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European Journal of Heart Failure 2004 6(7):861-868; doi:10.1016/j.ejheart.2004.04.017
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© 2004 European Society of Cardiology

Two novel mutations in the β-myosin heavy chain gene associated with dilated cardiomyopathy

Satu Kärkkäinena, Tiina Heliöb, Pertti Jääskeläinena, Raija Miettinena, Petri Tuomainena, Kari Ylitaloc, Maija Kaartinenb, Eeva Reissellb, Lauri Toivonenb, Markku S. Nieminenb, Johanna Kuusistoa, Markku Laaksoa and Keijo Peuhkurinena,*

a Department of Medicine, Kuopio University Hospital P.O. Box 1777, 70211 Kuopio, Finland
b Department of Medicine, University of Helsinki Helsinki, Finland
c Department of Medicine, University of Oulu Oulu, Finland

* Corresponding author. Tel.: +358-17-173956; Fax: +358-17-173959. E-mail address: Keijo.Peuhkurinen{at}kuh.fi


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Dilated cardiomyopathy (DCM) is familial in approximately 20–35% of cases of idiopathic DCM. Several mutations in the different sarcomere protein genes have been reported to cause DCM.

Aims: We wanted to investigate the role of sarcomere protein gene variants in Finnish DCM patients.

Methods and results: We screened all coding exons of five sarcomere protein genes (β-myosin heavy chain, {alpha}-tropomyosin, troponin C, troponin I and troponin T) in a well-characterized population of 52 DCM patients in Eastern Finland by the PCR-SSCP and sequencing method. Two novel mutations, Arg1053Gln and Arg1500Trp, in the β-myosin heavy chain gene in two index patients were detected. The proband with the Arg1053Gln mutation had a dilated left ventricle and impaired systolic function, but other family members carrying this mutation presented with septal hypertrophy. It thus seems that the Arg1053Gln mutation is primarily a HCM mutation, which can also lead to DCM. The other mutation, Arg1500Trp, was associated with a typical DCM phenotype. The Arg1500Trp mutation carrier had only one family member alive, but she did not carry the mutation and, therefore, cosegregation of the mutation and the disease in this family could not be reliably verified. No disease-causing mutations were found in the other sarcomere protein genes.

Conclusions: Two novel mutations in the β-myosin heavy chain gene were detected in patients with DCM. Overall, mutations in the β-myosin heavy chain gene seem to be relatively uncommon in Finnish DCM patients.

Key Words: Dilated • Hypertrophy cardiomyopathy • Sarcomere protein gene

Received December 4, 2003; Revised March 28, 2004; Accepted April 2, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Dilated cardiomyopathy (DCM) is a heterogeneous disease having variable etiological and clinical features. DCM is familial in approximately 20–35% of cases of idiopathic DCM, but the genetic basis of this disease is largely unknown [1,2]. To date, the disease-associated gene defects have been reported in 16 different genes [3–17]. Over 10 DCM-associated mutations have been reported in eight different sarcomere protein genes including cardiac actin, {alpha}-tropomyosin, β-myosin heavy chain, troponin T, myosin-binding protein-C, titin, telethonin and troponin I genes [3,7,10,11,14,16–19]. The DCM-causing mechanisms have been classified into four main groups: in the first group force generation, in the second group force transmission, in the third group energy production are affected and in the last group the disease-causing mechanisms remain unclear [20].

Over 150 mutations in 11 sarcomere protein genes have been reported to be associated with hypertrophic cardiomyopathy (HCM) [21–23]. Primarily, HCM patients have normal systolic function and no dilatation of the left ventricle. However, a small proportion (~10%) of HCM patients develop heart failure with dilatation of left ventricle and reduced ejection fraction, the phenotype resembling that of DCM [24]. Several clinical reports of transition from HCM to DCM have been published [25–27], but only a few specific mutations associated with the transition forms of HCM have been described to date. Mutations in the troponin T, {alpha}-tropomyosin, β-myosin heavy chain, and myosin binding protein-C genes, but also in the mitochondrial genome (mtDNA), are known to be associated with a transition from HCM-type disease to DCM-type disease [28–35]. Mutations in the mtDNA, e.g., 3243A>G, usually cause HCM, but also primary DCM has been encountered [36].

