Original Article
Characteristics and Prognostic Implications of Myosin Missense Mutations in Familial Hypertrophic Cardiomyopathy
N Engl J Med 1992; 326:1108-1114April 23, 1992
- Abstract
- Abstract
Background
Familial hypertrophic cardiomyopathy is characterized by a variable degree of myocardial hypertrophy and a wide range of symptoms. Different mutations in the β cardiac myosin heavy-chain gene have been identified in three affected families. However, neither the proportion of cases attributable to myosin mutations nor the effects of different mutations on clinical outcome are known.
Methods
Using a ribonuclease protection assay, we screened the β cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy; this assay is a sensitive method for detecting the presence and location of mutations. We further defined the mutations by analyzing their nucleotide sequences. The clinical features of the disease were compared in families with various myosin mutations.
Results
Seven mutations in the β cardiac myosin heavy-chain gene were identified in 12 of the 25 families. All were missense mutations (i.e., causing the substitution of a single amino acid) clustered in the head and head—rod junction regions of the molecule. Six mutations resulted in a change in the charge of the amino acid. Patients with mutations that changed the charge of the altered amino acid (such as that from arginine to glutamine at nucleotide 403 or from arginine to cysteine at nucleotide 453) had a significantly shorter life expectancy (mean age at death, 33 years), whereas patients with the one mutation that did not produce a change in charge (Val606Met) had nearly normal survival. However, patients with different mutations did not differ appreciably in their clinical manifestations of familial hypertrophic cardiomyopathy.
Conclusions
Different missense mutations in the β cardiac myosin heavy-chain gene can be identified in approximately 50 percent of families with hypertrophic cardiomyopathy. In those families, a definite genetic diagnosis can be made in all members. Since the location of a mutation or its DNA-sequence alteration (or both) appears to Influence survival, we suggest that the precise definition of the disease-causing mutation can provide important prognostic information about affected members. (N Engl J Med 1992;326:1108–14.)
Article Activity
- Article
FAMILIAL hypertrophic cardiomyopathy is one of the most common forms of heritable cardiac disease and an important cause of sudden death in adolescents and young adults.1 2 3 Clinical studies have identified both morphologic and functional abnormalities in patients with this condition. However, no known electrocardiographic, echocardiographic, or hemodynamic features correlate with prognosis, particularly with the risk of sudden death.4 5 6 7 Although several studies have suggested that premature deaths are more common in some families than in others,8 statistical validation of differences in survival has been limited by the small numbers of affected members of families, and no accurate indicators of risk have been established.
Molecular-genetic studies have demonstrated linkage of familial hypertrophic cardiomyopathy to the cardiac myosin heavy-chain genes on chromosome 14 in some but not all families,9 10 11 indicating genetic heterogeneity.12 Two distinct genes on chromosome 14 code for two isoforms of myosin heavy chains, the a and β forms, β Cardiac myosin heavy chains predominate in human ventricular myocardium. Two types of mutations in the β cardiac myosin heavy-chain gene have been found in the three families with hypertrophic cardiomyopathy that have been analyzed. Affected members of two families have missense mutations in highly conserved residues of the β cardiac myosin heavy-chain gene,13 , 14 and those of the third family have an α/β cardiac myosin heavy-chain hybrid gene.15
Genetic heterogeneity resulting from the presence of different disease genes or different mutations within a given gene may account in part for the clinical differences among patients with familial hypertrophie cardiomyopathy. Studies of other inherited disorders have demonstrated that different mutations within the same gene can cause different phenotypes. For example, certain types of mutation of dystrophin lead to the development of Duchenne's muscular dystrophy, whereas other mutations produce a milder variant, Becker's muscular dystrophy.16
To estimate the proportion of families with hypertrophic cardiomyopathy caused by myosin heavy-chain mutations and to determine the relation between different mutations and clinical findings, we studied 25 families with this disorder. Preliminary research had indicated that major structural abnormalities of the α or β cardiac myosin heavy-chain genes are not a common cause of familial hypertrophic cardiomyopathy (unpublished data). We therefore used ribonuclease (RNase) protection assays to screen directly for point mutations or other small alterations in the β cardiac myosin heavy-chain gene, which encodes the predominant isoform of myosin expressed in the ventricles of adults.17 , 18
Methods
Clinical Evaluation
After informed consent was obtained in accordance with the guidelines of the Brigham and Women's Hospital Committee for the Protection of Human Subjects from Research Risks, blood samples were obtained from family members. Clinical, electrocardiographic, and echocardiographic assessments were performed as previously described.9 The diagnosis of hypertrophic cardiomyopathy was based on the demonstration of unexplained hypertrophy of either ventricle or both ventricles. Clinical records, family histories, or both were obtained to determine the number of disease-related deaths, the number of sudden deaths (disease-related deaths due to unexpected cardiac arrest or abrupt circulatory collapse), and the age at death or the current age of all affected members of each family. Kaplan–Meier product-limit survival curves were produced as described elsewhere19 , 20 and compared according to the log-rank method of Peto and Peto.21 All P values were calculated with the assumption of a two-tailed distribution.
