.0019) in 2 south Indian families with CMH, 1 of which was also known to carry a mutation in the MYH7 gene. The polymorphism was detected in 16 of 229 unrelated healthy Indian individuals but not in western European individuals, and the authors considered that it represents a regional polymorphism restricted to southern India. Waldmuller et al. (2003) stated that the relationship to disease was 'not unequivocal' and suggested that the deletion may represent a modifier polymorphism that may enhance the phenotypes of mutations responsible for disease. Dhandapany et al. (2009) analyzed the 25-bp deletion in the MYBPC3 gene in Indian patients with hypertrophic, dilated, and restrictive cardiomyopathies and identified an association with familial cardiomyopathy and an increased risk of heart failure (overall odds ratio, 6.99; p = 4 x 10(-11)).
After typing 811 genomewide short-tandem repeat markers in 100 members of a CMH family originally reported by Niimura et al. (1998), 36 of whom carried the MYBPC3 791insG mutation (600958.0011), Daw et al. (2007) performed oligogenic simultaneous segregation and linkage analyses using Markov chain Monte Carlo methods and detected the strongest signals on chromosomes 10p13 and 17q24, with log of the posterior placement probability ratio (LOP) scores of 4.86 and 4.17, respectively. The effect size of the MYBPC3 mutation on left ventricular mass was significantly decreased when modifier loci were included in the analysis, suggesting an interaction between the causal mutation and modifier genes.
In a 28-year-old Australian man who was diagnosed at age 18 years with severe CMH, Ingles et al. (2005) detected compound heterozygous missense mutations in the MYBPC3 gene (600958.0021 and 600958.0022). Chiu et al. (2007) also identified a heterozygous R73Q substitution in the CALR3 gene (611414) in this patient. Chiu et al. (2007) suggested that calreticulin may be involved in both disease pathogenesis and modification.
In a female infant with fatal cardiomyopathy who also showed evidence of skeletal myopathy, Tajsharghi et al. (2010) identified homozygosity for a nonsense mutation in the MYBPC3 gene (R943X; 600958.0023). Skeletal muscle biopsy at 2 months of age showed pronounced myopathic changes with numerous small fibers; immunohistochemical staining showed the presence of cardiac MYBPC in the small abnormal fibers, and RT-PCR and sequencing demonstrated the mutation in transcripts of skeletal muscle. Tajsharghi et al. (2010) noted that cardiac MYBPC is not normally expressed in skeletal muscle and stated that the reason for the ectopic expression of cardiac MYBPC remained unknown.
Hershberger et al. (2010) screened 5 cardiomyopathy-associated genes in 312 patients with CMD, who had previously been studied by Hershberger et al. (2008), and identified 12 MYBPC3 variants in 13 (4.2%) of the probands, of which 2 were considered to be 'likely' disease-causing mutations: A833T (600958.0024) and C1264F (600958.0025). The A833T change was identified in affected individuals from 3 families; haplotype analysis suggested a founder mutation. Hershberger et al. (2010) noted that the A833T mutation had previously been identified in a family with CMH (Morner et al., 2003).
In a cohort of 63 unrelated white patients of western European descent with left ventricular noncompaction (LVNC10; see 615396), Probst et al. (2011) analyzed 8 sarcomere genes and identified 5 probands with 4 different heterozygous mutations in the MYBPC3 gene (see, e.g., 600958.0026-600958.0028). In a 21-year-old man from a consanguineous Chinese family with hypertrophic cardiomyopathy, Wang et al. (2013) screened the coding sequence and flanking regions of 26 CMH-related genes and identified a homozygous missense mutation in the MYBPC3 gene (G490V; 600958.0029). His affected younger brother was also homozygous for the mutation; 6 other relatives, including their unaffected parents, were heterozygous for the mutation. None of the heterozygous carriers had any of the typical clinical manifestations of CMH, including the 2 oldest carriers at ages 62 years and 71 years, and none showed abnormalities on electrocardiography or left ventricular hypertrophy on echocardiography. CMR of 3 heterozygous individuals showed no structural abnormalities or cardiac fibrosis. Wang et al. (2013) noted that a different mutation at the same residue, G490R (600958.0026), had previously been reported to cause disease in heterozygosity; they proposed that the difference in inheritance pattern might stem from the fact that G490R produces a more prominent structural change by substituting a small side chain for a bulky one and changing the polarity from neutral to basic, whereas G490V keeps the side chain small and polarity neutral.
