CLINICAL STUDY: CARDIOMYOPATHY
A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients
Tetsuo Konno, MD*,
Masami Shimizu, MD*,*,
Hidekazu Ino, MD*,
Toru Matsuyama, MD*,
Masato Yamaguchi, MD*,
Hidenobu Terai, MD*,
Kenshi Hayashi, MD*,
Tomohito Mabuchi, MD*,
Masaru Kiyama, MD*,
Kenji Sakata, MD*,
Tatsumi Hayashi, MD*,
Masaru Inoue, MD*,
Tomoya Kaneda, MD* and
Hiroshi Mabuchi, MD*
* Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
Manuscript received December 7, 2001;
revised manuscript received July 23, 2002,
accepted October 17, 2002.
* Reprint requests and correspondence: Dr. Masami Shimizu, Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan.
shimizu{at}med.kanazawa-u.ac.jp
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Abstract
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OBJECTIVES: We studied the clinical features of hypertrophic cardiomyopathy (HCM) caused by a novel mutation in the myosin binding protein-C (MyBP-C) gene in patients and family members of Japanese descent.
BACKGROUND: Previous reports have demonstrated that the clinical features of HCM associated with mutations in the MyBP-C gene include late onset and a favorable clinical course. Recently, some mutations in genes encoding sarcomeric proteins have been reported to be a cause of dilated cardiomyopathy (DCM), as well as HCM. However, mutations of the MyBP-C gene have not been reported as a cause of DCM up to now.
METHODS: We analyzed MyBP-C gene mutations in 250 unrelated probands with HCM and in 90 with DCM. We used electrocardiography (ECG) and echocardiography to determine clinical phenotypes.
RESULTS: We identified 17 individuals in 8 families (7 HCM, 1 DCM) with an Arg820Gln mutation in the MyBP-C gene. Overall, 2 (40%) of 5 carriers age >70 years displayed "burnt-out" phase HCM, and one of them had been diagnosed as having DCM before genetic identification. The disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and that in those age <50 years was 40% and 50%, respectively.
CONCLUSIONS: Elderly patients with Arg820Gln mutation may show "burnt-out" phase HCM, and patients with this mutation may be included among those diagnosed as having DCM. Screening of patients with DCM, as well as HCM, for this mutation is of significant importance because patients with this mutation may be diagnosed clinically as having DCM.
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Abbreviations and Acronyms
| | DCM | | dilated cardiomyopathy | | DNA | | deoxyribonucleic acid | | ECG | | electrocardiography | | HCM | | hypertrophic cardiomyopathy | | LV | | left ventricle | | MyBP-C | | myosin binding protein-C | | PCR | | polymerase chain reaction | | SSCP | | single-strand conformational polymorphism |
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Hypertrophic cardiomyopathy (HCM) is a primary cardiac disorder, often transmitted genetically, with heterogeneous clinical and morphologic expression. Recent molecular genetic studies have revealed that HCM is caused by mutations in the genes that encode the sarcomeric proteins (1). Myosin binding protein-C (MyBP-C) is one of these sarcomeric proteins, and mutations in the MyBP-C gene on chromosome 11 are a frequent cause of HCM (2). Several reports have demonstrated a genotype-phenotype correlation, in that the clinical features of mutations in the MyBP-C gene include late onset and a favorable clinical course (2–5). However, it seems that there are some differences between the various mutations in the MyBP-C gene in terms of the clinical manifestations of the disease (6).
On the other hand, the pathogenesis of idiopathic dilated cardiomyopathy (DCM) is poorly understood. It has been reported that dystrophin, desmin, tafazzin, and lamin A/C gene mutations are associated with DCM (7–11). Interestingly, in addition to these findings, mutations of actin, beta-myosin heavy chain, and the troponin T gene encoding sarcomeric proteins have been reported to be causes of DCM as well as HCM (12,13). These reports suggest that patients with mutations in other genes encoding sarcomeric proteins may be diagnosed as having DCM. However, mutation of the MyBP-C gene has not been reported as a cause of DCM up to now. The purpose of this study was to screen for MyBP-C gene mutation in the probands and family members of patients with HCM and DCM, and to clarify the genotype-phenotype correlation of the disease.
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Methods
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Subjects.
The study subjects comprised 250 unrelated probands with HCM (118 familial, 132 sporadic) and 90 unrelated probands with DCM (12 familial, 78 sporadic or unknown). All probands were identified at the Kanazawa University Hospital and associated hospitals (from primary to tertiary care centers). The diagnosis of HCM was based on the echocardiographic demonstration of a non-dilated, hypertrophied left ventricle (LV) in the absence of other cardiac or systemic causes of LV hypertrophy (14). The diagnosis of DCM was based on the echocardiographic demonstration of a dilated LV in the absence of other cardiac or systemic causes of LV dilation (15). If the mutation was identified in the probands with HCM or DCM, their family members were studied genetically and clinically. Informed consent was obtained from all subjects or their guardians in accordance with the guidelines of the Bioethical Committee on Medical Researches, School of Medicine, Kanazawa University.
Detection of mutation.
