(Circulation. 1995;91:2911-2915.)
© 1995 American Heart Association, Inc.
Articles |
A Myosin Missense Mutation, Not A Null Allele, Causes Familial Hypertrophic Cardiomyopathy
From the Third Department of Internal Medicine, Kurume University School of Medicine, Kurume (H.N., H.H., Y.K., K.A., K.M., T.K., T.I., H.T.), and the Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka (H.N., A.K., H.H., T.K., S.Y., T.S.), Japan.
Correspondence to A. Kimura, MD, Department of Tissue Physiology, Division of Adult Diseases, Medical Research Institute, Tokyo Medical and Dental University, Kandasurugadai 2-3-10, Chiyoda-ku, Tokyo 101, Japan.
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Abstract |
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Background Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac ß–myosin-heavy-chain (ß-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac ß-MHC gene, ie, an
/ß
hybrid gene and partial deletion of the gene, have also been reported.
The direct correlation between gross abnormalities and development of
HCM is not well understood. Methods and Results We analyzed the structure of the cardiac ß-MHC gene from patients with HCM by using polymerase chain reaction–DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined for the mutations. It was revealed that the missense mutation was inherited from the affected father and the nonsense mutation from the unaffected grandmother through the unaffected mother. In addition, the missense mutation was also found in seven other patients from two other unrelated multiplex HCM families.
Conclusions The Arg870His mutation was suggested to cause HCM. In contrast, the gene with the nonsense mutation would encode for a cardiac ß-MHC protein of only 53 amino acid residues, which may be too short to be incorporated into the thick filament assembly of cardiac myosin chains and showed no dominant phenotype of heart disease. This is the first report of a nonsense mutation in the human cardiac ß-MHC gene.
Key Words: hypertrophy • cardiomyopathy • gene • myosin
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology accompanied with disarray of myocardial fibers. HCM is one of the major causes of sudden death in young adults.1 Patients with HCM often show a familial occurrence consistent with autosomal-dominant inheritance. After the first report2 of missense mutation in the cardiac ß–myosin-heavy-chain (ß-MHC) gene, various missense mutations have been identified3 4 5 6 7 8 9 10 11 12 in patients with HCM. The manner in which a missense mutation produces morphological abnormalities characteristic of HCM has not been fully elucidated; however, these missense mutations were considered to be the cause of HCM because they were detected at the evolutionary conserved amino acid residues among various MHC genes and linked to HCM in the affected families. There are reports of the accumulation of mutant cardiac ß-MHC in cardiac and skeletal tissues at the mRNA13 or protein14 level. Furthermore, the abnormal mobility of MHC protein on actin caused by the presence of mutant cardiac ß-MHC proteins was noted in skeletal muscle.14 15 Gross structural abnormalities of the cardiac ß-MHC gene, an
/ß hybrid gene,16 and a
small deletion17 have also been reported. Whether there is
a direct correlation between these gross abnormalities and development
of HCM, however, is unknown. We reported three missense mutations in
the cardiac ß-MHC gene from Japanese HCM
patients8 11 12
detected by the polymerase chain reaction–DNA conformation
polymorphism (PCR-DCP)
analysis.18 19 20 21 We
report
here a nonsense mutation in exon 3 and a missense mutation in exon 22
in a patient with HCM. Family analysis revealed that the nonsense
mutation was inherited from the unaffected grandmother through the
unaffected mother, while the missense mutation was found in the
affected father and in affected members of two other multiplex families
of HCM. The relevance of these mutations in HCM is discussed. |
Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical Evaluation
Patients and family members were evaluated by physical examinations, ECGs, and two-dimensional (2D) echocardiograms. The diagnosis of HCM was based on evidence of unexplained hypertrophy of the left ventricle and confirmed by cardiac catheterization in the probands. No patient with apical hypertrophy was included in this study. Blood samples were obtained from each subject after the acquisition of informed consent.