From 2000 to 2012, Das et al. (2014) studied a total of 136 unrelated hypertrophic cardiomyopathy (192600) probands, of which 63 (46%) carried at least 1 pathogenic mutation. MYBPC3 accounted for 34 patients, or 47%, and MYH7 (160760) accounted for 23 patients, or 32%. Together, these gene variants accounted for 79%. In this study, 5 variants in 6 probands (10%) were reclassified: 2 variants of uncertain significance were upgraded to pathogenic, 1 variant of uncertain significance and 1 pathogenic variant were downgraded to benign, and 1 pathogenic variant (found in 2 families) was downgraded to a variant of uncertain significance. Das et al. (2014) concluded that given the rapid growth of genetic information available, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.
Charron et al. (1998) studied clinical features of 76 individuals heterozygous for disease-causing mutations in the MYBPC3 gene. Little phenotypic variation was noted among the 7 MYBPC3 mutations described. Compared to 52 individuals with familial hypertrophic cardiomyopathy due to myosin heavy chain gene mutations, prognosis was significantly better in patients with CMH due to MYBPC3 mutations. In patients with MYBPC3 mutations, the mean age of onset was higher and penetrance below the age of 30 was lower, leading to a milder phenotype with less hypertrophy and fewer T-wave abnormalities. No deaths occurred below the age of 40 regardless of the mutation involved. Cause of death was sudden death in 4 of 9 individuals, refractory heart failure in 3 of 9 individuals, and stroke in 2 of 9 individuals.
To test the hypothesis that some cardiac hypertrophy of the elderly might be attributable to sarcomere protein gene mutations, Niimura et al. (2002) conducted a genetic analysis of 31 individuals with late-onset hypertrophic cardiomyopathy and no other family history. Five individuals with pathogenic mutations in MYBPC were identified. The mean age of symptom development in this group was 56 +/- 13.2 with a mean age at diagnosis of 60.2 +/- 8.9. The reported mutations in the MYBPC3 gene included missense mutations, truncating mutations, and splice mutations. The authors highlighted the importance of these findings for counseling relatives of individuals with elderly-onset hypertrophic cardiomyopathy.
Seidman (2000) pointed out that correlations between genotype and prognosis in hypertrophic cardiomyopathy is possible. Life expectancy is markedly diminished in individuals with the R719W (160760.0017) and R403Q (160760.0001) mutations in the MYH7 gene but near normal in individuals with the E542Q (600958.0006) and 791insG (600958.0011) mutations in the MYBPC3 gene.
Verweij and Hamel (2002) discussed the moral dilemma when there are unexpected findings in identifiable stored blood samples collected for an unrelated study and not carrying consent for other use. The case in point was that of a woman in a family with triphalangeal thumb-polysyndactyly syndrome (174500) in which the disorder was mapped to 7q36 (Tsukurov et al., 1994). The samples were used to study genes involved in hypertrophic cardiomyopathy, and a mutation in the MYBPC3 gene was found. Verweij and Hamel (2002) discussed the benefits and harmful consequences of disclosure, including the uncertainty of the functional significance of the particular mutation.
Van Driest et al. (2004) analyzed the MYBPC3 gene in a cohort of 389 CMH probands who had previously been genotyped for mutation in genes encoding the sarcomeric proteins comprising the thick filament (MYH7 and the regulatory and essential light chains, MYL2 and MYL3) and the thin filament (TNNT2, TNNI3, TPM1, and ACTC). Forty-six different MYBPC3 mutations were identified in 71 (18%) of the patients. Patients with MYBPC3 mutations did not differ significantly from patients with thick filament-CMH, thin filament-CMH, or genotype-negative CMH with respect to age at diagnosis, degree of hypertrophy, incidence of myectomy, or family history of CMH or sudden death. The 10 patients with multiple mutations (2.6% of the total cohort) had the most severe disease presentation.
In a cohort of 97 Italian CMH probands, Calore et al. (2015) identified a founder 2-bp deletion in the MYBPC3 gene (600958.0030) in 19. Probands carrying the founder mutation exhibited significantly higher prevalence of nonsustained ventricular tachycardia and implantable cardioverter-defibrillator placement compared to patients without MYBPC3 mutations or with other MYBPC3 mutations. Calore et al. (2015) noted that the overall annual mortality rate of 2% among the 48 affected founder-mutation carriers was higher than that previously described in MYBPC3 carriers and in the general population of CMH patients.
