Alternative titles; symbols
HGNC Approved Gene Symbol: MYH7
SNOMEDCT: 129620000, 764859001; ICD10CM: G71.09;
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:23,412,740-23,435,660 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Cardiomyopathy, dilated, 1S | 613426 | Autosomal dominant | 3 |
| Cardiomyopathy, hypertrophic, 1 | 192600 | Autosomal dominant; Digenic dominant | 3 | |
| Congenital myopathy 7A, myosin storage, autosomal dominant | 608358 | Autosomal dominant | 3 | |
| Congenital myopathy 7B, myosin storage, autosomal recessive | 255160 | Autosomal recessive | 3 | |
| Laing distal myopathy | 160500 | Autosomal dominant | 3 | |
| Left ventricular noncompaction 5 | 613426 | Autosomal dominant | 3 |
The MYH7 gene encodes the beta-cardiac/slow skeletal myosin heavy chain (MyHC-slow), expressed predominantly in the cardiac ventricles and slow skeletal (type 1) myofibers. Myosin acts as a molecular motor through its interaction with actin of the thin filament, which is vital for skeletal muscle force generation (summary by Beecroft et al., 2019).
The structural gene for the beta heavy chain of myosin is expressed predominantly in fetal life and is switched on in older animals under conditions of thyroid hormone depletion/replacement and in response to some physical stresses. Jandreski et al. (1987) presented evidence indicating that the cardiac beta-myosin heavy chain mRNA is expressed in skeletal muscle tissue. The expression of cardiac beta-myosin heavy chain mRNA was particularly prominent in the soleus muscle, which is rich in slow-twitch type I muscle fibers. There were only trace amounts in the vastus lateralis and vastus medialis, which consist predominantly of fast-twitch type II fibers.
Diederich et al. (1989) cloned the entire gene.
By scanning mouse myosin genes for intronic microRNAs (miRNAs), van Rooij et al. (2009) identified Mir208b (613613) within intron 31 of the Myh7 gene. Northern blot analysis showed that Myh7 and Mir208b were highly expressed in mouse slow-twitch soleus muscle. Little to no expression was detected in heart and in the fast-twitch gastrocnemius/plantaris, tibialis anterior, and extensor digitorum longus muscles. However, van Rooij et al. (2009) noted that Myh7 is the predominant myosin in adult heart in large animals, whereas Myh6 (160710) predominates in adult mouse heart.
Jaenicke et al. (1990) demonstrated that the MYH7 gene is 22,883 bp long. The 1,935 amino acids of this protein are encoded by 38 exons. The 5-prime untranslated region (86 bp) is split by 2 introns. The 3-prime untranslated region is 114 bp long. Three Alu repeats were identified within the gene and a fourth one in the 3-prime flanking intergenic region.
Liew et al. (1990) found that like the rat skeletal myosin heavy chain gene, the cardiac beta-myosin heavy chain gene is divided into 41 exons, the first 2 of which are noncoding. However, exons 37 and 38 are fused; they do not have an intervening intron. The gene extends for 21,828 nucleotides and encodes a deduced 1,1939-amino acid protein with a molecular mass of 222,937 Da.
Van Rooij et al. (2009) identified a microRNA (miRNA), Mir208b (613613), within intron 31 of the mouse Myh7 gene.
Matsuoka et al. (1989) found that both the alpha and the beta human cardiac myosin heavy chain genes are located in the 14cen-q13 region; the assignment was by somatic cell hybridization and in situ hybridization. Qin et al. (1990) localized the MYH7 gene to 14q12 by in situ hybridization.
The beta cardiac myosin heavy chain is located on chromosome 14, 3.6 kb upstream from the alpha cardiac myosin gene. The 2 genes are oriented in a head-to-tail tandem fashion (Yamauchi-Takihara et al., 1989; Geisterfer-Lowrance et al., 1990).
Van Rooij et al. (2007) found that miRNA208A (MIR208A; 611116), a cardiac-specific miRNA encoded by intron 27 of the mouse and human MYH6 gene, was required for cardiomyocyte hypertrophy, fibrosis, and expression of Myh7 in response to stress and hypothyroidism in mice.
Van Rooij et al. (2009) found that expression of Myh7 and its intronically encoded miRNA, Mir208b, was upregulated in mouse heart by hypothyroidism caused by inhibition of triiodothyronine (T3; see 188450) synthesis. This upregulation was reversed by T3 administration. Gain- and loss-of-function experiments in mice showed that expression of Myh7 and Mir208b was controlled by the dominant miRNA in mouse heart, Mir208a. However, van Rooij et al. (2009) noted that, in large animals, Myh7 is the predominant myosin in adult heart. In contrast, the predominant myosin in adult mouse heart is Myh6, the host gene of Mir208a. Thus, van Rooij et al. (2009) suggested that Mir208b, which shares the same seed sequence as Mir208a, may fulfill the function of Mir208a in large animals.
In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6; 160710), whereas embryonic cardiomyocytes express beta-MHC (Myh7). 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.
Hypertrophic Cardiomyopathy 1
McKenna (1993) estimated that 40 to 50% of cases of hypertrophic cardiomyopathy (CMH; 192600) are due to mutations in the MYH7 gene. He stated that Kaplan-Meier survival curves for these mutations showed that the val606-to-met mutation (160760.0005) was associated with normal survivorship, whereas the arg453-to-cys mutation (160760.0003) was associated with death in about half the affected individuals by age 40 years.
Anan et al. (1994) presented a schematic of 15 mutations within the MYH7 gene that cause CMH. They described a phe513-to-cys mutation (160760.0016) in which affected family members had near-normal life expectancy, and an arg719-to-trp mutation (160760.0017) in 4 unrelated CMH families with a high incidence of premature death and an average life expectancy in affected individuals of 38 years. They suggested that these findings supported the hypothesis that mutations that alter the charge of the encoded amino acid affects survival more significantly than those that produce a conservative amino acid change. Kelly and Strauss (1994) pointed out that all but one of the known mutations of the MYH7 gene that produce hypertrophic cardiomyopathy result in amino acid substitutions in the protein head or the region in which the head and rod of the molecule intersect. In their Figure 2, they diagrammed the cardiac myosin heavy-chain dimer and the site of the mutations. They suggested that these mutations represent dominant negatives by disturbing contractile function despite the production of a normal protein by the remaining normal allele. Consistent with this conclusion is the finding of Cuda et al. (1993) that mutant beta-myosin separated from the heart muscle in cases of hypertrophic cardiomyopathy of the chromosome 14 type translocate actin filaments with an abnormally low sliding velocity in motility assays in vitro.