Although several mutations in the sarcomere protein genes in DCM have been reported, they explain the disease only in isolated families. Previously, we have already screened the cardiac actin gene in our DCM study group, but did not find any disease-associated variants [37]. To investigate further whether defects in other sarcomere protein genes would cause DCM in Finnish patients, we screened the entire coding regions of the β-myosin heavy chain, {alpha}-tropomyosin, cardiac troponin C, I and T genes.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects and clinical evaluation
We studied 52 DCM patients from the Kuopio University Hospital region in Eastern Finland. Eight index patients were classified as familial and 44 index patients as sporadic cases. The diagnostic criteria for DCM were left ventricular ejection fraction <45% and left ventricular end-diastolic diameter >27 mm/m2 in the absence of secondary causes for DCM [38]. The diagnostic criteria for HCM were left ventricular wall thickness ≥15 mm, blood pressure ≤160/100 mm Hg, and no other causes for ventricular hypertrophy (e.g., primary valvular disease). The patients were evaluated by personal and family history, physical examination, 12-lead electrocardiography (ECG), chest X-ray and transthoracic echocardiography (M-mode, two-dimensional and Doppler). Furthermore, 87% of patients with DCM underwent diagnostic coronary angiography. All available first-degree relatives of the eight families were evaluated by physical examination, 12-lead ECG and transthoracic echocardiography. The diagnostic criteria for family members were the same as previously described [39]. The study protocol was approved by the Ethics Committees of the University of Kuopio and University of Helsinki, and it was in accordance with the Helsinki Declaration.

The study group consisted of 37 men and 15 women, and the mean age at the time of diagnosis was 50 years (range, 11 to 71 years). Left ventricular end-diastolic diameter (LVEDD) varied from 51 to 99 mm (mean 65 mm) and the mean ejection fraction was 34%.

2.2. Additional study group
We screened an additional group of 104 DCM patients for the two mutations (which were found in this study in exons 25 and 32) in the β-myosin heavy chain gene. In this additional study group there were 15 subjects with confirmed familial disease, and the rest of the group was determined to represent sporadic cases. The majority of patients in this additional study group (n=66) underwent heart transplantation, the others living in the area of Helsinki University Hospital.

2.3. Controls
One hundred fifty clinically healthy control subjects without any family history of DCM formed the control group. Echocardiography was performed on 82 of these control subjects and it did not reveal any findings suggesting cardiomyopathy. Control subjects were screened by PCR-SSCP method.

2.4. Laboratory methods
Genomic DNA extraction and the details of the polymerase chain reaction (PCR) and single-strand conformation polymorphism analysis (SSCP) have been described [37]. Our SSCP method has been previously validated against the known variants of the lipoprotein lipase gene [40,41]. Primers for the β-myosin heavy chain, troponin C, I and T genes were designed according to the Genbank sequences M57965 [GenBank] , M37984 [GenBank] , X90780 [GenBank] and AY044273 [GenBank] , respectively, and primers for the {alpha}-tropomyosin gene were synthesized as previously reported [42]. The PCR conditions were denatured at 94 °C for 3 min, followed by 35 cycles of denaturation at 94 °C for 40 s, annealing at 56–68 °C for 20–45 s and extension at 72 °C for 30–60 s with final extension at 72 °C for 4 min.

Genomic DNA from individuals with variant SSCP patterns was sequenced with ABI Prism BigDye Terminator Cycle Sequencing Ready Reaction Kits using ABI Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Variants in the β-myosin heavy chain gene
All 38 coding exons of the β-myosin heavy chain gene were screened with the PCR-SSCP method for variants. We detected two formerly unreported mutations, Arg1053Gln and Arg1500Trp, in the β-myosin heavy chain gene in two Finnish patients with DCM (Figs. 1 and 2). The Arg1053Gln mutation showed consegregation with the clinical disease (Fig. 1 and Table 2). The Arg1500Trp mutation was detected only in one DCM patient, and her healthy offspring did not carry the mutation. The deceased mother of the index patient with the Arg1500Trp mutation suffered heart failure and cardiomegaly was detected in her chest X-ray, however. Because DNA sample was not available the presence of the mutation could not be verified. Additionally, none of these mutations was found in 150 healthy control subjects nor in the additional study group of DCM patients (n=104), excluding the possibility of common polymorphism. Several other variants were also found in the β-myosin heavy chain among the 52 DCM patients, but all these variants were silent nucleotide substitutions and almost all have also been previously reported. The variants in the β-myosin heavy chain are listed in Table 1.