Yang et al. (1998) created transgenic mice in which varying amounts of a mutated MYBPC gene, lacking the myosin and titin binding domains, were expressed in the heart. The transgenically encoded, truncated protein was stable but was not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the calcium-force curve and their power output was reduced. Additionally, expression of the mutant protein led to decreased levels of endogenous myosin-binding protein C, resulting in a striking pattern of sarcomere disorganization and dysgenesis.
Yang et al. (1999) generated a second series of transgenic mice containing a mutant MYBPC gene lacking only the myosin binding site. In contrast to this group's previous mouse model (see Yang et al. (1998)), expression of mutant protein was reduced in the heterozygote transgenic mouse myocardium. Immunofluorescence studies demonstrated correct incorporation of the mutant protein into the sarcomere, but transmission electron microscopy revealed marked disorganization of sarcomeric ultrastructure. Gross cardiac morphology in transgenic mice was also abnormal, with a globular heart and mild thickening of the left ventricular free wall and papillary muscle. Functional analysis of skinned papillary fibers demonstrated reductions in unloaded shortening velocity, maximum shortening velocity, and relative maximal power output. This mutant polypeptide appeared to behave in a dominant-negative fashion.
Meurs et al. (2005) identified a reduction in Mybpc3 protein in myocardium from Maine Coon cats with hypertrophic cardiomyopathy in comparison to control cats (P less than 0.001). In affected cats, the authors identified a G-C transversion in exon 3 of the feline Mybpc3 gene, resulting in an ala31-to-pro (A31P) substitution in the linker region between the C0 and C1 domains. The mutation was predicted to alter protein conformation and result in sarcomeric disorganization. Affected cats had some variability of phenotype from mildly affected to severe hypertrophy. Some cats developed congestive heart failure, and others died suddenly.
Pohlmann et al. (2007) found that cardiac myocytes from 6-week-old Mybpc3-null mice exhibited mild hypertrophy that became more pronounced by 30 weeks of age. Isolated Mybpc3-null myocytes showed markedly lower diastolic sarcomere length without change in diastolic Ca(2+). This reduced sarcomere length was partially abolished by inhibition of actin-myosin ATPase, indicating residual actin-myosin interaction in diastole. Mybpc3-null myocytes started to contract at lower Ca(2+) concentration, and both sarcomere shortening and Ca(2+) transients were prolonged in Mybpc3-null cells. Isolated Mybpc3-null left atria exhibited a marked increase in sensitivity to external Ca(2+) and, in contrast to wildtype, continued to develop twitch force at low micromolar Ca(2+) concentration. Pohlmann et al. (2007) concluded that MYBPC3 functions as a restraint on myosin-actin interaction at low Ca(2+) concentrations and short sarcomere length to allow complete relaxation during diastole.
To determine if mutation of the cardiac MYBPC gene caused hypertrophic cardiomyopathy in chromosome 11-linked families (CMH4; 115197), Watkins et al. (1995) amplified lymphocyte RNA by reverse-transcription and nested PCR. An abnormally short cDNA in one patient was found to be the result of a G-to-C transversion at position 5 of the 5-prime splice donor sequence GTGAGC in the following intron. The G-to-C transversion created a new BstEII site, allowing independent confirmation of the mutation which was present in all clinically affected members and not present in unaffected members (except for 2, who carried a disease-associated haplotype).
In a family with chromosome 11-linked familial hypertrophic cardiomyopathy (CMH4; 115197), Watkins et al. (1995) demonstrated a heterozygous 18-bp tandem duplication of nucleotide residues 3774-3791. Sequencing of the genomic product confirmed the duplication, which occurred in the penultimate exon of the coding sequence (denoted exon P). The duplication was demonstrated in all affected members of the family and also in a presumed nonpenetrant 16-year-old member. It was not present in the other unaffected family members or in 200 chromosomes from unrelated, unaffected individuals.