Genomic DNA Extraction and PCR-DCP Analysis
DNA was extracted
from peripheral blood leukocytes of each
subject as described previously.8 Primers flanking exons 3
(BEX3-5, 5'-TTTAAGCTTCTGCTCCACTCCAG-3', and BEX3-3,
5'-TTTTCTAGACTCTCACATCAGCCTGA-3') and exon 22 (BEX22-5a,
5'-CTCAGCACTCCTTTCAATGG-3'; BEX22-3a,
5'-GCGCCTCTTTGAGGGCTGT-3';
BEX22-5b, 5'-CTGCTGAAGAGTGCAGAAAG-3'; and BEX22-3b,
5'-AGGGTGGAAGAGCCAACAGT-3') of the cardiac ß-MHC gene were
synthesized in a DNA synthesizer (Cyclon Plus, MilliGen/Biosearch,
Burlington) based on the reported sequences of normal human cardiac
ß-MHC gene.22 To improve the sensitivity of the PCR-DCP
analysis, we divided exon 22 into two parts; this exon consisted of
322 base pairs, and sequence variation can be detected more effectively
in a short DNA fragment.23 The 5' half of exon 22 was
amplified with BEX22-5a and BEX22-3a, whereas the 3' half of exon 22
was amplified with BEX22-5b and BEX22-3b. The conditions of PCR and the
procedures of PCR-DCP analysis were as described
previously.8
Sequencing Analysis
Sequence variations detected in exons 3
and 22 were determined
for the nucleotide sequences by the direct sequencing
method.24 First, genomic DNA was amplified with the PCR
primers BEX3-5 and BEX3-3 or with primers BEX22-5a and BEX22-3b.
Second, a nested asymmetric PCR was done from 0.1 to 0.2 ng of the PCR
products to generate exon 3–specific single-stranded DNAs by altering
the proportion of one primer to the another primer, 20 pmol:0.2 pmol
BEX3-52 (5'-TTCTGCTCCACTCCAGGCA-3'):BEX3-32
(5'-CTCTCACATCAGCCTGACAC-3') or vice versa, in a 50-µL PCR
mixture.
Similarly, a portion of the PCR product from exon 22 was subjected to a
nested PCR with altering amounts of 20 pmol:0.2 pmol BEX22-52
(5'-AGCACTCCTTTCAATGGGCC-3'):BEX22-32
(5'-GTGGAAGAGCCAACAGTAGC-3') or
vice versa in a 50-µL PCR mixture. DNA sequences were determined by
the dideoxy chain termination method25 with the
32P-labeled sequencing primers BEX3-5S
(5'-CTCCACTCCAGGCA-3') or BEX3-3S
(5'-ACATCAGCCTGACA-3') for exon 3 and
BEX22-5S (5'-CCCTCAAAGAGGCGCTAG-3') or BEX22-3S
(5'-TGGAAGAGCCAACAGTAGC-3') for exon 22 with a sequencing kit
(SEQUENASE version 2.0, USB, obtained through TOYOBO Co
LTD) according to the manufacturer's instructions.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Using the PCR-DCP analysis, we examined sequence variations in the cardiac ß-MHC gene from more than 100 unrelated patients with HCM. Sequence variations in exons 3 and 22 were found in a patient with HCM. In this patient, the abnormality in his ECG was noted when he was 16 years old. His ECG at the first diagnosis showed normal sinus rhythm with abnormal Q waves in leads II, III, aVF, V5, and V6 and inverted T waves in leads I and aVL. A 2D echocardiogram showed that he had asymmetrical septal hypertrophy (ASH) with normal left ventricular systolic function (thickness of the ventricular septum, 20 mm; posterior wall thickness, 11 mm; left ventricular diastolic dimension, 38 mm; left ventricular systolic dimension, 21 mm; left ventricular ejection fraction, 83%). Cardiac catheterization showed features of HCM, and endomyocardial biopsy showed typical pathological changes. His family members (pedigree 26) also were examined by ECG and 2D echocardiogram. His 40-year-old father was found to be affected; the ECG showed complete right bundle branch block, and the 2D echocardiogram showed ASH with normal left ventricular systolic function (thickness of the ventricular septum, 20 mm; posterior wall thickness, 11 mm; left ventricular diastolic dimension, 45 mm; left ventricular systolic dimension, 27 mm; left ventricular ejection fraction, 78%). The other family members, his mother (38 years old) and two sisters (14 and 12 years old), were considered to be unaffected on the basis of clinical investigations (Fig 1
).