Lankford et al. (1995) compared the contractile properties of single slow-twitch muscle fibers from patients with 3 distinct CMH-causing MYH7 mutations with those from normal controls. Fibers from the gly741-to-arg mutation (160760.0011), located near the binding site of essential light chain, demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal). Fibers with the arg403-to-gln mutation (160760.0001) (at the actin interface of myosin) showed lower force/stiffness ratio (56% of normal) and depressed velocity of shortening (50% of normal). Both of these mutation-containing fibers displayed abnormal force-velocity relationships and reduced power output. Fibers from the gly256-to-glu mutation (160760.0012), located at the end of the ATP-binding pocket, had contractile properties that were indistinguishable from normal. Thus, variability was found in the nature and extent of functional impairments in skeletal fibers containing different MYH7 gene mutations, and this variability may correlate with the severity and penetrance of the disease resulting from each mutation.
Rayment et al. (1995) examined 29 missense mutations in the MYH7 gene that are responsible for 10 to 30% of familial hypertrophic cardiomyopathy cases and analyzed their effects on the 3-dimensional structure of skeletal muscle myosin. Arai et al. (1995) reported a thirtieth missense mutation and stated that these had been found in 49 families worldwide at that time. Almost all were located in the region of the gene coding for the globular head of the molecule and only 1 mutation was found in both Caucasian and Japanese families.
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.
Woo et al. (2003) screened 70 probands with hypertrophic cardiomyopathy for mutations in the beta-MHC gene. Mutations in this gene were detected in 15 of 70 probands (21%). Eleven mutations were detected, including 4 novel mutations. Median survival was 66 years (95% CI 64 to 77 years) in all affected subjects. There was a significant difference in survival between subjects according to the affected functional domain. Significant independent predictors of decreased survival were the nonconservative missense mutations that affected the actin binding site and those that affected the rod portion of beta-MHC.
Hougs et al. (2005) screened for mutations in the rod region (exons 24 to 40) of MYH7 in 92 Danish patients with hypertrophic cardiomyopathy. Using capillary electrophoresis single-strand conformation polymorphism, 3 disease-causing mutations of the rod region were identified in 4 patients, including the R1712W (160760.0032) mutation in 2 patients. Two of the patients had already been shown to carry other FHC-associated mutations.
Arad et al. (2005) identified 2 different MYH7 missense mutations in 2 probands with apical hypertrophy from families in which the mutations also caused other CMH morphologies (see 160760.0038 and 160760.0039, respectively), and 1 in a sporadic patient with apical hypertrophy (R243H; 160760.0040).
In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a missense mutation in the JPH2 gene (605267.0004); subsequent analysis of 15 known CMH-associated genes revealed that the proband also carried 2 mutations in MYH7, F513C (160760.0016) and A26V. The authors suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband.
In a 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified a heterozygous mutation in the TNNI3 gene (P82S; 191044.0003) and a heterozygous mutation in the MYH7 gene (R453S; 160760.0043).
From 2000 to 2012, Das et al. (2014) studied a total of 136 unrelated hypertrophic cardiomyopathy probands, of which 63 (46%) carried at least 1 pathogenic mutation. MYBPC3 (600958) accounted for 34 patients, or 47%, and MYH7 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.
Dilated Cardiomyopathy 1S
Kamisago et al. (2000) performed clinical evaluations in 21 kindreds with familial dilated cardiomyopathy (CMD1S; 613426). In a genomewide linkage study, a genetic locus for mutations associated with dilated cardiomyopathy was identified at chromosome 14q11.2-q13 (maximum lod score = 5.11 at theta = 0.0). Analysis of MYH7 and other genes for sarcomere proteins revealed heterozygous missense mutations in MYH7 in 2 kindreds (S532P, 160760.0022 and P764L, 160760.0023, respectively). Affected individuals had neither antecedent cardiac hypertrophy nor histopathologic findings characteristic of hypertrophy.
Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins (lys36 to gln in TNNI3 (191044.0012), gly159 to asp in TNNC1 (191040.0001), and glu1426 to lys in MYH7), and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM.
Left Ventricular Noncompaction 5
Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in 63 unrelated adult probands with left ventricular noncompaction (LVNC) but no other congenital heart anomalies (see LVNC5; 613426), and identified 7 different heterozygous mutations in the MYH7 gene in the probands from 4 families and in 4 sporadic patients (see, e.g., 160760.0040-160760.0042). Klaassen et al. (2008) noted that 5 of the 7 mutations were located within the genomic sequence of exon 8 to exon 9 of MYH7, which appeared to be a cluster for LVNC mutations.
In a mother with myosin storage myopathy, who later developed CMH, and in her daughter, who had early-symptomatic LVNC, Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7 (160760.0037).
In an analysis of the MYH7 gene in 141 white probands of western European descent diagnosed with Ebstein anomaly (see 224700), Postma et al. (2011) identified heterozygous mutations in 8 (see, e.g., 160760.0045 and 160760.0046). Of these 8 probands, LVNC was present in 7 and uncertain in 1, whereas none of the 133 mutation-negative probands had LVNC. Evaluation of all available family members of mutation-positive probands revealed 3 families in which additional mutation-positive individuals had cardiomyopathy or congenital heart malformations, including type II atrial septal defect, ventricular septal defect, bicuspid aortic valve, aortic coarctation, and pulmonary artery stenosis/hypoplasia.
For a detailed discussion of a family with left ventricular noncompaction (LVNC) that segregated with mutations in the MYH7, MKL2 (609463), and NKX2-5 (600584) genes, see LVNC5 (613426).
Laing Distal Myopathy
Laing et al. (1995) mapped Laing distal myopathy (MPD1; 160500) to chromosome 14. In affected members of 7 separate families with Laing distal myopathy, Meredith et al. (2004) sequenced the MYH7 gene, a positional candidate for the site of the causative mutation. They identified 5 heterozygous mutations in 6 families (see 160760.0029-160760.0030) and no mutations in the seventh family. All 5 mutations were predicted, by in silico analysis, to disrupt locally the ability of the myosin tail to form a coiled coil, which is its normal structure. The findings demonstrated that heterozygous mutations toward the 3-prime end of MYH7 can cause Laing distal myopathy.
Autosomal Dominant Myosin Storage Congenital Myopathy 7A
In affected members of a family and in an unrelated patient with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358), Tajsharghi et al. (2003) identified a heterozygous missense mutation in the MYH7 gene (R1845W; 160760.0028).
In affected members of a Saudi Arabian family with autosomal dominant CMYP7A Bohlega et al. (2003), Bohlega et al. (2004) identified a heterozygous mutation in the MYH7 gene (H1904L; 160760.0031).
In a Belgian patient with myosin storage myopathy, originally reported by Ceuterick et al. (1993), Laing et al. (2005) identified a heterozygous mutation in the MYH7 gene (R1845W; 160760.0028).