In 2 French kindreds with chromosome 11-linked hypertrophic cardiomyopathy (CMH4; 115197), Bonne et al. (1995) found 2 cDNAs of different lengths, 336 bp and 196 bp, in affected individuals. Direct sequencing of the 336 nucleotide product gave 2 different sequences; the normal cDNA and a cDNA with an 11-bp deletion between nucleotides 1960 and 1970. Sequencing of the 196-bp product gave a cDNA with a 140-bp deletion between positions 1960 and 2099. Both deletions resulted in a frameshift followed by a premature stop codon. Studies of genomic DNA revealed an A-to-G transition at a 3-prime splice acceptor site in affected individuals. This mutation accounted for both aberrant transcripts since the 140-bp deletion resulted from skipping the exon that spans positions 1060 to 2099, while the 11-bp deletion resulted from the use of a cryptic splice site downstream from the normal splice site that had been inactivated. The A-to-G transition mutation introduced a new NlaIV restriction site which was used to screen affected and unaffected individuals.
In a family with hypertrophic cardiomyopathy linked to polymorphic markers on chromosome 11 (CMH4; 115197), Rottbauer et al. (1997) found a mutation of a splice donor site of the MYBPC gene. The mutation, a G-to-A transition at position +1 of the donor splice site of exon N, caused skipping of the associated exon in mRNA from lymphocytes and myocardium. The skipping of the exon with a consecutive reading frameshift led to premature termination of translation and was expected to produce a truncated cardiac myosin-binding protein-C. Western blot analysis of endomyocardial biopsies from histologically affected left ventricular myocardium failed to show the expected truncated protein. The absence of a mutant protein and of significantly reduced amounts of wildtype protein in the presence of the mutated mRNA argued against the 'poison protein' and the 'null allele' hypotheses and suggested yet unknown mechanisms relevant to the genesis of chromosome 11-associated familial hypertrophic cardiomyopathy.
One of the 6 new mutations associated with hypertrophic cardiomyopathy (CMH4; 115197) discovered by Carrier et al. (1997) in 7 unrelated French families was a G-to-A transition at position +5 in intron 7. The G residue is highly conserved at this position in the splice donor consensus sequence. The mutation resulted in skipping of the 49-bp exon 7 and a frameshift. The aberrant cDNA encoded 258 normal residues, followed by 25 new amino acids and a premature termination of translation. This was predicted to produce a large truncated protein, missing approximately 80% of the normal protein and lacking the motif containing the phosphorylation sites and the titin (188840) and myosin (160710)-binding sites.
The second of the 6 new mutations discovered by Carrier et al. (1997) in 7 unrelated French families with hypertrophic cardiomyopathy (CMH4; 115197) was a G-to-C transversion at position 1656 in exon 17 of the MYBPC3 gene. This was found in 2 families and produced the missense change glu542-to-gln in the C3 domain. In addition, the mutation affected the last nucleotide of the exon, which is part of the consensus splicing site. A common feature in human exon/intron boundaries is that 80% of exons finish with a guanine; this proportion is 85% in MYBPC3. As a result exon 17 was skipped. The aberrant cDNA encoded 486 normal residues, leading to a truncated protein that lacked about 62%, including the titin (188840) and myosin (160710)-binding sites.
The third of 6 new mutations discovered by Carrier et al. (1997) in French families with hypertrophic cardiomyopathy (CMH4; 115197) was a G-to-A transition at position +1 in the splice donor site of intron 23 that inactivated the splicing site and produced skipping of the 160-bp exon 23. The mutated cDNA encoded 717 normal residues and then 51 novel amino acids, followed by premature termination of the translation in the C5 domain. The resulting protein was predicted to be truncated with a loss of 44%, including the titin (188840) and myosin (160710)-binding domains.
The fourth of the 6 novel mutations discovered by Carrier et al. (1997) in French families with hypertrophic cardiomyopathy (CMH4; 115197) involved a change from TGAT to TGGT in intron 23. This A-to-G transition inactivated a potential branch point consensus sequence (URAY). Although 3 potential branch points existed upstream from the mutation they did not seem to be used, since analysis of the transcripts in lymphocytes indicated the existence of 2 aberrant cDNAs. One corresponded to skipping of the 105-bp exon 24 without frameshift and encoded a polypeptide depleted of 35 amino acids in the C6 domain. The other cDNA retained the 724-bp intron 23. The mutant cDNA was associated with a frameshift; it encoded 770 normal residues and then 100 novel amino acids, followed by a stop codon, and the corresponding truncated protein was predicted to be missing 40% of its structure and should not react with either titin (188840) or myosin (160710).