Strategy for the Detection of Mutations
The polymerase chain reaction (PCR) was used to amplify the sequences of β cardiac myosin heavy-chain genes or messenger RNA (mRNA) in lymphocytes from affected family members that were transformed by the Epstein–Barr virus (Fig. 1Figure 1
Detection of Mutations by RNase Protection Assay. Panel A shows the location within normal human β cardiac myosin heavy-chain (MHC) mRNA (shaded bar) of the sequences of a proband's DNA and the riboprobe templates used in the RNase protection assay. The segments of DNA used for protection are cDNA segments 1 through 6, derived from peripheral-blood leukocyte mRNA (heavy lines represent the initial PCR products, and light lines the products of a second amplification with an inner primer pair), and exons from genomic DNA (see the Methods section). The eight templates used as riboprobes, numbered according to nucleotide residue,22 are shown in the bottom half of the panel. Segment 3421–3811 was amplified from exon 27, not mRNA (see text).A). Both normal and mutationally altered β cardiac myosin heavy-chain mRNA can be detected in these cell lines.14 Amplified sequences were hybridized to RNA probes derived from an unaffected member, and an RNase A protection assay was performed as previously described.14 , 23 To increase the probability of identifying all mutations, both sense and antisense riboprobes were used. The entire β cardiac myosin heavy-chain coding sequence of each proband was examined to determine whether any of these sequences contained more than one mutation. Amplified DNA samples yielding abnormal RNase cleavage patterns were reanalyzed with new DNA isolates to exclude artifacts arising from the PCR and were then subjected to nucleotide-sequence analysis. Amino acid sequences were deduced from DNA sequences. Throughout this article, mutations are denoted by the three-letter code for the normal amino acid, followed by the residue number (as defined by Jaenicke et al.22) and the code for the predicted amino acid residue resulting from each mutation.Templates for the Riboprobes
Twenty-five—base oligonucleotide primers (containing nucleotide sequences as numbered by Jaenicke et al.22 and a selected restriction-enzyme site) were used to reverse-transcribe and amplify seven segments of normal human β cardiac myosin heavy-chain mRNA (Fig. 1A). One segment (3421 through 3811) could not be amplified from mRNA with PCR and was produced by amplifying exon 27 from human DNA. Each amplified product was cloned into a Blue-script SK vector (Stratagene) according to standard procedures.24 These eight different β cardiac myosin heavy-chain clones were linearized by restriction-enzyme digestion and transcribed with the use of T3 or T7 RNA polymerase.
DNA for Screening
Segments of β cardiac myosin heavy-chain complementary DNA (cDNA) were obtained by nested PCR amplification of cDNA reverse-transcribed from peripheral-leukocyte mRNA (as described previously14), or individual exons were amplified from genomic DNA. cDNA segments, numbered 1 through 6 (Fig. 1A), were amplified with the former approach; diluted product from an initial PCR amplification with outer primers was used as the template for a second PCR amplification with an inner-primer pair. This technique could not be used throughout the study because of difficulties in amplifying some mRNA sequences encoding the rod region; these areas were screened by amplifying the sequences of individual exons. Section 1203 through 2398 (corresponding to exons 13 through 20) was screened with DNA templates produced according to both techniques, with identical findings.
The following nucleotide numbers are those of the primers used in the nested PCR amplification of cDNA (all were 25-mers, each numbered by its 5′ residue according to the cDNA sequence22; see Fig. 1A): 1, outer 20 to 475, inner 50 to 450; 2, outer 401 to 1235, inner 425 to 800 and 750 to 1175; 3, outer 750 to 1700, inner 1101 to 1600; 4, outer 1501 to 2450, inner 1526 to 2025 and 1925 to 2424; 5, outer 2300 to 3301, inner 2325 to 2325 and 2726 to 3276; and 6, outer 4401 to 5105, inner 4449 to 5080. The following are the primers for the exons (all 25-mers, each numbered by its 5′ residue according to the gene sequence22): 27, 19178 to 19597; 28, 19740 to 20048; 29, 20101 to 20279; 30, 20973 to 21257; 31, 21689 to 21954; 32, 22033 to 22313; 35, 23567 to 23848; 36, 23902 to 24088; 37, 24123 to 24457; 38, 25293 to 25470; 39, 25508 to 25698; and 40, 26539 to 26724.