In 1 of the affected sibs with congenital myopathy originally reported by Cancilla et al. (1971), Dye et al. (2006) identified a heterozygous mutation in the MYH7 gene (L1793P; 160760.0037), confirming that the disease in that family was autosomal dominant myosin storage myopathy (CMYP7A). Dye et al. (2006) noted that contact with the family had been lost and DNA studies were performed on archival postmortem sections from the affected sister who died at age 25 years. The sibs presumably had the disease because of gonadal mosaicism in 1 of the unaffected parents, although this could not be confirmed.
In a large multigenerational family (family A) in which 9 individuals had variable manifestations of CMYP7A, Pegoraro et al. (2007) identified a heterozygous missense mutation in the MYH7 gene (R1845W; 160760.0028). Two affected members of another family (family B) carried the same heterozygous mutation.
In 12 affected members of a 5-generation Spanish family previously reported by Sobrido et al. (2005) with CMYP7A, Ortolano et al. (2011) identified a heterozygous mutation in the C-terminal region of the MYH7 gene (160760.0048). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. It was not present in 202 population controls. Two skeletal muscle samples studied had normal expression of type I and II myosin heavy chains, but only a younger patient showed decreased MYH7 transcript levels compared to controls.
In a mother with myosin storage myopathy, who later developed CMH, and in her daughter, who had early-symptomatic LVNC, Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7 (160760.0037).
Armel and Leinwand (2009) analyzed the functional effects of 4 different heterozygous MYH7 mutations in the rod or tail domain that were found to be responsible for myosin storage myopathy: R1845W (160760.0028), H1901L (160760.0031), E1886K (160760.0035), and L1793P (160760.0037). None of the mutations altered the secondary structure of the protein, but L1793P and H1901L showed decreased thermodynamic stability. All mutations decreased the extent of self-assembly of the light meromyosin rod (less than 50 to 60%) compared to the wildtype protein. R1845W and H1901L showed formation of more stable and larger filaments, whereas L1793P and E1886K showed more rapid filament degradation. Armel and Leinwand (2009) noted that the assembly of muscle filaments is a multistep process that involves both the proper folding of alpha-helices into coiled-coils, and the assembly of these coiled-coils, in proper register, into filaments, and concluded that defects in any one of these steps can result in improper filament formation leading to muscle disease.
In a review, Tajsharghi and Oldfors (2013) noted that mutations causing CMYP7A are usually found in the distal rod region of the MYH7 gene.
Autosomal Recessive Myosin Storage Congenital Myopathy 7B
In the proband of a consanguineous British family in which 3 sibs with autosomal recessive myosin storage congenital myopathy-7B (CMYP7B; 255160) developed hypertrophic cardiomyopathy and respiratory failure, Tajsharghi et al. (2007) identified a homozygous missense mutation in the MYH7 gene (E1886K; 160760.0035).
In 2 Turkish brothers, born of related parents, with CMYP7B, who were originally reported by Onengut et al. (2004), Yuceyar et al. (2015) identified a homozygous missense mutation in the MYH7 gene (R1820W; 160760.0047). The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family; functional studies of the variant were not performed. Both patients had young adult onset of scapuloperoneal weakness and atrophy; 1 brother developed severe dilated cardiomyopathy in his forties, whereas the other had milder cardiac symptoms.
In 3 patients from 2 unrelated families with CMYP7B, Beecroft et al. (2019) identified homozygous or compound heterozygous mutations in the MYH7 gene. Two sibs from a consanguineous family (AUS1) carried a homozygous missense mutation (R1712W, 160760.0032), and an unrelated woman (UK1) was compound heterozygous for a nonsense and a missense mutation (Q1567X, 160760.0049 and E1555G, 160760.0050). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent in both families. None were present in the gnomAD database.
Geisterfer-Lowrance et al. (1996) engineered the human CMH cardiac myosin heavy chain gene mutation arg403-to-gln (R403Q; 160760.0001) into the mouse genome to create a murine model of familial hypertrophic cardiomyopathy. Homozygous mice died within a week after birth, while heterozygous mice displayed both histologic and hemodynamic abnormalities characteristic of CMH. In addition, the CMH mice demonstrated gender and developmental differences. Male CMH mice demonstrated more severe myocyte hypertrophy, disarray, and interstitial fibrosis than their female littermates, and both sexes showed increased cardiac dysfunction and histopathology as they aged. Heterozygous CMH mice also had sudden death of uncertain etiology, especially during periods of exercise. Berul et al. (1997) found that in contrast to wildtype mice which had completely normal cardiac electrophysiology, CMH mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiologic abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy.
Fatkin et al. (1999) reported further studies of the CMH mouse in which the arg403-to-gln mutation had been introduced by homologous recombination. Heterozygous mice developed myocardial histologic abnormalities similar to those in human CMH by 15 weeks of age. Sedentary heterozygous mice had a normal life span. Homozygous mutant mice were liveborn, but, unlike their heterozygous littermates, all died within 1 week. Fatkin et al. (1999) found that neonatal lethality was caused by a fulminant dilated cardiomyopathy characterized by myocyte dysfunction and loss. They studied cardiac dimensions and functions for the first time in neonatal mice by high frequency (45 MHz) echocardiography and found that both were normal at birth. Between days 4 and 6, homozygous deficient mice developed a rapidly progressive cardiomyopathy with left ventricular dilation, wall thinning, and reduced systolic contraction. Histopathology revealed myocardial necrosis with dystrophic calcification. Electron microscopy showed normal architecture intermixed with focal myofibrillar disarray. Fatkin et al. (1999) speculated that variable incorporation of mutant and normal MYHC into sarcomeres of heterozygotes may account for focal myocyte death in familial hypertrophic cardiomyopathy.
In R403Q-knockin mice, Gao et al. (1999) observed that during twitch contractions, peak intracellular Ca(2+) was higher in mutant muscles than in wildtype muscles, but force development was equivalent in both. Developed force fell at higher stimulation rates in the mutants but not in controls. Gao et al. (1999) concluded that calcium cycling and myofilament properties are both altered in CMH mutant mice.
Marian et al. (1999) created a transgenic rabbit model of hypertrophic cardiomyopathy by injecting a transgene carrying the R403Q mutation into fertilized zygotes. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in the myocardium. Mean septal thickness was comparable between rabbits carrying the wildtype transgene and nontransgenic littermates, but was significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wildtype transgenic rabbits or in nontransgenic littermates. Thus, the phenotype of patients with the R403Q mutation of the MYH7 was reproduced.
To minimize confounding variables while assessing relationships between CMH histopathology and arrhythmia vulnerability, Wolf et al. (2005) generated inbred CMH mice carrying the R403Q mutation and observed variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of fibrosis and myocyte disarray. There was no correlation between the amount and/or pattern of fibrosis or the quantity of myocyte disarray and the propensity for arrhythmia as assessed by ex vivo high-resolution mapping and in vivo electrophysiologic study; however, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. Wolf et al. (2005) concluded that the 3 cardinal manifestations of CMH (cardiac hypertrophy, myocyte fibrosis, and disarray) reflect independent pathologic processes within myocytes carrying a sarcomere gene mutation and that the severity of fibrosis and disarray is substantially influenced by unknown somatic factors, and they suggested that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in CMH.