The fifth the of 6 novel mutations in the MYBPC3 gene discovered by Carrier et al. (1997) in French families with hypertrophic cardiomyopathy (CMH4; 115197) was a 5-bp deletion (-GCGTC) in exon 25. The deletion produced a frameshift; the aberrant cDNA identified in lymphocytes encoded 845 normal residues and then 35 novel amino acids, followed by premature stop codon in domain C6 that should produce a truncated protein missing 34% and loosing the C-terminal region containing both the titin (188840)- and myosin (160710)-binding sites.
One of the 6 novel mutations in the MYBPC3 gene discovered by Carrier et al. (1997) in French families with hypertrophic cardiomyopathy (CMH4; 115197) was a 12-bp duplication and a 4-bp deletion in exon 33. This modification introduced a frameshift at position 3691 that led to 1,220 normal MyBPC residues and then 19 novel amino acids, followed by a premature stop codon in the last third of the C10 domain. The predicted truncated protein, lacking 4%, should lose part of its myosin (160710) binding site.
In 115 members of 3 families with hypertrophic cardiomyopathy (CMH4; 115197), Niimura et al. (1998) identified a 1-bp insertion in codon 791 (791insG, or 2405insG) in exon 25 of the MYBPC3 gene. Of mutation-positive individuals who underwent examination, only 1 of 19 less than 20 years of age had cardiac hypertrophy, whereas 44 of 72 mutation-positive individuals 20 years old or older had cardiac hypertrophy.
Moolman et al. (2000) reported a large family segregating CMH4 caused by a single base insertion (G) in exon 25 of the MYBPC3 gene. This created a 5-prime splice donor site (AGGTGGG). Moolman et al. (2000) demonstrated that this mutation resulted in the loss of 40 basepairs at the 3-prime end of exon 25 in mRNA extracted from affected myocardium. This in turn led to a premature translation stop and a truncated protein in which the C-terminal binding sites for myosin heavy chain and titin were lost. This study also examined the phenotypic consequences of this mutation in 27 carriers within the same family. Overall, only 15 (56%) showed features of hypertrophic cardiomyopathy. Age of onset of symptoms varied from 29 to 68, with most individuals developing their first symptoms from the fourth decade onwards. The Kaplan-Meier survival curve for this group was similar to that of carriers of the asp175-to-asn tropomyosin-1 mutation (191010.0002) and significantly better than that of carriers of cardiac troponin T2 (191045) or cardiac beta-myosin heavy chain (160760) mutations. Twelve mutation carriers were entirely asymptomatic and had no changes on echocardiography or ECG at the time of the study. This mutation was therefore considered to have considerably reduced penetrance and delayed onset.
In a study of late-onset hypertrophic cardiomyopathy (CMH4; 115197), Niimura et al. (2002) reported an individual with an A-to-G transition at nucleotide 206 of the MYBPC3 gene that was predicted to replace the normal, conserved hydrophilic polar threonine with a hydrophobic nonpolar alanine at amino acid residue 59 (T59A). The individual had no family history of hypertrophic cardiomyopathy.
In a 40-year-old man diagnosed at the age of 36 years with dilated cardiomyopathy (CMD1MM; see 615396), Daehmlow et al. (2002) found heterozygosity for an A-to-C transversion at nucleotide 16575 in exon 27 of the MYBPC3 gene, resulting in an asn948-to-thr (N948T) substitution at a highly conserved residue. Daehmlow et al. (2002) noted that they could not confirm the disease-causing nature of this variant because family members for the calculation of 2-point lod scores could not be obtained for further investigation.
In a family with hypertrophic cardiomyopathy (CMH4; 115197), previously reported by Hengstenberg et al. (1993, 1994), Richard et al. (1999) found that of 8 affected members, 2 had a G-to-T mutation at codon 1096 of the MYBPC3 gene, leading to a TAA termination codon (E1096X); 4 had a G-to-A transition in exon 15 of the MYH7 gene (160760.0033) and 2 were doubly heterozygous for the 2 mutations. The E1096X mutation was predicted to produce a truncated protein without the C-terminal domain, which binds to titin and myosin.
