Alternative titles; symbols
HGNC Approved Gene Symbol: MYH6
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:23,381,987-23,408,273 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | {Sick sinus syndrome 3} | 614090 | 3 | |
| Atrial septal defect 3 | 614089 | 3 | ||
| Cardiomyopathy, dilated, 1EE | 613252 | Autosomal dominant | 3 | |
| Cardiomyopathy, hypertrophic, 14 | 613251 | Autosomal dominant | 3 |
Cardiac muscle myosin is one of the major components of the sarcomere, the building block of the contractile system of cardiac muscle (summary by Holm et al., 2011). The MYH6 gene encodes the alpha heavy chain subunit of cardiac myosin (alpha-MHC), a fast ATPase primarily expressed in atrial tissue.
Kurabayashi et al. (1988) constructed and characterized 2 types of myosin heavy chain cDNA clones from a fetal human heart cDNA library. Nucleotide and deduced amino acid sequences showed 95.1 and 96.2% homology, respectively. The carboxyl-terminal peptide and 3-prime untranslated regions were highly divergent and specific. They showed that one was transcribed exclusively in the atrium and therefore represented the alpha form of MYHC, whereas the other was predominantly expressed in the ventricle and therefore represented the beta form.
The level of expression of fetal and adult MYH genes varies throughout the life span of the animal and can be modulated reversibly by physiologic conditions such as mechanical overload and level of circulating hormones. Striking nucleotide sequence homology of the mRNAs of adult cardiac, embryonic and adult skeletal MYH suggests that they arose from a common ancestral gene (Mahdavi et al., 1982). (Mahdavi et al. (1982) used the abbreviation MHC for myosin heavy chain, but this presents confusion with the major histocompatibility complex.)
Mahdavi et al. (1984) found that in the rat the alpha and beta genes are organized in tandem and span 50 kilobases of the chromosome. The beta-MYHC gene (MYH7; 160760), predominantly expressed in late fetal life, is located 4 kb upstream from the alpha-MYHC gene, predominantly expressed in the adult. The 2 genes are closely related in nucleotide sequence, suggesting that they have arisen by duplication of a common ancestor, yet their expression in the ventricular myocardium is regulated in an antithetic manner by thyroid hormone. The parallel to hemoglobin genes in anatomic positioning in relation to expression in ontogeny is obvious. The embryonic, newborn, and adult skeletal muscle MYHC genes are also, it seems, organized in a head-to-tail fashion in the order of their developmental expression. Unlike the hemoglobin and immunoglobulin examples in which switches are unidirectional--a gene switched off in a terminally differentiated cell cannot be switched on again--the beta-MYHC gene can be switched on again either spontaneously in older animals or experimentally in response to thyroid hormone depletion/replacement or different mechanical stimuli. The alpha-MYHC gene is expressed also in atrial muscle and the beta-MYHC gene in skeletal slow-twitch muscle.
Buckingham et al. (1986) provided a summary of the actin (see 102540) and myosin multigene families in mouse and man. In both mouse and man, the cardiac and skeletal actin and myosin genes map to different chromosomes (Robert et al., 1985). The only linkage observed is between myosin heavy chain genes expressed sequentially during striated muscle development. Thus, cardiac myosin heavy chain genes map to mouse chromosome 14, whereas the embryonic or early fetal, perinatal and adult myosin heavy chain genes expressed in skeletal muscle are present as a gene cluster on mouse chromosome 11 (Weydert et al., 1985). This suggests that cis-acting factors are important in the sequential expression of these genes during development, whereas transacting factors are implicated in the coexpression of genes in different multigene families in a given phenotype. The myosin heavy chains are coded by a multigene family consisting of at least 10 members. The heavy chains for skeletal muscle myosin are coded by chromosome 17.
Geisterfer-Lowrance et al. (1990) diagrammed the exon map of the cardiac MYHC genes.
Epp et al. (1993) reported the complete nucleotide sequence of the human MYH6 gene, encompassing 26,159 bp as well as the entire 4,484-bp 5-prime flanking intergenic region. The MYH6 gene consists of 39 exons, 37 of which contain coding information. The 5-prime untranslated region is split into 3 exons, with the third exon containing the AUG translation initiation codon. With the exception of intron 13 of the cardiac beta-myosin heavy chain gene (MYH7), which is not present within the alpha-isogene, all exon/intron boundaries are conserved.