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 (160710) 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.
Green et al. (2016) identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. They demonstrated that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis, and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations (e.g., R403Q, 160760.0001; R453C, 160760.0003; and R719W, 160760.0017) in the myosin heavy chain. (Because adult mouse cardiomyocytes primarily express alpha-myosin heavy chain, and because the mouse alpha chain is 92% identical to the human beta chain, these mutations were introduced into the mouse Myh6 gene.) These data indicated that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
In the large French-Canadian kindred originally reported by Pare et al. (1961) and shown to have linkage of the cardiac disorder (CMH1; 192600) to markers on the proximal portion of 14q, Geisterfer-Lowrance et al. (1990) found a missense mutation in the beta cardiac myosin heavy chain that converted arginine-403 to glutamine (R403Q). A guanine residue at position 10,162 (enumerated as in Jaenicke et al., 1990) was mutated to an adenine residue. The mutation generated a new DdeI site and changed the CGG(arg) codon to CAG(gln). Perryman et al. (1992) found that the R403Q mutation was identifiable in myocardial mRNA. Ross and Knowlton (1992) reviewed this discovery beginning with the patients first seen by Pare in the 1950s.
Using an isolated, isovolumic heart preparation where cardiac performance was measured simultaneously with cardiac energetics using (31)P nuclear magnetic resonance spectroscopy, Spindler et al. (1998) studied the effects of the codon 403 missense mutation. They observed 3 major alterations in the physiology and bioenergetics of the mutant mouse hearts. First, while there was no evidence for systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions the mutant R403Q mouse hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, mutant hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wildtypes. The authors concluded that the hearts from mice carrying the R403Q mutation have workload-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggested that an energy-requiring process may contribute to the observed diastolic dysfunction.
Bashyam et al. (2003) pointed out that polymorphism in the ACE1 gene (106180) had been shown to affect the prognosis in familial hypertrophic cardiomyopathy. The DD allele of the ACE1 gene (106180.0001) was associated with a severe form of hypertrophy and sudden death in patients with familial hypertrophic cardiomyopathy (Iwai et al., 1994). Tesson et al. (1997) established an association of the D allele at the ACE1 locus with the R403Q mutation in MYH7, but not with MYBPC3 (600958) mutations.
Using a ribonuclease protection assay, Watkins et al. (1992) screened the beta cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy (CMH1; 192600). Seven different mutations were identified in 12 of the 25 families; see 160760.0003-160760.0007. All were missense mutations; 5 were clustered in the head of the beta-chain, which comprises the 5-prime 866 amino acids, and 2 were located in the 5-prime or hinge portion of the rod part. Six of the mutations resulted in a change in the charge of the amino acid. These patients had a shorter life expectancy (mean age at death, 33 years) than did patients with the one mutation that did not produce a change in charge, val606-to-met. One of the mutations they found was a substitution of glutamine for arginine-249.
See 160760.0002. Watkins et al. (1992) found substitution of cysteine for arginine-453 in 2 unrelated families with familial hypertrophic cardiomyopathy (CMH1; 192600). One of the families also had an alpha/beta cardiac myosin heavy chain hybrid gene which was presumably of no functional significance, inasmuch as the 5-prime promoter region was derived from the alpha subunit.
In a 3-generation Chinese family, Ko et al. (1996) observed the coexistence of sudden death and end-stage heart failure due to the arg453-to-cys mutation. The average age of death in affected members of the family was 34 years.
See 160760.0002. Watkins et al. (1992) found the gly584-to-arg mutation in 2 unrelated families with familial hypertrophic cardiomyopathy (CMH1; 192600).
See 160760.0002. Watkins et al. (1992) found this mutation in 3 unrelated families with familial hypertrophic cardiomyopathy (CMH1; 192600). Of the 7 mutations they found, this was the only one that produced no change in the charge of the amino acid. Although the affected patients did not differ in other clinical manifestations of familial hypertrophic cardiomyopathy, patients in this family had nearly normal survival; mean age at death was 33 years in the 11 families with one or another mutation that substituted an amino acid with a different charge.
Blair et al. (2001) identified the val606-to-met mutation in a family in which 2 individuals had suffered sudden death at an early age. The mutation was found to be in cis with an ala728-to-val (A728V) mutation (160760.0025).
See 160760.0002. Watkins et al. (1992) found this mutation in 1 family with familial hypertrophic cardiomyopathy (CMH1; 192600). The mutation was found in exon 23 by RNase protection assay. It occurred as a new mutation in a 44-year-old female; the parents lacked the mutation which, however, was transmitted to her 24-year-old daughter.
See 160760.0002. Watkins et al. (1992) found this mutation in 1 family with familial hypertrophic cardiomyopathy (CMH1; 192600).
Among 7 individuals with sporadic hypertrophic cardiomyopathy (CMH1; 192600), Watkins et al. (1992) identified mutations in the beta cardiac MHC genes in 2. Since the parents were neither clinically nor genetically affected, the authors concluded that the mutations in each proband arose de novo. Transmission of the mutation and disease to an offspring occurred in 1 pedigree (160760.0006), predicting that these were germline mutations. One proband, a 40-year-old female, was shown by RNase protection assay to have a C-to-T transition in exon 20 at nucleotide 2253, leading to a change from arginine to cysteine at codon 723. Arginine residue 723 is conserved among all known cardiac MHCs and all vertebrate striated muscle MHCs except the human perinatal and rabbit skeletal isoforms; mutation of a cysteine residue constitutes a nonconservative substitution with a change in net charge.
In a family with several members affected with hypertrophic cardiomyopathy (CMH1; 192600), Marian et al. (1992) identified a novel 9.5-kb BamHI RFLP detected by an MYH7 probe on Southern blots of DNA from the proband. PCR was used to amplify the segment of the gene; sequence analysis showed a 2.4-kb deletion involving 1 allele. The deletion included part of intron 39, exon 40 including the 3-prime untranslated region and the polyadenylation signal, and part of the region between the beta and alpha myosin heavy chain genes. The deletion was inherited by 2 daughters of the proband and a grandson, aged 33, 32, and 10 years, respectively, who were, however, free of signs of the disorder. The 67-year-old proband had late onset of the disorder which was first diagnosed in him at the age of 59 when he presented with atypical chest pain, lightheadedness, and decreased exercise tolerance. On cardiac examination, he showed an S4 heart sound and a systolic ejection murmur. EKG showed left ventricular hypertrophy with repolarization abnormalities. Ventricular hypertrophy was demonstrated by echocardiogram which also showed systolic anterior motion of the anterior leaflet of the mitral valve. There was a 25-mm Hg left ventricular outflow tract gradient. From observations in C. elegans, it was predicted that an unstable mRNA might result from this mutation.