In 16 affected members of 7 families with hypertrophic cardiomyopathy (CMH4; 115197) and in a 71-year-old man with a clinical diagnosis of dilated cardiomyopathy (see 115200), Konno et al. (2003) identified heterozygosity for a G-A transition in exon 25 of the MYBPC3 gene, resulting in an arg820-to-gln (R820Q) substitution at a conserved residue. The mutation was not found in 6 clinically unaffected family members or in 100 controls. The authors suggested that the elderly man with a clinical diagnosis of CMD was in the 'burnt-out' phase of hypertrophic cardiomyopathy; cardiac biopsy showed mild fibrosis, no myocardial hypertrophy, and no myofibrillar disarray. In a follow-up study of this patient, Shimizu et al. (2005) stated that it was unclear whether this patient had 'burnt-out' CMH or had had CMD from the outset.
In a 32-year-old man of Greek Cypriot descent who had mild cardiac hypertrophy (CMH4; 115197) and severe left ventricular outflow tract obstruction treated with left ventricular myectomy, Frank-Hansen et al. (2008) identified heterozygosity for a splice site transition (1224-19G-A) near exon 14 of the MYBPC3 gene. RT-PCR analysis of peripheral blood leukocytes from the patient revealed that the mutation produced a de novo acceptor splice site and extended the transcript by 17 nucleotides, thus introducing a frameshift and premature termination codon in exon 15. The mutation was also identified in 2 other unrelated probands, 1 Indian and 1 British, with mild hypertrophic cardiomyopathy, and was not found in DNA samples from 192 Caucasian controls.
In a 57-year-old woman with hypertrophic cardiomyopathy (CMH4; 115197) involving asymmetric septal hypertrophy with systolic anterior motion, Frank-Hansen et al. (2008) identified compound heterozygosity for 2 mutations in the MYBPC3 gene: a splice site mutation (906-1G-C) near exon 10 and a val1125-to-met (V1125M) substitution (600958.0018). RT-PCR analysis of peripheral blood leukocytes from the patient revealed that the 906-1G-C transversion disrupted the existing 3-prime splice site and activated a neighboring cryptic 3-prime splice site positioned 2 nucleotides downstream, resulting in exclusion of the first 2 bases of exon 10, producing a frameshift and premature termination codon in exon 12. The proband's 64-year-old older sister also carried both mutations, and had asymmetrical septal hypertrophy, right bundle branch block, and left atrium dilatation; her son, the proband's nephew, who had a borderline diagnosis of cardiac hypertrophy, was found to carry only the V1125M mutation. The proband's mother and son carried only the 906-1G-C mutation; her 94-year-old mother had a borderline diagnosis with T-wave inversion in the lateral leads and abnormal Q waves in the high lateral leads on electrocardiogram, but a normal echocardiogram; the 26-year-old son was unaffected, with normal electrocardiogram and echocardiogram. Neither mutation was found in DNA samples from 192 Caucasian controls.
For discussion of the val1125-to-met (V1125M) mutation in the MYBPC3 gene that was found in compound heterozygous state in a patient with hypertrophic cardiomyopathy (CMH4; 115197) by Frank-Hansen et al. (2008), see 600958.0017.
In a south Indian family with mild hypertrophic cardiomyopathy (CMH4; 115197) and another south Indian family with CMH1 (192600) due to mutation in the MYH7 gene (160760), Waldmuller et al. (2003) identified a 25-bp deletion (nt21348-21372) in intron 32 of the MYBPC3 gene, predicted to cause loss of the splicing branch point. Exon 33 sequences in processed mRNA were significantly reduced in COS-1 cells and neonatal rat cardiomyocytes transfected with the deletion but not in cells transfected with wildtype; however, residual normal splicing was observed. Noting that the 25-bp deletion was observed in 16 of 229 unrelated Indian controls from Kerala and Tamil Nadu but not in 270 Caucasians from Russia and western Europe, Waldmuller et al. (2003) suggested that the deletion may represent a regional polymorphism of southern India and may be a modifier enhancing the phenotypes of mutations responsible for disease.
Dhandapany et al. (2009) analyzed the 25-bp MYBPC3 deletion in 354 Indian patients with cardiomyopathy and 238 healthy controls and found an association with cardiomyopathy (odds ratio, 5.3; p = 2 x 10(-6)). The findings were replicated in 446 cases and 466 controls from 6 independent Indian cohorts (combined odds ratio, 6.99; p = 4 x 10(-11)). Analysis of RNA and protein from endomyocardial biopsies of 2 heterozygous individuals revealed 2 transcript structures, a normal transcript and a mutated allele with skipping of the associated exon, but the altered protein was not detected in tissue samples. Expression of mutant and wildtype protein in neonatal rat cardiomyocytes demonstrated a highly disorganized and diffuse pattern of sarcomeric architecture as a result of aberrant incorporation of the mutant protein. Dhandapany et al. (2009) concluded that the 25-bp MYBPC3 deletion is associated with a lifelong increased risk of heart failure.