Figure 1
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  		Fig. 1 (A) The pedigree of the family carrying the Arg1053Gln mutation in the β-myosin heavy chain gene. Squares indicate male family members, circles female family members and symbols with slash deceased members. Solid symbols indicate affected family members and open symbols unaffected members. Mutation carrier is indicated by a + sign; subjects without mutation are indicated by a – sign. N means not clinically studied. (B) The SSCP film showing mutated and normal DNA. The Arg1053Gln mutation makes an additional restriction site for AlwNI. (C) The sequences of normal and mutated DNA indicate a substitution of G to A in codon 1053.

 


Figure 2
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  		Fig. 2 (A) The pedigree of the family with the Arg1500Trp mutation. Solid symbols indicate affected family members and open symbols unaffected members. Semicircle indicates family member, who had symptoms and signs of DCM, but the diagnosis of DCM was not confirmed. Mutation carrier is indicated by a + sign; subjects without mutation are indicated a – sign. (B) The SSCP-film showing mutated and normal DNA. M=mutation, N=Normal. (C) The sequences of normal and mutated DNA indicating substitution of C to T in codon 1500.

 


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  		Table 1 Variants of the β-myosin heavy chain, {alpha}-tropomyosin and troponin C, I and T genes found in 52 DCM patients

 
3.2. Patients with the Arg1053Gln mutation in the β-myosin heavy chain gene
The family with the Arg1053Gln mutation presented with two different phenotypes of cardiomyopathy. The clinical characteristics of the family with the Arg1053Gln mutation are presented in Table 2. One of the family members (II: 2) was clinically examined at the age of 14 years. Cardiomegaly in the chest X-ray (530 cm3/m2) and left ventricular hypertrophy with normal duration of QRS complex on ECG were diagnosed. His blood pressure was normal. At the age of 31 years the size of the heart was further increased (620 cm3/m2), but the patient was asymptomatic. The first echocardiography was performed at the age of 36 years. LVEDD was not reported in the hospital charts, but EF was normal (70%) and the end-diastolic thickness of myocardium varied between 10 and 12 mm, and no valvular abnormalities were observed. After 30 years (at the age of 44 years) of the first finding of cardiomegaly, the patient developed slow atrial fibrillation and congestive heart failure, and a permanent pacemaker was implanted. In echocardiography the left ventricle was observed to be dilated and ejection fraction to be decreased (LVEDD 68 mm and EF 41%). Additionally, there was slight hypertrophy of the interventricular septum (IVSD, 13 mm) and of the posterior wall of the left ventricle (LVPWD, 13 mm). During 3 years of follow-up, the findings in echocardiography remained unchanged. In diagnostic coronary angiography no signs of coronary artery disease were found. The patient died suddenly after a slight exercise at the age of 48 years. Death was classified as sudden cardiac death, and in the autopsy the anterior wall of the enlarged left ventricle was stiff and diffusely fibrotic.


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  		Table 2 Characteristics of the disease in the Arg1053Gln mutation

 
Both of the index patients' siblings (II: 3 and II: 5) were carriers of the Arg1053Gln mutation, and fulfilled the diagnostic criteria for HCM. Proband's brother (II: 3) had his first symptoms (palpitations especially during exercise) of the disease at the age of 36 years. His ECG revealed negative T waves in lateral leads and left ventricular hypertrophy. In echocardiography, LVEDD and ejection fraction were normal (LVEDD 49 mm and EF 72%); IVSD was 11 mm and LVPWD was 10 mm. He suffered from drug-resistant rapid atrial fibrillation and later developed cardiac hypertrophy. At the age of 51 years IVSD was 17 mm, but the diameters and systolic function of the left ventricle were normal (LVEDD 50 mm, EF 71%). Ambulatory 24-h ECG monitoring revealed supraventricular extrasystoles and episodes of supraventricular tachycardia.