Fananapazir et al. (1993) found evidence, on soleus muscle biopsy, of central core disease (117000) in 10 of 13 hypertrophic cardiomyopathy (CMH1; 192600) patients with the leu908-to-val mutation. Although the mutations in the MYH7 gene were associated with skeletal muscle changes characteristic of central core disease, such was not found in patients with hypertrophic cardiomyopathy unlinked to MYH7. Notably, in 1 branch of a family with the L908V mutation, 2 adults and 3 children had histologic changes of central core disease without evidence of cardiac hypertrophy by echocardiogram. One of the adults had skeletal myopathic changes. McKenna (1993), who stated that he had never seen clinical evidence of skeletal myopathy in patients with CMH1, doubted the significance of the findings.
In 1 of 3 patients with hypertrophic cardiomyopathy (CMH1; 192600) and the G741R mutation, Fananapazir et al. (1993) found microscopic changes of central core disease on soleus muscle biopsy.
In 1 patient with the G256E mutation and familial hypertrophic cardiomyopathy (CMH1; 192600), Fananapazir et al. (1993) found histologic changes on soleus muscle biopsy consistent with central core disease.
In 5 unrelated Japanese patients and their affected family members with hypertrophic cardiomyopathy (CMH1; 192600), Harada et al. (1993) used PCR-DNA conformation polymorphism analysis to detect an A-to-G transition at codon 778 leading to replacement of the asp residue by gly (asp778 to gly, D778G).
In 2 French pedigrees with familial hypertrophic cardiomyopathy (CMH1; 192600), Dausse et al. (1993) performed linkage analysis using 2 microsatellite markers located in the MYH7 gene, as well as 4 highly informative markers that mapped to the 14q11-q12 region. Linkage to the markers was found in pedigree 720, but results were not conclusive for pedigree 730. Haplotype of 6 markers allowed identification of affected individuals and of some unaffected subjects who were carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing: arg403 to leu (R403L) and arg403 to trp (R403W) in families 720 and 730, respectively. The arg403-to-leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the arg403-to-trp mutation appeared to be less severe. Codon 403 of the MYH7 gene appears, therefore, to be a hotspot for mutations causing CMH. The first mutation identified in this disorder involved codon 403 (160760.0001).
See 160760.0014.
In a family of Japanese ancestry in which a mild form of familial hypertrophic cardiomyopathy (CMH1; 192600) occurred, Anan et al. (1994) found a 1624T-G transversion in exon 15, resulting in a phe513-to-cys (F513C) substitution. The F513C mutation did not alter the charge of the encoded amino acid, which may be related to the finding of near-normal life expectancy in this family.
In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a missense mutation in the JPH2 gene (605267.0004); subsequent analysis of 15 known CMH-associated genes revealed that the proband also carried 2 heterozygous mutations in MYH7, F513C and A26V. Her newborn son, who had no signs of CMH on echocardiography at 1 day of age, carried both the JPH2 G505S mutation and the MYH7 A26V mutation. The authors suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband.
In 4 unrelated families with hypertrophic cardiomyopathy (CMH1; 192600) with a high incidence of premature death and an average life expectancy in affected individuals of 38 years, Anan et al. (1994) found an R719W mutation in exon 19 changing the charge of the amino acid by -1. The difference in survival of individuals bearing the R719W mutation as compared with those with the F513C mutation (160760.0016) was demonstrated by Kaplan-Meier product-limit curves (their Figure 4).
In a 6.5-year-old boy with a severe form of hypertrophic cardiomyopathy, Jeschke et al. (1998) identified 2 missense mutations: one was the R719W mutation and the other was an M349T mutation (160760.0020), which was inherited through the maternal grandmother. Six family members who were carriers of the M349T mutation were clinically unaffected. The authors hypothesized that compound heterozygosity for the R719W and M349T mutations resulted in the particularly severe phenotype of early onset.
In a small family from the U.K. in which 2 individuals affected by hypertrophic cardiomyopathy (CMH1; 192600) were alive, including one who had been resuscitated after sudden death at age 19, Anan et al. (1994) found a G-to-A transition at nucleotide 2232 resulting in a gly716-to-arg (G716R) substitution (charge change = +1) of the encoded amino acid.
In 2 brothers with hypertrophic cardiomyopathy (CMH1; 192600) who died in their thirties, Nishi et al. (1994) found a G-to-A transition in codon 935 of the MYH7 gene, leading to a replacement of glutamic acid with lysine. The brothers were homozygous, whereas the parents, who were first cousins, were heterozygous for the mutation and had cardiac hypertrophy without clinical symptoms. An elder sister was also heterozygous for the mutation but did not manifest cardiac hypertrophy. Nishi et al. (1994) suggested that there was a gene dosage effect on clinical manifestations in this family.
For discussion of a met349-to-thr (M349T) mutation in the MYH7 gene that was found in compound heterozygous state in a patient with hypertrophic cardiomyopathy (CMH1; 192600) by Jeschke et al. (1998), see 160760.0017.
In a study of mutations causing hypertrophic cardiomyopathy (CMH1; 192600) in 2 South African subpopulations, Moolman-Smook et al. (1999) identified an arg719-to-gln (R719Q) mutation in the MYH7 gene. The mutation occurred in a family of white ancestry and had previously been described by Watkins et al. (1992) in a Canadian family. The codon is the same as that involved in the arg719-to-trp mutation (160760.0017).
In a family with familial dilated cardiomyopathy-1S (CMD1S; 613426), Kamisago et al. (2000) demonstrated a T-to-C change at nucleotide 1680 in exon 16 of the cardiac beta-myosin heavy chain gene, causing a ser532-to-pro missense mutation. An affected member of this family had received a cardiac transplant cardiac beta-myosin heavy chain gene. An affected member of this family had received a cardiac transplant at 23 years of age. A 20-year-old female suffered postpartum congestive heart failure and sudden death. A female child developed congestive heart failure at 2 years of age.
In a family with familial dilated cardiomyopathy-1S (CMD1S; 613426), Kamisago et al. (2000) found a C-to-G transversion at nucleotide 2378 in exon 21 of the cardiac beta-myosin heavy chain gene, causing a phe764-to-leu missense mutation. The 33-year-old father was given a diagnosis of dilated cardiomyopathy at age 11 years. A daughter died suddenly at the age of 2 months. A 4-year-old daughter, diagnosed with dilated cardiomyopathy at the time of birth, was found to have fetal left ventricular dilatation.
