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(Circulation. 2000;102:663.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Clinical Features of Hypertrophic Cardiomyopathy Caused by a Lys183 Deletion Mutation in the Cardiac Troponin I Gene

Hiromasa Kokado, MD; Masami Shimizu, MD; Hiroyuki Yoshio, MD; Hidekazu Ino, MD; Kazuyasu Okeie, MD; Yorito Emoto, MD; Toru Matsuyama, MD; Masato Yamaguchi, MD; Toshihiko Yasuda, MD; Noboru Fujino, MD; Hideki Ito, MD; Hiroshi Mabuchi, MD

From The Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa, Japan.

Correspondence to Hiromasa Kokado, MD, The Second Department of Internal Medicine, School of Medicine, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan. E-mail fcc13{at}lilac.ocn.ne.jp

	Abstract

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Background—Mutations that cause hypertrophic cardiomyopathy (HCM) have been identified in 9 genes that code proteins in the sarcomere. Previous reports have demonstrated that cardiac troponin I (cTnI) gene mutations may account for familial HCM; however, the clinical characteristics and prognosis of patients with HCM caused by cTnI gene mutations are not known.

Methods and Results—We analyzed cTnI gene mutations in 130 unrelated probands with HCM and their families to clarify the genotype-phenotype correlations. We identified 25 individuals in 7 families with a Lys183 deletion (Lys183 del) mutation in exon 7 of the cTnI gene. The disease penetrance in subjects aged >20 years was 88% by echocardiography and 96% by ECG. Sudden death occurred in 7 individuals of 4 families at any age. Overall, 7 (43.8%) of 16 individuals aged >40 years had left ventricular systolic dysfunction, and 3 (18.8%) displayed dilated cardiomyopathy-like features. Of affected individuals, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up.

Conclusions—The Lys183 del mutation in the cTnI gene in patients with HCM is associated with variable clinical features and outcomes. HCM caused by the Lys183 del mutation has a significant disease penetrance. This mutation is associated with sudden death at any age and dilated cardiomyopathy-like features in those aged >40 years. However, it remains unclear whether screening of families with HCM for this mutation will be useful in patient management and counseling.

Key Words: hypertrophy • cardiomyopathy • genes • prognosis • proteins

	Introduction

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Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease with varying morphological, functional, and clinical features.¹ Inheritance of HCM is often autosomal dominant. Recent advances in molecular genetics have made it possible to investigate the etiology of HCM at the DNA level. HCM can be caused by a mutation in any 1 of the following 9 genes that encode proteins in the sarcomere: ß-cardiac myosin heavy chain (chromosome 14), -tropomyosin (chromosome 15), cardiac troponin T (cTnT, chromosome 1), cardiac troponin I (cTnI, chromosome 19), cardiac myosin binding protein C (chromosome 11), cardiac myosin regulatory light chain (chromosome 12), cardiac myosin essential light chain genes (chromosome 3), -cardiac actin (chromosome 1), and titin (chromosome 2).^{2 3 4 5 6 7 8} Although several pathological mutations have been defined for HCM, the clinical consequences of these genetic defects and their contribution to the incidence of disease are not completely understood. Recently, 6 mutations (5 missense and 1 deletion in exons 7 and 8) in the cTnI gene were identified. Only 1 family with 2 individuals affected with a Lys183 deletion (Lys183 del) mutation has been reported.⁶ However, the clinical characteristics and prognosis of patients with cTnI gene mutations are not known. We analyzed this gene in individuals from families with HCM to further clarify the genotype-phenotype correlations caused by cTnI mutations.

	Methods

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Subjects
Study subjects were composed of 130 unrelated probands with familial and sporadic HCM; 73 cases had family histories (familial HCM), whereas apparent family history was not observed in the other 57 cases (sporadic HCM). All probands were identified at the Kanazawa University Hospital or its related hospitals (from primary to tertiary care centers). The diagnosis of HCM was based on the echocardiographic demonstration of a nondilated hypertrophied left ventricle in the absence of other cardiac or systemic causes for the left ventricular hypertrophy.⁹ These patients also met the definition and classification proposed by the 1995 World Health Organization/International Society and Federation of Cardiology Task Force.¹⁰ Family members whose probands had a Lys183 del mutation were studied genetically and clinically. Informed consent was obtained from all subjects or from the parents of minors participating in the study.