Proband's sister (II: 5) had severe chest pain at the age of 45 years and underwent diagnostic coronary angiography. There were no significant stenoses in coronary arteries, but clear myocardial bridging in the left anterior descending coronary artery (LAD) was detected. Echocardiography revealed myocardial hypertrophy (IVSD 17 mm) with normal LVEDD (42 mm) and EF (over 50%). After 10 years myocardial hypertrophy had progressed (IVSD 22 mm), but there were no signs of left ventricular dilatation or decreased ejection fraction.

All children of the affected family members were clinically examined with the exception of one (III: 4), who had died due to stomach cancer. Three family members of the third generation were clinically and genetically affected. All of them had similar phenotype and findings in echocardiography (LVH on ECG and IVSDs of 15/16/18 mm). None of them had ventricular dilatation, and EF was normal. One family member (III: 7) had normal ECG and echocardiography, but she refused from genetic analyses. Two asymptomatic family members (III: 2 and III: 4) did not have any signs of HCM or DCM in echocardiography and they were not mutation carriers.

3.3. Patient with the Arg1500Trp mutation in the β-myosin heavy chain gene
The first symptoms (palpitation, dyspnea and chest pain) of the disease in the Arg1500Trp mutation carrier appeared at the age of 55 years. P-terminal force (PTF) and left ventricular hypertrophy (LVH) were detected on ECG. In echocardiography the diagnostic criteria for DCM were fulfilled, LVEDD being 70 mm and EF 32%. No ventricular hypertrophy, but secondary mitral regurgitation, was found. In coronary angiography there were no signs of coronary artery disease. After primary diagnosis medical treatment (ACE-inhibitors, β-blockers, digitalis and warfarin) was started and during 7 years of follow-up she has been stable ever since, echocardiographic parameters showing some improvement.

Her mother died at the age of 75 years due to heart failure. She had had first symptoms and signs of heart failure in her 60s. Echocardiography was not performed, but in chest X-ray cardiomegaly was detected. She had normal blood pressure and type II diabetes. There was no suspicion of coronary artery disease in her medical charts. Unfortunately, DNA sample is not available from her. The mother of the index patient had 14 siblings, but they have all died, some of them at a young age. Since DNA was not available we were not able to verify that the disease was familial in nature. The father of the index patient died in the war, and he did not have any cardiac symptoms. The daughter of the index patient is not a mutation carrier and she is also clinically healthy with normal findings in echocardiography. The clinical characteristics of the family with the Arg1500Trp mutation are presented in Table 3.


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  		Table 3 Clinical characteristics of the family with the Arg1500Trp mutation

 
3.4. Variants in the {alpha}-tropomyosin, troponin C, I and T genes
We also screened 9 exons of {alpha}-tropomyosin, 6 exons of troponin C, 8 exons of troponin I and 16 exons of troponin T genes. Several variants in the {alpha}-tropomyosin, troponin C, I and T genes were detected. None of these variants was clearly associated with DCM, since all the variants were detected also in control patients with two exceptions (Table 1). Two variants were located in the non-coding regions of the troponin C (A->C in 3'UTR region) and troponin T (intron 6–50 bp G->T/A) genes, and therefore they are probably not disease-causing variants, because they were not located in the coding regions or splicing cites of the genes. Previously, only one variant associated with cardiomyopathy has been detected in the non-coding region of the troponin T gene (IVS 15+1 G->A [43]). Another variant, Lys263Arg, in exon 15 of the troponin T gene was detected, but the same variant was also found in control subjects and patients with hypertrophic cardiomyopathy excluding the possibility of disease-causing effect of the variant [43].