Davis et al. (2001) identified a double point mutation in the MYLK2 gene (606566) on the maternal haplotype in a 13-year-old white male proband with early midventricular hypertrophic cardiomyopathy (see CMH1, 192600). The MYLK2 mutations were ala87 to val (A87V; 606566.0001) and ala95 to glu (A95E; 606566.0002). The proband also inherited a glu743-to-asp mutation (E743D) in the beta-myosin gene (MYH7) from his father. Although the son had significant disease at an early age, the father and mother came to medical attention only after the diagnosis of the son. Echocardiographic evaluation showed that both parents had similarly abnormal asymmetrically thickened hearts. The kindred was too small for linkage analysis, and the authors proposed that the mutant MYLK2 may be functionally abnormal and may consequently stimulate cardiac hypertrophy. Davis et al. (2001) concluded that the increased severity of the disease at such a young age in the proband suggests a compound effect.
In a family with familial hypertrophic cardiomyopathy (CMH1; 192600) in which 3 individuals had suffered sudden death, Blair et al. (2001) identified a C-to-T transition in exon 20 resulting in an ala728-to-val (A728V) mutation in cis with a val606-to-met (V606M; 160760.0005) mutation. Blair et al. (2001) suggested that the A728V mutation in cis with the V606M mutation was responsible for the more severe phenotype in this family.
In a series of 46 young patients with dilated cardiomyopathy-1S (CMD1S; 613426), Daehmlow et al. (2002) identified 2 mutations in the MYH7 gene, one of which was a G-to-A transition in exon 8 at nucleotide 7799, resulting in an ala223-to-thr (A223T) substitution. The mutation affected a buried residue near the ATP-binding site. The patient with this mutation was 35 years old when diagnosed with dilated cardiomyopathy.
In a series of 46 young patients with dilated cardiomyopathy-1S (CMD1S; 613426), Daehmlow et al. (2002) found 2 mutations in the MYH7 gene, one of which was a C-to-T transition in exon 17 at nucleotide 12164, resulting in a ser642-to-leu (S642L) substitution at a highly conserved residue. The mutation occurred at the actin-myosin interface. The patient with this mutation was 18 years old when diagnosed with dilated cardiomyopathy.
In affected members of a family and in an unrelated patient with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) without cardiomyopathy, Tajsharghi et al. (2003) identified a heterozygous c.23014C-T transition in exon 37 of the MYH7 gene, resulting in an arg1845-to-trp (R1845W) substitution in the distal end of the filament-forming rod region of the protein. Tajsharghi et al. (2003) suggested that the mutation may interfere with the interaction of MYH7 with myosin-binding proteins and inhibit myosin assembly into thick filaments.
Laing et al. (2005) identified a heterozygous R1845W mutation in 2 unrelated Belgian patients with myosin storage myopathy. Neither patient had a family history of the disease. The mutation was predicted to impair the coiled-coil structure of the protein.
In a large multigenerational family (family A) in which 9 individuals had variable manifestations of CMYP7A, Pegoraro et al. (2007) identified a heterozygous c.5533C-T transition in the MYH7 gene, resulting in an R1845W substitution. Two affected members of another family (family B) carried the same heterozygous mutation.
Variant Function
By functional analysis, Armel and Leinwand (2009) showed that the R1845W mutant protein was nearly indistinguishable from wildtype in both secondary structural characteristics and biophysical parameters. However, compared to the wildtype protein, the mutant protein was unable to assemble to the same extent, formed larger structures, and formed more stable paracrystals. The results suggested that the R1845W mutation alters the interactions between filaments such that their assembly is less constrained, causing the formation of abnormally large, degradation-resistant structures. Similar results were found for H1901L (160760.0031).
In an Australian patient with sporadic Laing distal myopathy (MPD1; 160500), Meredith et al. (2004) identified an arg1500-to-pro (R1500P) mutation in exon 32 of the MYH7 gene. Mild talipes equinovarus had been noted at birth but corrected itself. By the time the patient was 4 years old, she was noted to have weakness of ankle dorsiflexion. Progressive weakness of legs and hands followed, with involvement of the arms at 11 years of age.
In affected members of previously reported families with Laing distal myopathy (MPD1; 160500) from Germany (Voit et al., 2001) and mutation. Austria (Zimprich et al., 2000), Meredith et al. (2004) identified deletion of a lysine at position 1617 in exon 34 of the MYH7 gene.
In affected members of a Saudi Arabian family with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358), reported by Bohlega et al. (2003), Bohlega et al. (2004) identified a c.25596A-T transversion in the MYH7 gene, resulting in a his1904-to-leu (H1904L) substitution in a highly conserved residue in the coiled-coil tail region of the protein. The mutation was not identified in 130 control chromosomes. None of the patients had cardiac abnormalities. The authors noted that the H1904L mutation is adjacent to a critical assembly competent domain and suggested that the mutation may cause improper assembly of the thick filament or interfere with stability of the protein.
Oldfors et al. (2005) used a different numbering system and stated that the mutation described by Bohlega et al. (2004) should be HIS1901LEU. They asserted that the histidine at residue 1901 occupies the 'f' position of the heptad repeat of the coiled-coil domain, whereas residue 1904 is not at an 'f' position in the heptad repeat sequence. In response, Meyer (2005) stated that the mutation occupies an 'f' position regardless of the numbering system used.
Variant Function
By functional analysis, Armel and Leinwand (2009), who also referred to this mutation as H1901L, indicated that the mutant protein had decreased thermodynamic stability. In addition, the extent of assembly of the tail region was decreased compared to wildtype, and the paracrystals were much larger and more stable than wildtype. The findings suggested that the E1901L mutation alters the interactions between filaments such that larger, more stable structures are formed. Similar results were observed for R1845W (160760.0028).
Familial Hypertrophic Cardiomyopathy 1
In 2 Danish patients with familial hypertrophic cardiomyopathy (CMH1; 192600), Hougs et al. (2005) identified a c.21815C-T transition in exon 35 of the MYH7 gene, resulting in an arg1712-to-trp substitution (R1712W) in the myosin rod region.
Autosomal Recessive Myosin Storage Congenital Myopathy 7B
In 2 sibs, born of consanguineous Middle Eastern parents (family AUS1) with autosomal recessive myosin storage myopathy-7B (CMYP7B; 255160), Beecroft et al. (2019) identified a homozygous c.5134C-T transition in the MYH7 gene, resulting in an R1712W substitution. The mutation, which was found by panel-based sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Neither patient had cardiac involvement. Transfection of the mutation into COS7 cells showed that the mutant protein formed small round inclusions, suggesting impaired ability to self-assemble into normal long filaments. Functional studies of myofibers from 1 of the patients showed that type II fibers had increased absolute force compared to control fibers, which may reflect a possible compensatory effect.
In a family with hypertrophic cardiomyopathy (CMH1; 192600) previously reported by Hengstenberg et al. (1993, 1994), Richard et al. (1999) found that of 8 affected members, 4 had a G-to-A transition in exon 15 of the MYH7 gene, leading to a glu483-to-lys (E483K) substitution; 2 had a G-to-T mutation at codon 1096 of the MYBPC3 gene (600958.0014) and 2 were doubly heterozygous for the 2 mutations. The E483K mutation was thought to affect a protein domain involved in actin fixation.