Dhandapany et al. (2009) tested 63 world population samples, comprising 2,085 individuals from 26 countries, for the 25-bp deletion, and they identified samples heterozygous for the deletion from Pakistan, Sri Lanka, Indonesia, and Malaysia but not in other samples. Haplotype analysis determined that the common 25-bp deletion likely arose approximately 33,000 years ago on the Indian subcontinent.
In 23 Old Order Amish infants with severe neonatal hypertrophic cardiomyopathy (CMH4; 115197), 20 of whom were from the Geauga County settlement in Ohio, Xin et al. (2007) identified homozygosity for a 3330+2T-G transversion in the splice donor site of intron 30 of the MYBPC3 gene, resulting in skipping of the 140-bp exon 30 and causing a frameshift and premature termination in exon 31. The mutation was found in heterozygosity in parents. Heterozygous carrier frequency of this mutation was calculated at 10% in the Geauga County settlement of Ohio. DNA analysis of a Mennonite couple with a child who had died from CMH revealed heterozygosity for the same 3330+2T-G mutation.
In a 28-year-old Australian man with familial hypertrophic cardiomyopathy (CMH4; 115197), Ingles et al. (2005) identified compound heterozygosity for 2 mutations in the MYBPC3 gene: an asp745-to-gly (R745G) substitution in exon 24 and a pro873-to-his (P873H; 600958.0022) substitution in exon 27. The proband was diagnosed at 18 years of age and had severe asymmetric septal hypertrophy on echocardiography and received an implantable cardioverter-defibrillator (ICD). The proband's 13-year-old son also had severe hypertrophy requiring myectomy on 2 occasions and received an ICD. The proband's father and a brother also had CMH, but declined to participate in the study. Chiu et al. (2007) also identified heterozygosity for an R73Q substitution in the CALR3 gene (611414) in this patient and suggested that calreticulin may be involved in both disease pathogenesis and modification.
For discussion of the pro873-to-his (P873H) mutation in the MYBPC3 gene that was found in compound heterozygous state in a patient with familial hypertrophic cardiomyopathy (CMH4; 115197) by Ingles et al. (2005), see 600958.0021.
In a female infant with fatal cardiomyopathy (CMH4; 115197) who also had evidence of skeletal myopathy, Tajsharghi et al. (2010) identified homozygosity for a 2827C-T transition, resulting in an arg943-to-ter (R943X) substitution in the MYBPC3 gene. Skeletal muscle biopsy at 2 months of age showed pronounced myopathic changes with numerous small fibers, which all expressed slow/beta-cardiac myosin heavy chain protein (MYH7; 160760). Electron microscopy revealed disorganization of the sarcomeres and partial depletion of thick filaments in the small fibers; immunohistochemical staining showed the presence of cardiac MYBPC in the small abnormal fibers. RT-PCR and sequencing demonstrated the mutation in transcripts of skeletal muscle. Tajsharghi et al. (2010) noted that cardiac MYBPC is not normally expressed in skeletal muscle, and stated that the reason for the ectopic expression of cardiac MYBPC remained unknown. The R943X mutation had previously been identified in compound heterozygosity with other truncating MYBPC3 mutations in 2 unrelated Dutch infants with fatal hypertrophic cardiomyopathy (Lekanne Deprez et al., 2006); skeletal myopathy was not mentioned in that report.
In 2 affected individuals from a family with dilated cardiomyopathy (CMD1MM; 615396), Hershberger et al. (2010) identified heterozygosity for a 17207G-A transition in exon 25 of the MYBPC3 gene (GenBank NM_000256.3), resulting in an ala833-to-thr (A833T) substitution at a highly conserved residue. The mutation was also identified in 2 unrelated CMD probands, but was not found in 246 controls. Haplotype sharing near the variant suggested a founder mutation. Hershberger et al. (2010) noted that the A833T variant had previously been identified in a family with hypertrophic cardiomyopathy (CMH4; 115197) by Morner et al. (2003); the proband's brother and father had mild cardiac hypertrophy.