Deoxyribonucleic acid (DNA) was isolated from peripheral white blood cells of all subjects using a DNA extractor 341 Nucleic Acid Purification System (GENEPURE, PE Biosystems, Foster City, California). In vitro amplification of genomic DNA was performed using the polymerase chain reaction (PCR). Oligonucleotide primers were used to amplify exons of the MyBP-C gene as described previously (16). Single-strand conformational polymorphism (SSCP) analysis of amplified DNA was then performed using a method described previously (17). For abnormal SSCP patterns, PCR products were subcloned into the pCR2.1 vector using the TOPO TA cloning kit (Invitrogen, Carlsbad, California). The nucleotide sequences of the cloned PCR products were determined on both strands by the dye terminator cycle sequencing method with use of an automated fluorescent sequencer (ABI PRISM 310 Genetic Analyzer, PE Biosystems). The sequence variation in the MyBP-C gene was confirmed by restriction enzyme digestion. The presence of an Arg820Gln missense mutation, which creates a Pvu II restriction site, was confirmed by digestion of genomic DNA with this enzyme. The same method was then used to determine the genotype in DNA from family members of the probands and in 100 healthy individuals.
Clinical evaluations.
Evaluation of the phenotype was completed before determination of the genotype. All subjects underwent echocardiography and/or 12-lead electrocardiography (ECG). Disease penetrance was determined by the following criteria: 1) LV end-diastolic maximal wall thickness  13 mm; 2) LV end-diastolic dimension >55 mm and fractional shortening <25%; 3) Q-wave 0.04 s in duration or one-fourth of the ensuing R-wave in depth in at least two leads; 4) significant ST-T changes; 5) left ventricular hypertrophy (Romhilt-Estes score >4); and 6) conduction disturbance. Family members were evaluated similarly.
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Results
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Genetic results.
The 250 probands with HCM comprised 190 men and 60 women, and the 90 probands with DCM comprised 65 men and 25 women. An Arg820Gln missense mutation in the MyBP-C gene was identified in 8 probands (7 in HCM, 1 in DCM) (Fig. 1). Although we screened for all MyBP-C exons in carriers with the Arg820Gln missense mutation, no other sequence variants were identified in the MyBP-C gene. Relatives of these eight probands were studied further, totaling 24 members of the various families (Fig. 2). Of these 24 individuals, 17 (9 men and 8 women, mean age 55.1 ± 20.0 years) had the Arg820Gln missense mutation in the cardiac MyBP-C gene. This mutation was not observed in any of 100 unrelated healthy individuals.
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Figure 1 A single base pair sequence variant on one allele (guanine to adenosine, second position) encodes a mutant myosin binding protein-C that contains glutamine at residue 820.
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Figure 2 Pedigrees of HCM-011, HCM-023, HCM-084, HCM-089, HCM-168, HCM-171, and DCM-006. The genotypic and phenotypic status of subjects is indicated in the key. DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy.
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Clinical manifestations.
All 17 carriers in the eight families were evaluated by ECG studies. Fifteen of these 17 carriers were examined by echocardiography, but agreement was not obtained from the other two. The echocardiographic results are shown in Table 1. Asymmetrical septal hypertrophy was found in seven subjects (47%). The mean maximal LV wall thickness was 15.1 ± 5.9 mm. "Burnt-out" phase HCM (fractional shortening <25%, and LV end-diastolic dimension >55 mm) was observed in two (40%) of five carriers age >70 years, and one of them had been diagnosed as having primary DCM before genetic identification (DCM-006). Echocardiographic abnormalities were noted in 9 of 15 carriers. The ECG results are shown in Table 2. Fifteen of 17 carriers had sinus rhythm. The other carriers had chronic atrial fibrillation, and one of them had been implanted with a pacemaker. Abnormal Q waves were noted in two subjects and significant ST-T changes in 15 subjects. The disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and in those age <50 years was 40% and 50%, respectively. Sudden death occurred in two subjects from one family (HCM-089, I-1, II-1).
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Discussion
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In this study, we demonstrated that elderly patients with the Arg820Gln mutation in the MyBP-C gene may show "burnt-out" phase HCM, and that patients with this mutation may be included among those diagnosed as having DCM.
Arg820Gln mutation in the MyBP-C gene and its consequences.
We identified the Arg820Gln missense mutation in exon 25 of the MyBP-C gene. This sequence variant was found in clinically affected patients and was absent in 100 normal controls. We screened for all MyBP-C exons in carriers with the Arg820Gln missense mutation, and there were no other sequence variants in the MyBP-C gene. These findings suggest that the Arg820Gln missense mutation in the MyBP-C gene may be associated with disease. This mutation occurs in motif VI (fibronectin type III repeat) (16). Arg820 is conserved in human, chicken, and mouse cardiac isoforms (Table 3). A missense mutation in a conserved position of the MyBP-C gene suggests a mechanism by which the function of the protein may be altered. However, Arg820 is not included in the region that is essential for A-band incorporation, titin-binding, or myosin-binding (6). Moreover, missense mutations in the MyBP-C gene cause a more mild disease phenotype than truncation mutations (6). For these reasons, carriers with the Arg820Gln mutation in the MyBP-C gene may not show a severe disease phenotype until middle age. On the other hand, this mutation resulted in a change of the charge of the altered amino acid. Anan et al. (18) suggested that patients with mutations that changed the charge of the altered amino acid in the beta-myosin heavy chain gene displayed a malignant phenotype. Concerning the MyBP-C gene, four mutations have been reported (Glu258Lys, Arg654His, Val896Met, Val1115Ile) which do not change the charge of the amino acid residue (2,6,19,20). The clinical features of carriers with two (Arg654His, Val1115Ile) of these four mutations have been described in previous reports, although extended family studies were not performed. There were no individuals with these mutations who showed "burnt-out" phase HCM. In our study, we observed LV dilation and dysfunction in elderly individuals. This unfavorable course in the elderly may relate to the mutation that changed the charge of the altered amino acid.