Linkage Analyses
When a sequence variant was identified in a proband, it was used to assess genetic linkage between the disease status of family members and the β cardiac myosin heavy-chain gene. Lod (logarithm of the odds) scores were calculated with the LINKMAP program,25 for a recombination fraction (θ) of 0.0, with a penetrance of 0.95 and an allele frequency of the sequence variant of 0.05. Lod scores of families with the same mutation were combined. A lod score greater than 1.3 indicates that the odds in support of linkage are higher than 20 to 1.
Results
Twenty-five kindreds with familial hypertrophic cardiomyopathy were chosen for genetic studies. The affected members of these families had features typical of hypertrophic cardiomyopathy as assessed by physical examination, two-dimensional Doppler echocardiography, and electrocardiography. The disease was inherited as an autosomal dominant trait in all cases, as documented by the history or clinical evaluation (or both) of relatives. The families were of European descent and were unrelated. In three families (A, B, and QQ), the disease locus was known to be linked to chromosome 14 band ql; in all other families, the status with respect to chromosomal linkage was unknown. A mutation had been previously identified in Families A and B from a limited analysis of the β cardiac myosin heavy-chain gene.13 , 14 One proband was selected from each family for genetic analysis. To identify mutations, we screened the entire coding sequence of the β cardiac myosin heavy-chain gene in these probands by RNase protection assays. These assays identified nine different variants from the normal sequence of the β cardiac myosin heavy-chain gene. These nine variants were found in 14 of the probands; two variants are shown in Figure 1B.
The nine variants were characterized by nucleotidesequence analysis. All the variants corresponded to single-nucleotide substitutions: eight variants were transitions (G to A, or C to T), and one was a transversion (G to C). Six of the eight transitions occurred at a CG dinucleotide, a common site of mutations in human disease loci.26 27 28 Seven DNA variants changed the coding sense of the β cardiac myosin heavy-chain gene (Fig. 2Figure 2
Location and Identity of Missense Mutations in Families with Familial Hypertrophic Cardiomyopathy. A schematic diagram of the normal β cardiac myosin heavy-chain gene is shown in the center (5′ to 3′), and the location of the missense mutations is shown according to exon. The amino acid substitutions predicted by each mutation are shown in the top of each box, and the families with these mutations are designated by letters. Sequences that encode the initiation of transcription (ATG), ATPase activity (ATP), actin binding (Actin I and Actin II), myosin light-chain binding (MLC), and hinge function (Hinge) are indicated. The head and rod regions of the encoded polypeptide are shown at the bottom of the figure.), and two (not shown) did not alter the encoded amino acid sequence. These two variants were silent polymorphisms, both of which were found in unaffected family members. All seven variants that changed the coding sense affected residues in the amino-terminal half of the β cardiac myosin heavy-chain polypeptide (Fig. 2). Four variant sequences were found in two or more probands. These included the mutation of arginine to glutamine at residue 403 (Arg403Gln), which was initially detected in affected members of Family A13 and was also found in the proband from Family SS.That the seven sequence variants were mutations causing familial hypertrophic cardiomyopathy was indicated by three findings. First, there was complete concordance between genotype and disease status in all adult relatives of each proband in whom a mutation was identified. Since many affected families were large, linkage analyses provided statistically significant information about six of the seven mutations (see below) (Table 1Table 1
β Cardiac Myosin Heavy-Chain Gene Mutations and Associated Laboratory and Clinical Features in Families with Familial Hypertrophic Cardiomyopathy.). Because these analyses were fully informative for all members, differences in lod scores reflected only differences in family size. Second, each sequence variant predicted that the encoded amino acid residue would be altered, and each altered amino acid was one that has been entirely conserved during the evolution of vertebrate striated muscle (data not shown), implying functional importance. Third, these variants were not found in analyses of more than 180 normal chromosomes (data not shown).Previous studies of Family B demonstrated that affected members had an α/β cardiac myosin heavy-chain hybrid gene in addition to nonrearranged α and β myosin heavy-chain genes.15 The proband from this family was included in the current analyses, and the Arg453Cys mutation was identified in the nonrearranged β myosin heavy-chain gene. This mutation was also identified in affected members of an unrelated family, Family E, all of whom lacked the hybrid gene. The natural history of the disease in affected members of these two families appeared to be similar. Because the Arg453Cys mutation occurred in affected members of two unrelated families who had a similar phenotype, we concluded that the missense mutation, and not the hybrid gene,15 was responsible for the familial hypertrophic cardiomyopathy in both families.