Van Rooij et al. (2007) found that microRNA-208 (MIRN208; 611116), a cardiac-specific microRNA encoded by intron 27 of the MYH6 gene, is required for cardiomyocyte hypertrophy, fibrosis, and expression of MYH7 in response to stress and hypothyroidism.
In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6), whereas embryonic cardiomyocytes express beta-MHC (also known as Myh7, 160760). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. Hang et al. (2010) showed that BRG1 (603254), a chromatin-remodeling protein, has a critical role in regulating cardiac growth, differentiation, and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 (608748) and suppressing p57(kip2) (600856) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylases (HDACs; see 601241) and poly(ADP ribose) polymerase (PARP; 173870) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathologic alpha-MHC-to-beta-MHC shift. Preventing Brg1 reexpression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Hang et al. (2010) concluded that their studies showed that BRG1 maintains cardiomyocytes in an embryonic state, and demonstrated an epigenetic mechanism by which 3 classes of chromatin-modifying factors, BRG1, HDAC, and PARP, cooperate to control developmental and pathologic gene expression.
Saez et al. (1987) used a gene-specific oligonucleotide to isolate the beta-myosin heavy chain gene (which is expressed in both cardiac and skeletal muscle) and showed that it is located 3.6 kb upstream of the alpha cardiac myosin gene. By studies in somatic cell hybrids, they showed, furthermore, that the beta and alpha cardiac myosin heavy chain genes are located on chromosome 14. No suggestion of hybridization with human chromosome 17 was detected, contrary to earlier findings (Rappold and Vosberg, 1983). Thus, just as the human skeletal and cardiac alpha-actin genes are located on separate chromosomes (15 and 1, respectively), the myosin genes are on separate chromosomes. As with the beta-myosin heavy chain genes, the cardiac actin gene is coexpressed in adult skeletal muscle. Matsuoka et al. (1988) showed that the MYHCA locus is on chromosome 14 by Southern analysis of human genomic DNA from human-Chinese hamster and human-mouse somatic cell hybrids.
Matsuoka et al. (1989) regionalized the assignments of MYH6 and MYH7 to 14q11.2-q13 by hybridization of probes to DNA from cell lines with deletions or duplications in chromosome 14 and by in situ hybridization. In the mouse, cardiac and skeletal myosin heavy chain genes are syntenic; this is not the case in man. The latter genes are located on human chromosome 17.
Yamauchi-Takihara et al. (1989) showed that the MYHCA and MYHCB genes are tandemly linked in a total length of 51 kb. The MYHCB gene, which is predominantly expressed in ventricle and in slow-twitch skeletal muscle, is located 4.5 kb upstream from the MYHCA gene, which is predominantly expressed in human atrium.
Geisterfer-Lowrance et al. (1990) diagrammed the head-to-tail orientation of the alpha and beta cardiac myosin heavy chain genes showing the beta gene located 5-prime to the alpha gene.
Nadal-Ginard and Mahdavi (1989) reviewed the molecular biology of the cardiac contractile apparatus and emphasized the plasticity in terms of isoform switches in response to physiologic and pathologic stimuli.
Familial Hypertrophic Cardiomyopathy 14
In a 75-year-old woman with late-onset hypertrophic cardiomyopathy (CMH14; 613251), Niimura et al. (2002) identified a heterozygous mutation in the MYH6 gene (R795Q; 160710.0002).
Carniel et al. (2005) analyzed the MYH6 gene in 21 families with hypertrophic cardiomyopathy (CMH) and identified heterozygous missense mutations in 1 CMH14 proband (160710.0004). The mutation was located at a highly conserved residue in the rod domain and was predicted to change the structure of MYHCA.
Dilated Cardiomyopathy 1EE
Carniel et al. (2005) analyzed the MYH6 gene in 69 families with dilated cardiomyopathy (CMD) and identified heterozygosity for 3 different missense mutations in 3 CMD1EE (613252) probands (160710.0005-160710.0007). All of the mutations were located at highly conserved residues, were predicted to change the structure or chemical bonds of MYHCA, and were absent in at least 300 control chromosomes from an ethnically similar population.