His 70-year-old maternal grandmother also was considered to be
unaffected; her echocardiogram showed no hypertrophy in any area of
both ventricles (thickness of the ventricular septum, 10 mm; posterior
wall thickness, 10 mm; left ventricular diastolic dimension, 48 mm;
left ventricular systolic dimension, 32 mm; left ventricular ejection
fraction, 70%).
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On analysis of exon 3, the proband showed an additional
slow-migrating DNA fragment, representing single-strand
conformation polymorphism, while there were no unusual PCR products
in his affected father. In contrast, this unusual fragment was found in
his unaffected mother and grandmother (Fig 2a).
Sequencing analysis revealed a C-to-T transition in codon 54 from
CGA (Arg) to TGA (ter) (Fig 3a). This sequence
substitution generates a termination codon; therefore, the mutant gene
should encode for a short (53-residue) variant cardiac ß-MHC protein.
Because both mutant and normal sequences were identified in codon 54,
the patient was heterozygous for the substitution. To further confirm
the mutation, PCR products from exon 3 were hybridized with
allele-specific oligonucleotide probes. DNA samples from the other 107
unrelated patients and 220 unrelated healthy individuals and from 3
family members (the proband's father and sisters) were hybridized
exclusively with the normal probe, while the proband, his mother, and
his grandmother showed positive hybridization signals with both normal
and mutant probes (data not shown). The finding that the nonsense
mutation was present in the proband, his unaffected mother, and his
unaffected grandmother is inconsistent with the clinical diagnosis of
HCM in the proband and his father. In addition, relatives of his mother
(except the proband) had no history of heart disease, further
suggesting that the nonsense mutation was not the cause of HCM in the
proband.
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Another sequence variation was found in exon 22 from the proband and
his father. Fig 2b
shows the PCR-DCP analysis for exon 22 of
the
cardiac ß-MHC gene. The sequence variation also cosegregated with HCM
in two other multiplex families. One base substitution in codon 870
leading to the replacement of Arg (CGC) with His (CAC) was demonstrated
by the direct sequencing analysis in pedigree 26 (Fig 3b). The
missense mutation in exon 22 was also confirmed by dot-blot
hybridization with a mutation-specific oligonucleotide probe in all
nine patients in these three multiplex families. In addition, a
30-year-old offspring (indicated by the asterisk in pedigree 6, Fig
2b)
carried this missense mutation. Although cardiac hypertrophy was not
evident on her echocardiogram, her ECG showed small Q waves in leads
II, III, aVF, and V6, which may be an early sign of HCM. Because the
missense mutation was found at the evolutionary conserved amino acid
residue of MHC proteins, as was observed with the other missense
mutations found in HCM, this mutation was strongly suspected to be the
cause of HCM in these patients, including the proband of pedigree 26.
The nature of the Arg870His mutation would not change the charge of the
cardiac ß-MHC protein.