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We describe here two novel missense mutations in the β-myosin heavy chain gene, which were primarily detected in patients with a DCM phenotype. The Arg1053Gln mutation was identified later to be associated with several patients carrying a HCM phenotype. The Arg1500Trp mutation was found in a patient with classical DCM, but it was not possible to prove the familiarity of the disease. We can assume that both of these mutations can cause DCM. The disease-associating effect of the mutations is supported by the fact that neither of the mutations was detected in 150 healthy controls or in the additional study group of DCM patients excluding the possibility of common polymorphism, and that both mutations affect conserved residues of the β-myosin heavy chain gene. Functional studies of the mutations are needed before clear conclusions about the disease-causing mechanisms can be established.

To our knowledge, DCM-causing mutations in the β-myosin heavy chain gene have been considered rare, and only four mutations of this kind have been found previously [3,10]. In our DCM patients the novel mutations in the β-myosin heavy chain gene seem to be rather uncommon, too. On the other hand, only one mutation in the β-myosin heavy chain gene has been previously detected among Finnish HCM patients, and this mutation explains only 3% of all HCM cases in the Eastern Finnish population [44]. In contrast, in other populations mutations in the β-myosin heavy chain gene are substantially more frequent (30%) in patients with HCM than DCM [22].

Most of the HCM-associated and all of the previously published DCM-associated β-myosin heavy chain mutations are located in the region encoding the globular head and head-rod junction of the protein [3,10,45]. The previously reported mutations (Ala223Thr, Ser532Pro, Ser642Leu and Phe764Leu) in the β-myosin heavy chain gene causing DCM are located in the region called S1, which has binding sites for actin and ATP [3,10]. Also previously reported mutations, Arg249Gln, Lys450Glu, Leu517Met, Gln734Glu in the β-myosin heavy chain gene associated with a transition form of HCM are located in the same region [30,35]. The DCM-associated mutations in the β-myosin heavy chain gene are thought to disrupt binding between myosin and actin, decrease efficiency of contraction by altering the magnitude or polarity of transmitted movement, or alternatively decrease thermostability or affect protein folding [3,10]. The Arg1053Gln and Arg1500Trp mutations are located in different regions of the protein compared to those reported by Kamisago et al. [10], Daehmlow et al. [3], Arbustini et al. [30] and Nanni et al. [35], and probably the disease-causing mechanisms are also different in these mutations. The Arg1053Gln mutation in exon 25 is located in the S2 domain participating in the interaction between cardiac myosin-binding protein-C and β-myosin heavy chain proteins [46]. On the other hand, the Arg1500Trp mutation in exon 32 is located in the rod domain of the protein called light meromyosin (LMM), which has a role in the assembly of the thick filament [47]. In this part of the protein there are also binding sites for titin and cardiac myosin-binding protein-C [45].

In our family with the Arg1053Gln mutation, the phenotypes of the mutation carriers were variable and one family member (II: 2) probably demonstrated a transition from a HCM to a DCM-type disease. His first clinical examination was performed at the time when there was no possibility to echocardiography, and therefore, the primary diagnosis is uncertain. However, later, his phenotype and echocardiographic findings fulfilled the diagnostic criteria for DCM, although some hypertrophy of septal myocardium was found. Therefore, his disease had characteristics of a transition from a HCM to a DCM-type disease. According to previous studies patients who first have HCM-type disease and later develop DCM-type disease are often young at the onset of symptoms [25,30,32]. Our patient was only 14 years old, when cardiomyopathy was first suspected. The transition form of HCM has been shown to be associated with poor prognosis including sudden death and need for heart transplantation, and in accordance with this our patient also died of sudden cardiac death at the age of 48 years [48,49].

In the small family with the Arg1500Trp mutation, the cosegregation of the mutation with the disease could not be confirmed, and this of course is a clear limitation in our study. Our index patient had a phenotype of DCM fulfilling all the diagnostic criteria for the disease, and her mother also suffered from heart failure. Because DNA was not available from the mother the familiarity could not be verified. The only family member alive, the index patients' daughter, is healthy, and did not carry the mutation.

In summary, we describe two novel mutations (Arg1053Gln and Arg1500Trp) in the β-myosin heavy chain gene in Finnish patients with dilated cardiomyopathy. Although mutations in the β-myosin heavy chain gene are quite uncommon in patients with DCM, they should perhaps be taken into consideration when genetic screening is performed in familial cases.