Detection of Mutation
DNA was isolated from peripheral white blood cells of all subjects by use of a DNA extractor 341 Nucleic Acid Purification System (GENEPURE, Applied Biosystems). In vitro amplification of genomic DNA was performed via polymerase chain reaction (PCR). Oligonucleotide primers were used to amplify exon 7 of the cTnI gene as described previously.⁶ Single-strand conformational polymorphism analysis of amplified DNA was then performed by use of a previously described method,¹¹ with a slight modification. For abnormal single-strand conformational polymorphism patterns, PCR products were subcloned into the pCR2.1 vector by using the TOPO TA cloning kit (Invitrogen). 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, Applied Biosystems). Family members of the affected probands were evaluated similarly. Samples from 100 normal individuals were also analyzed.

Clinical Evaluations
Evaluation of the phenotype was completed before determination of the genotype. All probands and family members underwent 12-lead ECG and M-mode and 2D echocardiography. The distribution of left ventricular hypertrophy was assessed primarily in the parasternal long-axis view, although the parasternal short-axis and the apical 2- and 4-chamber views were also used to integrate the information obtained from the long-axis images. Disease penetrance was determined by the following criteria: (1) left ventricular end-diastolic maximal wall thickness 13 mm, (2) presence of major abnormalities on the ECG (ie, SV₁+RV_5/63.5 mV, Q wave 0.04 seconds or Q wave 1/4 the R wave amplitude and significant ST-T changes), or (3) a combination of criteria 1 and 2. Family members were evaluated similarly.

	Results

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Genetic Results
Overall, 130 probands with familial and sporadic HCM (96 men and 34 women) were screened for mutations in the cTnI gene. A Lys183 del mutation was identified in 7 probands (Figure 1). Relatives of these 7 probands were studied further, totaling 47 members of the various families (Figures 2A and 2B). Of these 47 individuals, 25 (8 men and 17 women, mean age 47.8±19.1 years) had a Lys183 del mutation in the cTnI gene. This mutation has been identified previously as the HCM gene.⁶ This mutation was not detected in the 100 unrelated normal individuals (data not shown).

View larger version (59K): [in this window] [in a new window]   Figure 1. Partial sequence of exon 7 in cTnI gene. PCR product of exon 7 from patient was cloned and sequenced. Codon 183 of normal allele is AAG, and that of mutant allele is deleted, showing that patient is heterozygous in terms of deletion at codon 183.

View larger version (27K): [in this window] [in a new window]   Figure 2. A, Pedigree of family 001 with HCM caused by Lys183 del mutation in cTnI gene. Genotypic and phenotypic status of subjects is indicated in key. Ages of patients who died suddenly are shown in parentheses. B, Pedigrees of families 070, 006, 075, 088, 104, and 020 with HCM caused by Lys183 del mutation in cTnI gene.

Clinical Features
Of the 7 proband families studied, 47 individuals underwent clinical evaluation. Table 1 shows the echocardiographic and ECG data of the 25 individuals affected genetically. Asymmetrical septal hypertrophy (interventricular septal wall thickness 13 mm, interventricular septal thickness/LV posterior wall thickness 1.3) was found in 13 subjects (52.0%). The mean maximal left ventricular wall thickness was 14.2±4.8 mm. Left ventricular systolic dysfunction (fractional shortening <25%) was observed in 7 of 16 individuals aged >40 years. Maximal left ventricular wall thickness was 13 mm in these 7 individuals (mean 10.6±2.1 mm). Left ventricular end-diastolic dimension was >50 mm in 6 of these 7 individuals. However, fractional shortening was >25% in all subjects aged <40 years. Echocardiographic abnormalities were noted in 21 of 25 affected subjects. On ECG, 20 individuals had sinus rhythm, 1 had junctional rhythm, 3 had chronic atrial fibrillation, and 1 had paroxysmal atrial fibrillation. Q waves were noted in 17 subjects (SV₁+RV₅3.5 mV in 12 subjects and significant ST-T changes in 22 subjects). One subject had deep inverted T waves (-1.0 mV) in the precordial leads. All individuals, except for V-6 of family 001 and III-2 of family 075, had echocardiographic and/or ECG abnormalities.

View this table: [in this window] [in a new window]   Table 1. Echocardiographic and ECG Findings in the Affected Individuals

View this table: [in this window] [in a new window]   Table 1A. Continued

Clinical Course and Sudden Death
We followed 6 individuals for >5 years (8.7±2.5 years, range 6 to 13 years). Table 2 and Figure 3 show the echocardiographic changes during >5 years of follow-up. Four members of family 001 developed left ventricular systolic dysfunction and thinning of the hypertrophied septum. One in particular, IV-6, progressed to dilated cardiomyopathy-like features (fractional shortening was <25%, and left ventricular end-diastolic dimension was 55 mm) in the fourth decade of life. In regard to treatment, ß-blockers had been used in 2 individuals, and calcium antagonists had been used in 4 of 6 individuals. Nevertheless, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up. Overall, sudden death occurred in 7 participants (Figures 2A and 2B), and it occurred in any generation from the teens to the 70s (mean age 45.3±17.3 years). All individuals with left ventricular systolic dysfunction were aged >40 years (mean 58.9±9.3 years), and 3 (18.8%) of 16 individuals aged >40 years demonstrated dilated cardiomyopathy-like features (Table 1).