In 3 affected members of a large consanguineous Indian kindred with familial hypertrophic cardiomyopathy (CMH1; 192600), Tanjore et al. (2006) identified a G-to-A transition in exon 22 of the MYH7 gene, resulting in an arg870-to-his (R870H) substitution in the rod region. The 2 affected homozygotes had asymmetric septal hypertrophy without obstructive outflow, and one of them died of heart failure at age 37 years. The third patient was heterozygous for the R870H mutation and had hypertrophic cardiomyopathy with obstructive outflow. Analysis of family members identified the heterozygous R870H mutation in 18 individuals, of whom 10 were symptomatic. Tanjore et al. (2006) estimated the penetrance of the R870H mutation to be 59% in general, whereas 75% of males and 44% of females were clinically symptomatic, suggesting that female mutation carriers have a better prognosis.
In a 44-year-old man, born of second-cousin British parents, with autosomal recessive myosin storage congenital myopathy-7B (CMYP7B; 255160) and hypertrophic cardiomyopathy, Tajsharghi et al. (2007) identified a homozygous c.24012G-A transition in exon 38 of the MYH7 gene, resulting in a glu1883-to-lys (E1883K) substitution at a highly conserved residue in the distal end of the filament-forming rod region. The proband had 2 similarly affected sibs who had died at ages 32 years and 57 years of cardiorespiratory failure; muscle biopsies from all 3 sibs showed findings typical for myosin storage myopathy. The unaffected parents were presumed heterozygous carriers of the mutation, and another sib was unaffected.
Variant Function
By functional analysis, Armel and Leinwand (2009), who referred to this mutation as E1886K, showed that the mutant protein had no major differences in secondary structure or biophysical parameters from wildtype. However, that mutant protein had a decreased ability to assemble to the same extent as wildtype, and the paracrystals formed were more readily degraded by proteolysis. The authors concluded that altered packing of the filaments may destabilize them.
In a Tanzanian boy with Laing distal myopathy (MPD1; 160500), Darin et al. (2007) identified a heterozygous 1408C-T transition in the MYH7 gene, resulting in a thr441-to-met (T441M) substitution in the globular head of the myosin heavy chain. The patient had distal muscle weakness in the lower limbs and mild atrial enlargement. Darin et al. (2007) noted that most patients with Laing myopathy have mutations in the rod region of the protein and suggested that the cardiac involvement in this child may be due to the mutation affecting the globular region.
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) identified a heterozygous c.5378T-C transition in exon 37 of the MYH7 gene, resulting in a leu1793-to-pro (L1793P) substitution in the light meromyosin (LMM) region of the myosin heavy chain tail. The sibs presumably had the disease because of gonadal mosaicism in 1 of the unaffected parents, although this could not be confirmed.
In a mother with myosin storage myopathy who later developed hypertrophic cardiomyopathy (CMH1; 192600) and in her daughter who had early symptomatic left ventricular noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7. The daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment, and she had some difficulty with heel-walking.
Variant Function
By functional analysis, Armel and Leinwand (2009) showed that the L1793P mutation did not differ in protein secondary structure or in the alpha-helical content compared to wildtype, but decreased thermodynamic stability compared to wildtype. The L1793P mutation altered the ability of LMM to assemble, presumably because of the increased instability of the molecule. Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly.
In affected members of a family with hypertrophic cardiomyopathy-1 (CMH1; 192600), Arad et al. (2005) identified heterozygosity for a glu497-to-asp (E497D) substitution in the MYH7 gene. The proband had apical hypertrophy with associated electrocardiographic changes of left ventricular hypertrophy and deeply inverted precordial T waves, whereas a family member with concurrent coronary artery disease who carried the mutation had massive concentric hypertrophy with an interventricular septal thickness of 29 mm.
In 2 sibs with hypertrophic cardiomyopathy-1 (CMH1; 192600), Arad et al. (2005) identified heterozygosity for an asp906-to-gly (D906G) substitution in the MYH7 gene. The proband had apical hypertrophy, whereas the sib, who had sudden death at 45 years of age, was found on necropsy to have massive asymmetrical left ventricular hypertrophy with an interventricular septal thickness greater than 30 mm and a posterior left ventricular wall that was 18 mm thick. Arad et al. (2005) noted that the D906G mutation had previously been identified by Ho et al. (2002) in 22 affected members of a CMH family with a range of maximum left ventricular wall thickness of 13 to 29 mm; none had apical hypertrophy.
In a 40-year-old man with hypertrophic cardiomyopathy-1 (CMH1; 192600) who presented with presyncope and was found to have apical hypertrophy, Arad et al. (2005) identified heterozygosity for an arg243-to-his (R243H) substitution in the MYH7 gene.
In affected members of a 3-generation family segregating autosomal dominant left ventricular noncompaction but no other congenital heart anomalies (LVNC5; see 613426), previously studied by Sasse-Klaassen et al. (2003) as 'family INVM-107,' Klaassen et al. (2008) identified heterozygosity for an 814G-A transition in the MYH7 gene, resulting in the R243H substitution. Noncompaction in all 4 affected individuals involved the apex and mid-left ventricular wall, and the right ventricle was involved as well in 2 patients.
In affected members of 2 families segregating autosomal dominant left ventricular noncompaction but no other congenital heart anomalies (LVNC5; see 613426), 1 of which was previously studied by Sasse-Klaassen et al. (2003) as 'family INVM-101,' Klaassen et al. (2008) identified heterozygosity for an 818+1G-A transition at the splice donor site in intron 8 of the MYH7 gene. The mutation segregated with disease in both families; haplotype analysis ruled out a founding mutation. Clinical evaluation in both families was remarkable for the very pronounced morphology of LVNC. The proband of family INVM-101 was diagnosed because of inverted T-waves and later had a stroke and systemic peripheral emboli, whereas his brother initially presented with decompensated heart failure and pulmonary emboli; both patients remained stable over a period of 8 years. Other affected members of family INVM-101 fulfilled morphologic LVNC criteria but were clinically asymptomatic. The proband of the other family was diagnosed because of atypical chest pain; he and his affected 8-year-old son had no signs of heart failure.
In a 20-year-old man with left ventricular noncompaction but no other congenital heart anomalies (LVNC5; see 613426), Klaassen et al. (2008) identified heterozygosity for a de novo 5382G-A transition in exon 37 of the MYH7 gene, resulting in an ala1766-to-thr (A1766T) substitution. The proband was initially diagnosed due to arrhythmias on routine electrocardiogram, but his left ventricular systolic function subsequently deteriorated over a period of 6 years; sustained ventricular tachycardia resulted in implantation of an intracardiac defibrillator. The mutation was not present in his unaffected parents.