   Acknowledgements
 
This study was supported by Finnish Foundation for Cardiovascular Research, Finnish Cardiac Society, Aarne Koskelo Foundation, Ida Montin foundation, The North-Savo Fund of the Finnish Cultural foundation, Kuopio University Hospital (EVO grant no. 5140) and Helsinki University Hospital (EVO grant no. T1010K0002).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Grunig E., Tasman J.A., Kucherer H., Franz W., Kubler W., Katus H.A. Frequency and phenotypes of familial dilated cardiomyopathy. J. Am. Coll. Cardiol (1998) 31(1):186–194.[Abstract/Free Full Text]
  2. Michels V.V., Moll P.P., Miller F.A., Tajik A.J., Chu J.S., Driscoll D.J., et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N. Engl. J. Med (1992) 326(2):77–82.[Abstract]
  3. Daehmlow S., Erdmann J., Knueppel T., Gille C., Froemmel C., Hummel M., et al. Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem. Biophys. Res. Commun (2002) 298(1):116.[CrossRef][Web of Science][Medline]
  4. Bione S., D'Adamo P., Maestrini E., Gedeon A.K., Bolhuis P.A., Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat. Genet (1996) 12(4):385–389.[CrossRef][Web of Science][Medline]
  5. Muntoni F., Cau M., Ganau A., Congiu R., Arvedi G., Mateddu A., et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N. Engl. J. Med (1993) 329(13):921–925.[Free Full Text]
  6. Towbin J.A., Hejtmancik J.F., Brink P., Gelb B., Zhu X.M., Chamberlain J.S., et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation (1993) 87(6):1854–1865.[Abstract/Free Full Text]
  7. Olson T.M., Michels V.V., Thibodeau S.N., Tai Y.S., Keating M.T. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science (1998) 280(5364):750–752.[Abstract/Free Full Text]
  8. Li D., Tapscoft T., Gonzalez O., Burch P.E., Quinones M.A., Zoghbi W.A., et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation (1999) 100(5):461–464.[Abstract/Free Full Text]
  9. Tsubata S., Bowles K.R., Vatta M., Zintz C., Titus J., Muhonen L., et al. Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J. Clin. Invest (2000) 106(5):655–662.[Web of Science][Medline]
  10. Kamisago M., Sharma S.D., De Palma S.R., Solomon S., Sharma P., McDonough B., et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N. Engl. J. Med (2000) 343(23):1688–1696.[Abstract/Free Full Text]
  11. Olson T.M., Kishimoto N.Y., Whitby F.G., Michels V.V. Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J. Mol. Cell Cardiol (2001) 33(4):723–732.[CrossRef][Web of Science][Medline]
  12. Fatkin D., MacRae C., Sasaki T., Wolff M.R., Porcu M., Frenneaux M., et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med (1999) 341(23):1715–1724.[Abstract/Free Full Text]
  13. Olson T.M., Illenberger S., Kishimoto N.Y., Huttelmaier S., Keating M.T., Jockusch B.M. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation (2002) 105(4):431–437.[Abstract/Free Full Text]
  14. Gerull B., Gramlich M., Atherton J., McNabb M., Trombitas K., Sasse-Klaassen S., et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat. Genet (2002) 14:14.
  15. Schmitt J.P., Kamisago M., Asahi M., Li G.H., Ahmad F., Mende U., et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science (2003) 299(5611):1410–1413.[Abstract/Free Full Text]
  16. Knöll R., Hoshijima M., Hoffman H., Person V., Lorenzen-Schmidt I., Bang M. The cardiac mechanical stretch sensor machinery involves a z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell (2002) 111:943–955.[CrossRef][Web of Science][Medline]
  17. Murphy R.T., Mogensen J., Shaw A., Kubo T., Hughes S., McKenna W.J. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet (2004) 363:371–372.[CrossRef][Web of Science][Medline]