View this table: [in this window] [in a new window]   Table 2. Echocardiographic Changes During >5 Years of Follow-Up

View larger version (11K): [in this window] [in a new window]   Figure 3. Echocardiographic changes during >5 years of follow-up. Four of 5 affected individuals aged >40 years followed by echocardiography over 5 years revealed decreased fractional shortening (FS) with thinning of the hypertrophied septum. Three of these 4 individuals progressed to left ventricular systolic dysfunction (fractional shortening <25%).

	Discussion

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Six different mutations in the cTnI gene have been reported to cause familial HCM.⁶ The clinical characteristics and prognosis of patients with the Lys183 del mutation in the cTnI gene are unclear because affected individuals are rare. Our genetic analyses identified 25 individuals with the Lys183 del mutation in the cTnI gene. We evaluated the echocardiographic and ECG findings and the clinical course in individuals with the Lys183 del mutation in the cTnI gene.

Penetrance and Clinical Features
Moolman et al¹² have reported that the cTnT mutation, Arg92Trp, is characterized by low disease penetrance (40% by echocardiography and 66% by ECG) in HCM. On the other hand, Anan et al¹³ reported a greater penetrance with the Phe110Ile mutation of cTnT (94% by ECG and 81% by echocardiography). No previous reports have focused on the penetrance of cTnI gene mutations. In the present study, we observed that the disease penetrance in subjects aged >20 years was 88% (21 of 24 individuals) by echocardiography and 96% (23 of 24 individuals) on the basis of ECG abnormalities. ECG seems to be more sensitive than echocardiography in detecting disease-causing mutations. The Lys183 del mutation in the cTnI gene was characterized by high disease penetrance. Because the Lys183 del mutation of cTnI demonstrated high disease penetrance and because this mutation was found at the evolutionarily conserved amino acid of troponin I,^{14 15 16 17 18 19} this region is believed to be of increased functional significance. Because the same mutation has been reported previously,⁶ it may also be a mutant " hot spot."

Hecht et al²⁰ described 7 families with genetically transmitted HCM evaluated with echocardiography, necropsy, or both. Family members with HCM, despite a common genetic substrate, may exhibit markedly diverse and distinct expression of the natural history of their disease, which can occur at any age. Few studies have addressed the cardiac morphology of genotyped individuals with HCM. Phe110Ile substitution in the cTnT gene has been reported to cause HCM with variable cardiac morphologies.¹³ Kimura et al⁶ recently reported that 3 (8.3%) of 36 individuals with apical hypertrophy had mutations in the cTnI gene, suggesting that apical hypertrophy is a form of HCM, a disease of the sarcomere. They also reported that a patient with the Lys183 del mutation was diagnosed with apical HCM, whereas his son with the same mutation developed typical HCM. We found that the ventricular morphology of individuals with HCM caused by the Lys183 del mutation in the cTnI gene varied considerably, inasmuch as only 1 individual with this mutation showed apical hypertrophy with asymmetrical septal hypertrophy. None of our subjects had apical hypertrophy alone. Our analysis demonstrates that the distribution of hypertrophy among affected individuals varies within and between families.