The spectrum of clinical features of familial hypertrophic cardiomyopathy was compared in affected members of families in which a mutation of the β cardiac myosin heavy-chain gene was identified. The incidence of angina, dyspnea, and syncope among members of a family with a given mutation could not be distinguished from the incidence among members of families with different mutations, nor could the severity of ventricular hypertrophy as assessed by two-dimensional echocardiography. The range of values for the maximal thickness of the left ventricular wall in patients with the same mutation was not significantly different from that in affected patients with different mutations (data not shown).
To determine whether the presence of a particular β cardiac myosin heavy-chain gene mutation is prognostic, we compared several indexes of survival in relation to genotype (Table 1 and Fig. 3Figure 3
Kaplan–Meier Product-Limit Curves for the Survival of Family Members, According to Mutation.), combining data on families with identical mutations. Disease-related deaths were less frequent in families with the Val606Met mutation than in families with the Arg249Gln, Arg403Gln, or Arg453Cys mutation (Table 1). Also, patients with the Arg249Gln mutation had a significantly longer life expectancy (Table 1) than those with the Arg403Gln mutation (P = 0.027) or those with the Arg453Cys mutation (P = 0.023). Survival analysis of the small families with the Gly584Arg, Glu924Lys, and Glu949Lys mutations provided little information.Sufficient numbers of affected members were available for Kaplan–Meier product-limit survival curves19 , 20 to be produced for five mutations. Since the survival curve for patients with the Arg453Cys mutation involving the hybrid gene (Family B) was indistinguishable from the curve for the patients without this gene (Family E), the data on these two families were combined. These analyses confirmed that the Val606Met mutation was associated with longer survival than was the Arg453Cys mutation (P = 0.002) or the Arg403Gln mutation (P = 0.002). The Arg249Gln mutation appeared to produce an intermediate phenotype; among patients with this mutation, survival was longer than among those with the Arg453Cys mutation (P = 0.027) or those with the Arg403Gln mutation (P = 0.015), but tended to be shorter than among patients with the Val606Met mutation (P = 0.067). Survival among patients with the Arg453Cys mutation (with or without the hybrid gene) was similar to survival among those with the Arg403Gln mutation (P = 0.79); both mutations were associated with a particularly poor prognosis.
Discussion
We have identified mutations in the β cardiac myosin heavy-chain gene in 12 of 25 families with familial hypertrophic cardiomyopathy. Seven different missense mutations were found that are located in the head or head—rod junction region of the myosin heavy chain. No mutations were detected in the rod region. Six of the seven nucleotide substitutions altered the charge of the encoded amino acids and were particularly likely to lead to regional conformational changes in the polypeptide. The survival of affected family members, but not the extent of cardiac hypertrophy or symptoms, appears to be influenced by the particular mutation. Given the known intrafamilial and age-dependent variation in morphologic features,1 , 2 we acknowledge the need to study more persons with the disease. The data provide insight into the mechanisms by which mutations in the β cardiac myosin heavy-chain gene lead to cardiac hypertrophy and suggest strategies for improving the clinical management of this disorder.