  18. Li D., Czernuszewicz G.Z., Gonzalez O., Tapscott T., Karibe A., Durand J.B., et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation (2001) 104(18):2188–2193.[Abstract/Free Full Text]
  19. Itoh-Satoh M., Hayashi T., Nishi H., Koga Y., Arimura T., Koyanagi T., et al. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem. Biophys. Res. Commun (2002) 291(2):385–393.[CrossRef][Web of Science][Medline]
  20. Schonberger J., Seidman C.E. Many roads lead to a broken heart: the genetics of dilated cardiomyopathy. Am. J. Hum. Genet (2001) 69(2):249–260.[CrossRef][Medline]
  21. Hoffmann B., Schmidt-Traub H., Perrot A., Osterziel K.J., Gessner R. First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy. Hum. Mutat (2001) 17(6):524.[Medline]
  22. Marian A.J., Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J. Mol. Cell Cardiol (2001) 33(4):655–670.[CrossRef][Web of Science][Medline]
  23. Niimura H., Patton K.K., McKenna W.J., Soults J., Maron B.J., Seidman J.G., et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation (2002) 105(4):446–451.[Abstract/Free Full Text]
  24. Spirito P., Maron B.J., Bonow R.O., Epstein S.E. Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am. J. Cardiol (1987) 60(1):123–129.[CrossRef][Web of Science][Medline]
  25. Okamoto S., Ozaki M., Konishi T., Nakano T. A case report of siblings with hypertrophic cardiomyopathy that progressed to dilated cardiomyopathy—case reports. Angiology (1993) 44(5):406–411.[CrossRef][Web of Science][Medline]
  26. Onodera T., Fujiwara H., Tanaka M., Wu D.J., Hamashima Y., Kawai C. Familial hypertrophic cardiomyopathy mimicking typical dilated cardiomyopathy. Jpn. Circ. J (1986) 50(7):614–618.[Medline]
  27. Horita Y., Shimizu M., Sugihara N., Suematsu T., Shibayama S., Itoh H., et al. An autopsy case of hypertrophic cardiomyopathy showing dilated cardiomyopathy-like features by serial ventriculography. Jpn. J. Med (1990) 29(4):448–453.[Medline]
  28. Fujino N., Shimizu M., Ino H., Okeie K., Yamaguchi M., Yasuda T., et al. Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy. Clin. Cardiol (2001) 24(5):397–402.[Web of Science][Medline]
  29. Fujino N., Shimizu M., Ino H., Yamaguchi M., Yasuda T., Nagata M., et al. A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy. Am. J. Cardiol (2002) 89(1):29–33.[CrossRef][Web of Science][Medline]
  30. Arbustini E., Fasani R., Morbini P., Diegoli M., Grasso M., Dal Bello B., et al. Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure. Heart (1998) 80(6):548–558.[Abstract/Free Full Text]
  31. Nakajima-Taniguchi C., Matsui H., Fujio Y., Nagata S., Kishimoto T., Yamauchi-Takihara K. Novel missense mutation in cardiac troponin T gene found in Japanese patient with hypertrophic cardiomyopathy. J. Mol. Cell Cardiol (1997) 29(2):839–843.[CrossRef][Web of Science][Medline]
  32. Regitz-Zagrosek V., Erdmann J., Wellnhofer E., Raible J., Fleck E. Novel mutation in the alpha-tropomyosin gene and transition from hypertrophic to hypocontractile dilated cardiomyopathy. Circulation (2000) 102(17):E112–E116.[Web of Science][Medline]
  33. Yamauchi-Takihara K., Nakajima-Taniguchi C., Matsui H., Fujio Y., Kunisada K., Nagata S., et al. Clinical implications of hypertrophic cardiomyopathy associated with mutations in the alpha-tropomyosin gene. Heart (1996) 76(1):63–65.[Abstract/Free Full Text]
  34. Konno T., Shimizu M., Ino H., Matsuyama T., Yamaguchi M., Terai H., et al. 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. J. Am. Coll. Cardiol (2003) 41(5):781–786.[Abstract/Free Full Text]
  35. Nanni L., Pieroni M., Chimenti C., Simionati B., Zimbello R., Maseri A., et al. Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Biochem. Biophys. Res. Commun (2003) 309(2):391–398.[CrossRef][Web of Science][Medline]