Clinical Course and Prognosis
HCM is a slowly progressive disorder that manifests remarkable evolution of clinical features during its long-term natural course.^{20 21} Certain mutations in the ß-myosin heavy chain appear to carry more serious prognostic implications than others; some may be associated with a largely benign clinical course and near-normal life expectancy (eg, Val606Met),^22–25 whereas others have been reported in a relatively small number of families, leading to decreased survival due to either sudden catastrophic events or heart failure (eg, Arg403Gln, Arg453Cys, and Arg719Trp).^{22 23 24 25 26} Mutations in the gene for myosin-binding protein C appear to be associated with a relatively favorable clinical course, and a substantial proportion of genetically affected adults exhibits no phenotypic evidence of disease on echocardiography.²⁷ Six mutations in the cTnT gene (Ile79Asn, Arg92Gln, Arg92Trp, Ala104Val, Glu160 del, and intron 15 G₁A) have been associated with an increased incidence of sudden death,^{12 28 29} whereas the Phe110Ile mutation in cTnT has a benign outcome.¹³ Regarding the mutations in the cTnI gene, there is no report. We found 25 individuals from 7 families with the Lys183 del mutation. Sudden death occurred in 7 individuals from 4 families and could occur at any age from the teens to the 70s. One young individual (III-3 of family 075) died suddenly during jogging, but sudden death occurred during mild activity in another 3 individuals: 2 (III-19 and IV-16 of family 001) died during walking at the home and in the hospital, respectively, and 1 died shortly after taking a bath. The exact activity at the time of death was unknown in the other 3 individuals. In young apparently healthy athletes with HCM, sudden death is often the first manifestation of the disease.^{30 31 32} On the other hand, because previous studies revealed that an abnormal blood pressure response during exercise was more common in young HCM patients and that an abnormal blood pressure response was associated with an increased risk of sudden cardiac death,^{33 34} it is recommended that young patients with HCM avoid intense training and competition in particular. Of 25 genetically affected individuals, 7 individuals with left ventricular systolic dysfunction were aged >40 years, with 3 individuals displaying dilated cardiomyopathy-like features. These data suggest that individuals with HCM caused by the Lys183 del mutation in the cTnI gene are likely to die suddenly at any age and that systolic dysfunction, evidenced by dilatation of the left ventricular cavities and thinning of left ventricular wall, is common after age 40. The Lys183 del mutation is associated with a comparatively malignant clinical course; we suggest that this mutation is the deletion of a positively charged amino acid, and this region is believed to be of increased functional significance. The cTnI isoform is expressed only in cardiac muscles³⁵ and contains several functional domains: (1) the NH₂-terminal extension, which contains 2 sites at serine residues 23 and 24, the phosphorylation of which alters calcium sensitivity and eliminates cooperative binding to actin, (2) the near NH₂-terminal domain, which binds to the COOH terminus of cardiac troponin C containing 2 sites at serine residues 42 and 44, the phosphorylation of which reduces the maximum ATPase rate, (3) the inhibitory region that binds both actin and cardiac troponin C to induce relaxation via inhibition of the actomyosin interaction, and (4) the COOH-terminal domain, which is important for calcium sensitivity of the myofilaments.^{36 37} Because Lys183 in cTnI is within the C-terminal domain, the Lys183 del mutation may cause an alteration of the calcium-dependent regulation of cardiac myofilament contraction. On the other hand, Lys183 lies immediately to the C-terminal side of the important region that binds actin-tropomyosin and enhances the inhibitory effect.³⁸ In addition, it has been reported that deletions of 23 [cTnI-(1-188)] and 60 [cTnI-(1-151)] residues from the C-terminus of cTnI cause reduced inhibition of actomyosin ATPase activity.³⁷ The loss of inhibitory function may weaken the interaction of cTnI with actin-tropomyosin and may influence muscle contraction and relaxation. The report of Huang et al³⁹ describing that the cTnI gene knockout mouse showed elevated resting tension, reduced calcium sensitivity during the development of active force, and shortened sarcomeres supports our speculations. They also reported that slow skeletal troponin I (ssTnI) initially compensated for the absence of cTnI, but beginning at approximately day 15 after birth, a steady loss of ssTnI occurred, giving rise to heart failure.³⁹ Because of a small reduction in the potency of inhibition of actomyosin ATPase caused by the Lys183 del mutation⁴⁰ and heterozygous patients, the impaired function of cTnI in patients with the Lys183 del mutation may be compensated for by ssTnI at a young age. However, a loss of ssTnI may occur with increasing age and may lead to heart failure in individuals aged >40 years. Further investigation of the phenotype in the Lys183 del mutation is necessary.

In regard to treatment, of 6 individuals followed for >5 years (8.7±2.5 years), ß-blockers had been used in 2 individuals, and calcium antagonists had been used in 4. Currently, ß-blockers and calcium antagonists have been used extensively in the treatment of HCM. But whether these drugs should be used prophylactically to delay disease progression and improve the prognosis has been a subject of debate for many years. In our patients, 4 of 5 aged >40 years that were followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up. The effectiveness of prophylactic treatment has not been tested prospectively because study populations are small.

Limitations of the Study
Because this mutation shows low prevalence, it is unclear whether early genetic diagnosis could lead to an intervention that would alter the outcomes. Large-scale analysis is required to clarify the phenotype-genotype correlations in the future.

Conclusion
A Lys183 del mutation was found in 7 of 130 Japanese families with HCM. HCM caused by the Lys183 del mutation of the cTnI gene shows a high disease penetrance. Approximately half of the individuals with this mutation aged >40 years may exhibit left ventricular systolic dysfunction, and some may develop a dilated cardiomyopathy. Sudden death may occur in individuals with this mutation at any age.

Received November 9, 1999; revision received February 16, 2000; accepted March 2, 2000.

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