Atrial Septal Defect 3
In all affected members of a 4-generation family with atrial septal defect (ASD3; 614089), Ching et al. (2005) found heterozygosity for an ile820-to-asn mutation (I820N; 160710.0003).
Sick Sinus Syndrome Susceptibility
Through complementary application of SNP genotyping, whole genome sequencing, and imputation in 38,384 Icelanders, Holm et al. (2011) identified MYH6 as a susceptibility gene for sick sinus syndrome (SSS3; 614090). A missense variant in this gene (160710.0008), arg721 to trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio of 12.53 and P = 1.5 x 10(-29). Holm et al. (2011) showed that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for noncarriers of this variant but is approximately 50% for carriers of the variant.
Associations Pending Confirmation
In a cohort of 2,871 probands with congenital heart disease, comprising 2,645 parent-offspring trios and 226 singletons, Jin et al. (2017) performed whole-exome sequencing and identified 7 probands with compound heterozygosity or homozygosity for missense, frameshift, splice site, and/or nonsense mutations in the MYH6 gene. Cardiac phenotypes included 4 patients with left ventricular outflow tract obstruction who manifested 'Shone complex' (mitral and aortic valve obstruction with aortic arch obstruction), 1 patient with conotruncal defects and transposition of the great arteries, 1 patient with atrioventricular canal defects, and 1 patient with multiple atrial septal defects with a membranous ventricular septal defect. Other features reported in these patients included learning disabilities in 2, 1 of whom was also reported to have hypothyroidism; the presence or absence of neurodevelopmental disorders was reported as 'unknown' in 3 patients because they were less than 1 year of age.
The human hypertrophic cardiomyopathy-causing mutation MYH7 R403Q (160760.0001) causes particularly severe disease characterized by early-onset and progressive myocardial dysfunction, with a high incidence of cardiac sudden death. MHC(403/+) mice express an R403Q mutation in Myh6 under the control of the endogenous Myh locus. Jiang et al. (2013) found that expression of the Myh6 R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of hypertrophic cardiomyopathy, for at least 6 months. Because inhibition of hypertrophic cardiomyopathy was achieved by only a 25% reduction in the levels of mutant transcripts, Jiang et al. (2013) suggested that the variable clinical phenotype in hypertrophic cardiomyopathy patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.
In a large 4-generation family segregating autosomal dominant familial hypertrophic cardiomyopathy (see CMH1, 192600) with linkage to markers in the region of the cardiac MYHC genes, Solomon et al. (1990) identified a novel restriction fragment in the cardiac MYHC genes of all affected members. Tanigawa et al. (1990) demonstrated that this novel fragment resulted from a Lepore-like alpha/beta cardiac MYHC hybrid gene. Since the mutation affected polypeptides critical to myofibril structure, the mutation was considered to be responsible for the disorder. They suggested that nonhomologous pairing of the alpha and beta cardiac myosin heavy chain genes and an unequal crossover event in or near exon 27 resulted in a hybrid gene as well as complete alpha and beta genes on the same chromosome. Thus the change is more comparable to hemoglobin P(Congo), in which a hybrid beta/delta gene is flanked by complete delta and beta hemoglobin genes (see 141900.0214), than to hemoglobin Lepore, which produces a delta/beta hemoglobin hybrid gene with deletion of both the delta and beta genes. Seidman (1992) later found that in fact this family had a missense mutation in exon 14 of the MYH7 gene (160760) which was probably the cause of the cardiomyopathy because all other affected families have had missense mutations and the family reported by Teare (1958) had the same missense mutation but lacked the fusion gene. The fusion gene has the promoter of the alpha (MYH6) gene and might not be expected to be expressed in the ventricle.
In a 75-year-old woman with late-onset hypertrophic cardiomyopathy (CMH14; 613251), Niimura et al. (2002) identified a heterozygous 2384G-A transition in exon 20 of the MYH6 gene, predicted to result in an arg795-to-glu (R795Q) substitution at a conserved residue within a conserved protein-binding motif through which the myosin heavy chain interacts with essential light chains. Niimura et al. (2002) suggested that substitution of a hydrophilic glutamine residue at this site could exert its effect by interfering with light chain interaction. The mutation was not found in more than 170 unrelated controls.