The effect of myosin heavy-chain mutations on muscle function has been assessed in nematodes, in which mutations in the unc-54 gene cause autosomal dominant paralysis.29 These are missense mutations in the globular head and head—rod junction regions of the myosin heavy chain, two thirds of which result in a change in the charge of the amino acid residue and thus appear similar to the mutations we have found in patients with familial hypertrophic cardiomyopathy. In nematodes, mutant heavy chains are incorporated into thick filaments and subsequently disrupt the assembly of thick filaments or sarcomeres. By analogy, we propose that mutated β cardiac myosin heavy-chain genes produce "poison polypeptides" that cause the formation of defective myofibrils in patients with familial hypertrophic cardiomyopathy. Unlike some myosin mutations in nematodes, none of the mutations in the patients alter amino acid residues known to be involved in the three identified functions of the head of the myosin heavy chain — namely, ATPase activity, actin binding, and myosin light-chain binding.30 31 32 The absence of mutations in the binding domains of the β cardiac myosin heavy chains in humans may indicate that such mutations are not compatible with survival; mutations at these sites produce the most severe paralysis in nematodes.29
Our studies provide an estimate of the fraction of families with familial hypertrophic cardiomyopathy in whom a β cardiac myosin heavy-chain mutation can be identified (12 of 25 families, or 48 percent). This may be an underestimate, because RNase A does not detect all nucleotide mismatches equally. However, other investigators have demonstrated that most point mutations can be detected with RNase A protection assays,33 , 34 and we have used high enzyme concentrations to detect types of mismatch usually considered resistant to RNase A cleavage (data not shown). We conclude that in approximately 50 percent of families of European descent with familial hypertrophic cardiomyopathy, the disease is caused by mutations in the β cardiac myosin heavy chain. The genetic diagnosis of this disorder through the screening of probands for mutations in the β cardiac myosin heavy-chain gene is clinically feasible.
Knowledge of the precise mutation that is associated with familial hypertrophic cardiomyopathy in an individual patient provides prognostic information. Previous studies have labeled families in which two or more premature deaths have occurred as having "malignant" disease.8 However, the increase in the risk of premature death and the age at which premature death was likely to occur could not be determined because of the small numbers of affected members of a particular family. Similarly, the known clinical and morphologic features of the disease (e.g., the severity of hypertrophy and the presence of obstruction or electrophysiologic abnormalities) do not accurately indicate prognosis.4 5 6 7 Our data on survival among patients with particular mutations suggest that the different missense mutations are associated with differences in survival, despite otherwise similar clinical findings. The three families with the Val606Met mutation illustrate this fact. Affected members of these unrelated families varied widely in the extent of ventricular hypertrophy (data not shown), but even those with marked hypertrophy typically survived longer than patients with other mutations. We attribute this longer life expectancy to the conservative nature of the amino acid substitution produced by this mutation: in contrast to all the other mutations in familial hypertrophic cardiomyopathy, the substitution of methionine for valine does not involve a change in charge. We suggest that the specific myosin mutation is a major determinant of survival among affected family members.
Our studies indicate that a mutation in the β cardiac myosin heavy-chain gene can be identified in approximately half the families affected by hypertrophic cardiomyopathy. Determining a patient's genotype is technically demanding, but once it has been achieved, it facilitates rapid genetic diagnosis in all family members (whether affected or unaffected) and allows their risk of premature death to be predicted. This information provides a rational basis for genetic counseling and perhaps for the selection of patients to receive aggressive approaches to treatment. Future research should be directed to the question of how mutant myosin heavy chains produce cardiac hypertrophy and adversely affect cardiac contractile function.
Supported by grants from the British Heart Foundation (to Dr. Watkins [recipient of a British Heart Foundation Clinical Scientist Fellowship] and Dr. McKenna), the National Institutes of Health (HL-02228 [to Dr. Rosenzweig], HL-46320 [to Dr. J.G. Seidman], and HL-41474 and HL-42467 [to Dr. CE. Seidman]), the Howard Hughes Medical Foundation (to Drs. Levi and J.G. Seidman), the American Heart Association (to Dr. C.E. Seidman), and Bristol Myers—Squibb Company (to Drs. C.E. Seidman and J.G. Seidman).
We are indebted to the family members without whose invaluable assistance this study would not have been possible; to K. Adams, A. O'Donoghue, J. Jarcho, S. Solomon, T. Traill, and J. Udelson for gathering data on the families; to M. Miri for technical help; to R. Jackson and R. Mortensen for introducing us to Kaplan–Meier analysis; and to the Clinfo data-management and analysis staff of Brigham and Women's Hospital, Boston.
Source Information
From the Cardiology Division, Brigham and Women's Hospital, and Harvard Medical School, Boston (H.W., D.-S.H., C.E.S.); the Department of Cardiological Sciences, St. George's Hospital Medical School, London (H.W., W.M.); the Department of Genetics, Harvard Medical School, Boston (A.R., T.L., J.G.S.); the Cardiac Unit, Massachusetts General Hospital, Boston (A.R.); the Division of Cardiology, Taichung Veterans General Hospital, Taichung, Taiwan (D.-S.H.); and the Howard Hughes Medical Institute, Boston (T.L., J.G.S.). Address reprint requests to Dr. Watkins at the Department of Genetics, Harvard Medical School, 25 Shattuck St., Boston, MA 02115.
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