In 2 affected individuals from a family with dilated cardiomyopathy (CMD1MM; 615396), Hershberger et al. (2010) identified heterozygosity for a 22608G-T transversion in exon 33 of the MYBPC3 gene (GenBank NM_000256.3), resulting in a cys1264-to-phe (C1264F) substitution at a conserved residue. The mutation was not found in 246 controls.
In a patient with dilated cardiomyopathy (CMD1MM; 615396), Hershberger et al. (2010) reported a heterozygous 11969G-A transition in exon 17 of the MYBPC3 gene (GenBank NM_000256.3), resulting in a gly490-to-arg (G490R) substitution at a highly conserved residue. No family members were available for segregation analysis. Hershberger et al. (2010) noted that the MYBPC3 G490R mutation had previously been associated with hypertrophic cardiomyopathy (CMH4; 115197) by Van Driest et al. (2004) and Morita et al. (2008).
In 2 unrelated white probands of western European descent with left ventricular noncompaction (LVNC10; see 615396), Probst et al. (2011) identified heterozygosity for a c.1523G-A transition in exon 18 of the MYBPC3 gene, resulting in the G490R substitution within the third cardiac-specific Ig-like domain. One proband was a 70-year-old man who presented with dyspnea; family screening revealed that his asymptomatic 32-year-old son was also affected. The other proband was a 24-year-old woman who had been evaluated for syncopal episodes. All 3 mutation-positive individuals had noncompacted segments of the left midventricular inferior and lateral wall on echocardiography.
In a 37-year-old white man of western European descent with left ventricular noncompaction (LVNC10; see 615396) who presented with decompensated congestive heart failure, Probst et al. (2011) identified heterozygosity for a c.2673C-T transition in exon 27 of the MYBPC3 gene, resulting in a pro873-to-leu (P873L) substitution within the seventh cardiac-specific Ig-like domain.
In a white woman of western European descent with left ventricular noncompaction (LVNC10; see 615396), who had nonsustained ventricular flutter and received an implantable cardioverter-defibrillator, Probst et al. (2011) identified heterozygosity for a 2-bp deletion (c.2919_2920delCT) in exon 28 of the MYBPC3 gene, causing a frameshift predicted to result in a premature termination codon in exon 30 (Pro955ArgfsTer95). The mutation was also detected in her 14-year-old unaffected daughter.
In 2 brothers from a consanguineous Chinese family with hypertrophic cardiomyopathy (CMH4; 115197), Wang et al. (2013) identified homozygosity for a c.1469G-T transversion in exon 17 of the MYBPC3 gene, resulting in a gly490-to-val (G490V) substitution at a highly conserved residue. The mutation was present in heterozygosity in their unaffected parents and 4 other unaffected relatives, none of whom had typical clinical manifestations of CMH or any abnormalities on electrocardiography or left ventricular hypertrophy on echocardiography. The mutation was not found in 376 Chinese controls or in the dbSNP or 1000 Genomes public polymorphism databases. Wang et al. (2013) noted that a different mutation at the same residue, G490R (600958.0026), had previously been reported to cause disease in heterozygosity; they proposed that the difference in inheritance pattern might stem from the fact that G490R produces a more prominent structural change by substituting a small side chain for a bulky one and changing the polarity from neutral to basic, whereas G490V keeps the side chain small and polarity neutral.
In 48 Italian patients with hypertrophic cardiomyopathy (CMH4; 115197) from 19 families from the Venuto region of northeastern Italy, Calore et al. (2015) identified heterozygosity for a 2-bp deletion (c.912_913delTT, NM_000256) in the MYBPC3 gene, causing a frameshift predicted to result in a premature termination codon (Phe305ProfsTer27). Haplotype analysis revealed a 1.29-Mb shared haplotype in all probands carrying the 2-bp deletion, indicating that a common founder was likely in these families. Probands carrying the deletion exhibited significantly higher prevalence of nonsustained ventricular tachycardia and implantable cardioverter-defibrillator placement compared to patients without MYBPC3 mutations or with other MYBPC3 mutations. Calore et al. (2015) noted that the overall annual mortality rate of 2% among the 48 affected founder-mutation carriers was higher than that previously described in MYBPC3 carriers and in the general population of CMH patients.
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