In all affected members, all obligate carriers, and in 1 other individual from a large family with dominantly inherited atrial septal defect (ASD3; 614089) and no other cardiac abnormalities, Ching et al. (2005) identified a 1849T-A transversion in exon 21 of the MYH6 gene, resulting in an ile820-to-asn (I820N) substitution in the neck region of the protein. This substitution places a polar side chain into an apolar environment, which suggests that the mutant complex is destabilized relative to the wildtype complex. Amino acid 820 was found to be conserved in type II myosins across all species examined; a hydrophilic amino acid at the site corresponding to the mutant residue had not previously been identified. The mutation was not identified in unaffected family members or in 200 chromosomes screened from healthy unrelated individuals.
In a Caucasian proband with hypertrophic cardiomyopathy (CMH14; 613251), who was diagnosed at 27 years of age and died from congestive heart failure at 45 years of age, Carniel et al. (2005) identified a heterozygous 3195G-C transversion in exon 24 of the MYH6 gene, resulting in a gln1065-to-his (Q1065H) substitution at a highly conserved residue of the rod domain. The mutation was not found in 2 unaffected offspring or 150 ethnically similar controls. Family history was significant for sudden death at age 47 years of the proband's affected mother.
In a 75-year-old Caucasian proband with dilated cardiomyopathy (CMD1EE; 613252), Carniel et al. (2005) identified a heterozygous 2489C-T transition in exon 21 of the MYH6 gene, resulting in a pro830-to-leu (P830L) substitution at a highly conserved residue in the globular head of MYHCA, predicted to alter the secondary structure of the light-chain binding domain. The patient was diagnosed at 56 years of age, and had developed congestive heart failure by 75 years of age. The mutation was not found in 150 ethnically similar controls.
In a 59-year-old Caucasian proband with dilated cardiomyopathy (CMD1EE; 613252), Carniel et al. (2005) identified a heterozygous 3010G-T transversion in exon 23 of the MYH6 gene, resulting in an ala1004-to-ser (A1004S) substitution that alters polarity in a highly conserved region of the rod domain. The mutation was not found in 150 ethnically similar controls. The patient was diagnosed at 51 years of age, and developed congestive heart failure by 59 years of age.
In a 57-year-old Caucasian proband with dilated cardiomyopathy (CMD1EE; 613252), Carniel et al. (2005) identified a heterozygous 4369G-A transition in exon 31 of the MYH6 gene, resulting in a glu1457-to-lys (E1457K) substitution at a highly conserved residue. This change was predicted to alter the alpha-helix of the rod domain, changing the conformation of a 4-amino acid region from an organized alpha-helix to a random-coil pattern. The mutation was not found in an unaffected relative or in 150 ethnically similar controls. The patient was diagnosed at 44 years of age, and had undergone heart transplantation by 57 years of age.
In a study of 38,384 Icelanders using complementary application of SNP genotyping, whole-genome sequencing, and imputation, Holm et al. (2011) identified a C-to-T transition at nucleotide 2161 (2161C-T) in exon 18 of the MYH6 gene, resulting in an arginine-to-tryptophan substitution at codon 721 (R721W), as a mutation predisposing to sick sinus syndrome (SSS3; 614090) (odds ratio = 12.53, 95% CI, 8.08-19.44, P = 1.5 x 10(-29)). The 2161C-T mutation was predicted to alter the structure of the converter domain of alpha-MHC, which plays a critical role in amplifying the structural rearrangements in the motor domain and transmitting them to the alpha-helical tail during movements of the myosin during contraction. Among Icelanders, the allelic frequency of this variant is 0.38%. Holm et al. (2011) showed that while the lifetime risk of being diagnosed with sick sinus syndrome is approximately 6% for noncarriers, the risk for carriers of being diagnosed is approximately 50%. There was also a significant association (P = 3.6 x 10(-25), OR = 10.17, 95% CI, 6.56-15.77) between the 2161C-T variant and the necessity for pacemaker implantation. There was a residual association, after exclusion of sick sinus syndrome cases, with several diseases, including atrial fibrillation and thoracic aortic aneurysm.
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