  36. Majamaa-Voltti K., Peuhkurinen K., Kortelainen M.L., Hassinen I.E., Majamaa K. Cardiac abnormalities in patients with mitochondrial DNA mutation 3243A>G. BMC Cardiovasc. Disord (2002) 2(1):12.[CrossRef][Medline]
  37. Kärkkäinen S., Peuhkurinen K., Jääskeläinen P., Miettinen R., Kärkkäinen P., Kuusisto J., et al. No variants in the cardiac actin gene in Finnish patients with dilated or hypertrophic cardiomyopathy. Am. Heart J (2002) 143(6):E6.[Medline]
  38. Manolio T.A., Baughman K.L., Rodeheffer R., Pearson T.A., Bristow J.D., Michels V.V., et al. Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop). Am. J. Cardiol (1992) 69(17):1458–1466.[CrossRef][Web of Science][Medline]
  39. Mestroni L., Maisch B., McKenna W.J., Schwartz K., Charron P., Rocco C., et al. Guidelines for the study of familial dilated cardiomyopathies. Collaborative research group of the European human and capital mobility project on familial dilated cardiomyopathy. Eur. Heart J (1999) 20(2):93–102.[Free Full Text]
  40. Reina M., Brunzell J.D., Deeb S.S. Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C-II genes. J. Lipid Res (1992) 33(12):1823–1832.[Abstract]
  41. Nevin D.N., Brunzell J.D., Deeb S.S. The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. Arterioscler. Thromb (1994) 14(6):869–873.[Abstract/Free Full Text]
  42. Thierfelder L., Watkins H., MacRae C., Lamas R., McKenna W., Vosberg H.P., et al. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell (1994) 77(5):701–712.[CrossRef][Web of Science][Medline]
  43. Watkins H., McKenna W.J., Thierfelder L., Suk H.J., Anan R., O'Donoghue A., et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N. Engl. J. Med (1995) 332(16):1058–1064.[Abstract/Free Full Text]
  44. Jääskeläinen P., Soranta M., Miettinen R., Saarinen L., Pihlajamäki J., Silvennoinen K., et al. The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population. J Am. Coll. Cardiol (1998) 32(6):1709–1716.[Abstract/Free Full Text]
  45. Blair E., Redwood C., de Jesus Oliveira M., Moolman-Smook J.C., Brink P., Corfield V.A., et al. Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy. Circ. Res (2002) 90(3):263–269.[Abstract/Free Full Text]
  46. Gruen M., Gautel M. Mutations in beta-myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin-binding protein-C. J. Mol. Biol (1999) 286(3):933–949.[CrossRef][Web of Science][Medline]
  47. Sohn R.L., Vikstrom K.L., Strauss M., Cohen C., Szent-Gyorgyi A.G., Leinwand L.A. A 29 residue region of the sarcomeric myosin rod is necessary for filament formation. J. Mol. Biol (1997) 266(2):317–330.[CrossRef][Web of Science][Medline]
  48. Hina K., Kusachi S., Iwasaki K., Nogami K., Moritani H., Kita T., et al. Progression of left ventricular enlargement in patients with hypertrophic cardiomyopathy: incidence and prognostic value. Clin. Cardiol (1993) 16(5):403–407.[Web of Science][Medline]
  49. Shirani J., Maron B.J., Cannon R.O. III, Shahin S., Roberts W.C. Clinicopathologic features of hypertrophic cardiomyopathy managed by cardiac transplantation. Am. J. Cardiol (1993) 72(5):434–440.[CrossRef][Web of Science][Medline]
  50. Jääskeläinen P., Miettinen R., Silvennoinen K., Vauhkonen I., Laakso M., Kuusisto J. The cardiac troponin I gene is not associated with hypertrophic cardiomyopathy in patients from eastern Finland. J. Mol. Cell Cardiol (1999) 31(11):2031–2036.[CrossRef][Web of Science][Medline]
  51. Farza H., Townsend P.J., Carrier L., Barton P.J., Mesnard L., Bahrend E., et al. Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene. J. Mol. Cell Cardiol (1998) 30(6):1247–1253.[CrossRef][Web of Science][Medline]

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