Because the proband of pedigree 26 should not carry a normal cardiac ß-MHC allele, it was of interest to examine whether he had a more severe phenotype than the other patients who had both the variant and normal cardiac ß-MHC genes. Light microscopic and electron microscopic findings in biopsied cardiac samples from the proband at the time of the first diagnosis were comparable to those in the other affected members (data not shown), implying that the presence of the nonsense mutation might not severely enhance the pathological changes. However, when we followed the clinical course of HCM in the proband of pedigree 26, clinical expression was rapidly progressive. During a 3-year follow-up, the abnormal Q waves in leads II, III, and aVF disappeared, and ST depression with T-wave flattening in leads V5 and V6 appeared in the ECG. Echocardiogram obtained when the proband was 19 years old showed progression to diffuse ventricular septal hypertrophy (thickness of the ventricular septum, 25 mm; posterior wall thickness, 12 mm; left ventricular diastolic dimension, 39 mm; left ventricular systolic dimension, 22 mm; left ventricular ejection fraction, 82%).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Since the first report of a missense mutation in the cardiac ß-MHC gene,2 various missense mutations and gross structural abnormalities (ie, fusion gene and small deletion) have been noted in relation to familial HCM. We report here for the first time a nonsense mutation in the human cardiac ß-MHC gene in a patient and his healthy relatives. The missense mutations were strongly suspected to be the cause of HCM because they were detected in patients with HCM and not in the unrelated healthy control subjects. On the other hand, the correlation between gross structural abnormalities of the cardiac ß-MHC gene and HCM remains to be elucidated. In the first report of gross structural abnormality of the cardiac MHC gene in a multiplex family with HCM, all the patients had an
/ß cardiac MHC hybrid
gene.16 However, subsequent analysis identified a
missense mutation (Arg453Cys) in the adjacent cardiac ß-MHC gene, and
the same mutation was identified in other unrelated HCM families in
which all patients lacked the hybrid gene.4 Thus, it was
strongly suggested that the missense mutation, not the hybrid gene, was
responsible for the familial HCM in this family. A small deletion of
the cardiac ß-MHC gene was noted in another patient with HCM; this
same deletion was found in three unaffected family
members.17 Whether the deletion is responsible for the HCM
has to be carefully discussed because the proband did not develop
symptoms of HCM until the age of 59, and the other three family members
with the same deletion were unaffected, although they were 10, 32, and
33 years of age. In addition, two siblings of the proband showed
cardiac hypertrophy in the absence of the deletion, although they were
hypertensive.17 Variant cardiac ß-MHC molecules
resulting from the nonsense mutation found in this study might be
degraded before incorporation into the thick filament assembly because
the gene with this nonsense mutation should encode for only the
N-terminal 53 amino acid residues. Because both patients in pedigree 26
(the proband and his father) had the missense mutation, which also was
found in two other unrelated multiplex families, and because the
nonsense mutation was found in his unaffected relatives (his
grandmother and mother), it is unlikely that the nonsense mutation that
is equivalent to a gross deletion of the cardiac ß-MHC gene has a
causative role for HCM, at least in this family.
Asymmetrical septal hypertrophy is one of the most common clinical
findings in HCM. It was suggested that asymmetrical hypertrophy might
reflect regional differences in the ratio of mutant to wild-type MHC.
Although the proband of pedigree 26 who carried the nonsense mutation
should not have a normal cardiac ß-MHC molecule, his echocardiogram
showed an apparent ASH. We previously reported two patients who were
homozygous for a missense mutation of the cardiac ß-MHC gene
(Glu935Lys mutation), and their echocardiograms showed typical
ASH.12 Other workers reported that the clinical phenotype
of HCM caused by a mutation in -tropomyosin or the cardiac troponin
T gene was similar to that seen with cardiac ß-MHC
mutations.26 These observations suggest that the
distribution of cardiac hypertrophy may be influenced by other factors,
eg, hemodynamic effects in left ventricle or growth potency of each
part of ventricle, rather than the regional expression or proportion of
variant sarcomeric proteins in the cardiac tissue.