Disease penetrance and sudden death.
Niimura et al. (2) have reported that the cardiac MyBP-C mutation is characterized by low disease penetrance in HCM. We observed that the disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and in those age <50 years was 40% and 50%, respectively. Our data are similar to four recent reports (2–5).
Onset of the disease associated with this mutation appears to be late. However, a 16-year-old youth (family HCM-011, IV-3) showed features typical of HCM. This finding indicates that we should also evaluate young family members of patients, because they already may be affected clinically.
It is reported that sudden death occurs rarely in family members with mutations in the MyBP-C gene (4). In this study, sudden death occurred in two subjects only in one (HCM-089) of these eight families. A middle-aged subject (HCM-089, I-1) died suddenly after exercise, and an elderly subject (HCM-089, II-1) died suddenly after dinner. These findings suggest that some modifying genes may be associated with sudden death occurring in members of this family. Further investigations are needed to clarify the modifying genes. Moreover, Niimura et al. (2) reported that some missense mutations in the MyBP-C gene showed a higher association with sudden death during exercise. Sudden death may occur in family members with mutations in the MyBP-C gene, including the Arg820Gln missense mutation.
Clinical manifestations.
Elderly carriers with the Arg820Gln missense mutation may show LV systolic dysfunction and dilation. We observed "burnt-out" phase HCM in two (40%) of five elderly carriers, and one of them had been diagnosed as having primary DCM before genetic identification (DCM-006). Previous reports suggested that a small fraction (<10%) of patients with HCM progress gradually to a "burnt-out" phase later in their lives (21,22). In medical practice, "burnt-out" phase HCM is not rare in elderly patients with this mutation. There are few previous reports that mention LV systolic dysfunction in patients with HCM associated with the MyBP-C gene. Moolman et al. (4) recently reported the clinical expression of HCM associated with a single base insertion in exon 25 of the MyBP-C gene. Their report did not include individuals with LV dysfunction and dilation. In contrast, Doi et al. (23) reported that four individuals with a one base deletion in codon 593 from TCC (Ser) to CC in exon 18 of the cardiac MyBP-C gene gradually progressed to the stage of LV dilation and dysfunction later in their lives. However, the percentage of the patients who progressed to LV dilation and dysfunction was not given in this report. We performed cardiac catheterization and myocardial biopsy for the proband of family DCM-006, who was diagnosed clinically as having DCM with the Arg820Gln missense mutation. Coronary arteriography showed no significant stenosis. Left ventriculography showed diffuse severe hypokinesis of the LV wall, and the LV ejection fraction was 15%. Myocardial biopsy revealed mild fibrosis, no myocardial hypertrophy, and no myofibrillar disarray. These findings suggest that it is difficult to differentiate clinically the "burnt-out" phase HCM from DCM. Indeed, he had been diagnosed clinically as having idiopathic DCM before genetic identification. We should screen patients diagnosed as having DCM for sarcomeric protein genes, including the cardiac MyBP-C gene. Some mutations in the beta-myosin heavy chain and the troponin T gene also have been reported to cause HCM with LV dysfunction (24–27). Kokado et al. (28) reported that a Lys183 deletion mutation in the troponin I gene in patients with HCM is associated with LV systolic dysfunction and dilation in those age >40 years. Similar to the Lys183 deletion mutation in the cardiac troponin I gene, the Arg820Gln missense mutation in the MyBP-C gene may be one of the genetic factors of "burnt-out" phase HCM in elderly patients. This is the first report that indicates a relationship between mutation and LV systolic dysfunction in the MyBP-C gene in patients with HCM. Furthermore, this is the first report that indicates that patients with "burnt-out" phase HCM caused by MyBP-C mutation may be included among those diagnosed as having DCM. We need to screen for the Arg820Gln missense mutation in patients with DCM, as well as those with HCM, because patients with this mutation may be diagnosed clinically as having DCM.
Conclusions.
The Arg820Gln missense mutation in the MyBP-C gene is associated with variable clinical features, and the clinical expression of this mutation is often delayed until middle age. Elderly patients with this mutation may show "burnt-out" phase HCM and may be included among those diagnosed as having DCM. We conclude that screening for this mutation in patients, especially those who are elderly, with DCM, as well as those with HCM, is of significant importance because patients with this mutation may be diagnosed clinically as having idiopathic DCM.
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Abstract
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