In a 32-year-old African American woman with severe hypertrophic cardiomyopathy (CMH1; 192600) and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified heterozygosity for a 1357C-A transversion in exon 14 of the MYH7 gene, resulting in an arg453-to-ser (R453S) substitution, as well as a heterozygous missense mutation in the TNNI3 gene (191044.0003). Her affected 8-year-old daughter carried only the heterozygous MYH7 mutation.
In affected members of an Italian American family with Laing distal myopathy (MPD1; 160500) reported by Hedera et al. (2003), Meredith et al. (2004) identified a heterozygous 3-bp deletion of 1 of 3 consecutive AAG triplets in exon 36 of the MYH7 gene, resulting in the deletion of lys1729 (lys1729del).
Muelas et al. (2010) identified the lys1729del mutation in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. There was great phenotypic variability. The age at onset ranged from congenital to 50 years, with a mean of 14 years. All patients presented with weakness of great toe/ankle dorsiflexors, and many had associated neck flexor (78%), finger extensor (78%), mild facial (70%), or proximal muscle (65%) weakness. Five patients had cardiac abnormalities, including dilated cardiomyopathy, left ventricular relaxation impairment, and conduction abnormalities. The spectrum of disability ranged from asymptomatic to wheelchair-confined, but life expectancy was not affected. EMG showed myopathic and neurogenic features, and muscle biopsies showed fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities. These findings expanded the phenotypic spectrum of Laing myopathy, but the wide spectrum associated with a single mutation was noteworthy.
Muelas et al. (2012) identified a common 41.2-kb short haplotype including the lys1729del mutation in both Spanish patients from the Safor region and in the Italian American family reported by Hedera et al. (2003), indicating a founder effect. However, microsatellite markers both up- and downstream of the mutation did not match, indicating multiple recombination events. The mutation was estimated to have been introduced into the Safor population about 375 to 420 years ago (15 generations ago). The region is located in the southeast of Valencia on the Mediterranean coast of Spain. Muelas et al. (2012) hypothesized that the families from Safor were descendants of the Genoese who had repopulated this Spanish region in the 17th century after the Muslims were expelled; in fact, many of the surnames of the Safor families with Laing myopathy had an Italian origin.
In affected individuals from 2 white families of western European descent segregating autosomal dominant left ventricular noncompaction (LVNC5; 613426), Postma et al. (2011) identified heterozygosity for a mutation at nucleotide 933 in exon 10 of the MYH7 gene, resulting in a tyr283-to-asp (Y283D) substitution at a highly conserved residue. The mutation segregated with disease in both families and was not found in more than 980 ethnically matched control chromosomes. The 2 probands had other cardiac malformations in addition to LVNC, including Ebstein anomaly in both as well as type II atrial septal defect in 1 and pulmonary artery hypoplasia in the other. One family had 5 more affected individuals over 3 generations, 2 of whom had other cardiac malformations, including Ebstein anomaly in 1 and perimembranous ventricular septal defect in 1; 2 of the patients had only mild left ventricular apical hypertrabeculation. In the other family, the proband's asymptomatic mutation-positive father was found to have LVNC by screening echocardiography; in addition, a paternal aunt was reported to have heart failure, and the paternal grandfather had received an implantable cardioverter-defibrillator.
In 4 affected individuals over 3 generations of a white family of western European descent with left ventricular noncompaction (LVNC5; 613426), Postma et al. (2011) identified heterozygosity for a mutation in exon 39 of the MYH7 gene, resulting in an asn1918-to-lys (N1918K) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in more than 980 ethnically matched control chromosomes. In addition to marked LVNC, the 39-year-old proband exhibited Ebstein anomaly, which was discovered upon evaluation of a cardiac murmur at 3 years of age. She remained asymptomatic despite significant tricuspid regurgitation from age 30 years. She had a mutation-positive son with bicuspid aortic valve and aortic coarctation in whom echocardiography at age 5 years also showed LVNC. Her asymptomatic mutation-positive mother and brother were both found to have LVNC by echocardiography, and her brother also had LV dilation with dysfunction. In an asymptomatic mutation-positive cousin, cardiomyopathy could not be ruled out due to poor imaging quality.
In 2 Turkish brothers, born of related parents, with autosomal recessive myosin storage congenital myopathy-7B (CMYP7B; 255160), who were originally reported by Onengut et al. (2004), Yuceyar et al. (2015) identified a homozygous c.5458C-T transition in exon 37 of the MYH7 gene, resulting in an arg1820-to-trp (R1820W) substitution. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in 353 Turkish controls or in the Exome Variant Server database. Functional studies of the variant were not performed. Both patients had young adult onset of scapuloperoneal weakness and atrophy; 1 brother developed severe dilated cardiomyopathy in his forties, whereas the other had milder cardiac symptoms.
In 12 affected members of a 5-generation Spanish family previously reported by Sobrido et al. (2005) with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358), Ortolano et al. (2011) identified a heterozygous c.5807A-G transition (c.5807A-G, NM_000257.2) in exon 40 of the MYH7 gene, changing the termination codon to a tryptophan-encoding sequence that was predicted to elongate the protein with 31 additional residues at the C-terminal tail of the protein (Ter1936TrpfsTer32). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. It was not present in 202 population controls. Skeletal muscle samples were available from 3 patients (at ages 25, 43, and 62). All showed features of congenital fiber type disproportion, and the oldest patient demonstrated subsarcolemmal hyaline accumulation in type I muscle fibers, suggesting that the pathologic findings can change over time. Two samples studied had normal expression of type I and II myosin heavy chains, but only the younger patient showed decreased MYH7 transcript levels compared to controls. The patients had an early-onset, slowly progressive predominantly proximal skeletal myopathy with mild distal involvement and no signs of cardiomyopathy.
In a 30-year-old woman (family UK1) with autosomal recessive myosin storage myopathy-7B (CMYP7B; 255160), Beecroft et al. (2019) identified compound heterozygous mutations in the MYH7 gene: a c.4699C-T transition, resulting in a gln1567-to-ter (Q1567X) substitution, and a c.4664A-G transition, resulting in a glu1555-to-gly (E1555G; 160760.0050) substitution at a conserved residue in the rod domain. The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Neither mutation was present in the gnomAD database. Functional studies of the variants were not performed. The patient had mildly delayed walking, proximal muscle weakness of the upper and lower limbs, distal muscle weakness, reduced muscle bulk, poor feeding, and progressive nocturnal hypoventilation.
For discussion of the c.4664A-G transition in the MYH7 gene, resulting in a glu1555-to-gly (E1555G) substitution, that was found in compound heterozygous state in a patient with autosomal recessive myosin storage myopathy-7B (CMYP7B; 255160) by Beecroft et al. (2019), see 160760.0049.
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