The effects of various MHC mutations on muscle functions have been well investigated in nematodes.27 28 29 Native myosin, commonly called a myosin dimer, contains two molecules of MHC to which four molecules of myosin light chains are bound. The myosin dimer is an important unit of the thick filament assembly. In nematodes, MHCs with missense mutations are incorporated into thick filaments and subsequently disrupt the assembly of thick filaments or sarcomeres.27 28 The missense mutations in the UNC54 gene, which caused the autosomal-dominant paralysis, were located within the globular head region of myosin.29 These findings are consistent with the fact that the missense mutations noted in HCM patients are found exclusively within the head and head-rod junction regions of the human cardiac ß-MHC. On the other hand, nonsense mutations and deletions were identified over the entire Caenorhabditis elegans UNC54 gene, and these mutations expressed the autosomal-recessive phenotype.29 These observations are consistent with the finding in the present study that the nonsense mutation did not cause HCM in a heterozygous subject, as was observed in the mother and grandmother of the proband in pedigree 26.
The effect of a null MHC allele was also well investigated in
Drosophila; it has been suggested that defects in
contractile protein synthesis are not compensated for in
Drosophila indirect flight muscles. In
Drosophila, the null alleles exhibit a dominant phenotype,
ie, stoichiometry is critical, in contrast to that in the nematodes. In
heterozygotes of the null alleles, the single functional gene is not
stimulated to produce twice the amount of
myosins.30 31 32 33 In
the present study, we could not obtain permission to analyze
cardiac ß-MHC gene expression in cardiac and skeletal muscles of the
proband's mother and grandmother; however, cardiac hypertrophy or
clinical signs of muscle weakness were not observed in them, and their
relatives had no history of heart or muscle disease. Therefore, we
suggest that the nonsense mutation of the cardiac ß-MHC gene found in
this family does not cause HCM or skeletal muscle disease in a
heterozygous subject. Expression of the MHC protein from the single
human cardiac ß-MHC gene might be sufficient to compensate for the
heterozygous defect of the null allele. Alternatively, the cardiac
-MHC gene, a cardiac MHC gene homologous to the cardiac ß-MHC
gene, might compensate for the defect of the cardiac ß-MHC gene in
these unaffected family relatives.
Watkins et al4 indicated that patients with mutations that
change the charge of the MHC protein had a significantly shorter life
expectancy. Because both arginine and histidine residues are classified
as basic amino acid residues, the nature of the Arg870His mutation does
not involve the change in charge. As Fig 4 shows,
patients with the Arg870His mutation survived longer than patients with
the Asp778Gly mutation,11 which has the charge alteration.
Therefore, the Arg870His mutation might not cause severe clinical
manifestations in young persons, as was the case with the 30-year-old
offspring in pedigree 6 (Fig 2b). The proband of pedigree 26,
however,
was heterozygous for the missense mutation and the nonsense mutation,
and thus no normal cardiac ß-MHC gene would be expressed. Because the
prognosis for the patients homozygous for the mutant cardiac ß-MHC
gene, ie, in the absence of a normal allele, is not
good,12 close follow-up is needed for the proband of
pedigree 26.
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From the findings in the current study and in previous reports on mutant myosins in humans and nematoda, it is suggested that gross abnormalities in the cardiac ß-MHC gene might have little pathogenic potential in the heterozygous state and that rather minor abnormalities in the cardiac ß-MHC gene, such as a missense mutation, may have a causative role in HCM. Our study underscores the importance of screening the full sequence of both alleles of the causative genes and the importance of a family study before the conclusion that a mutation causes the disease in unrelated patients with HCM is reached.
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Acknowledgments |
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This study was supported in part by grants-in-aid (05253215, 05670642, and 06274105) and a grant-in-aid for creative basic research (Human Genome Program) from the Ministry of Education, Culture, and Science, Japan; research grants from the Ministry of Health and Welfare, Japan; and research grants from the Kimura Memorial Heart Foundation and Naito Foundation. We thank Yuka Harada and Hideko Tsuji for technical assistance and Mariko Ohara for helpful comments on the manuscript.
Received January 25, 1995; revision received March 6, 1995; accepted March 13, 1995.
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