Clinical Chemistry Link to Randox Laboratories Web Site
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Clinical Chemistry 49: 1279-1285, 2003; 10.1373/49.8.1279
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (20)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by García-Castro, M.
Right arrow Articles by Coto, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by García-Castro, M.
Right arrow Articles by Coto, E.
Related Collections
Right arrow Molecular Diagnostics and Genetics
(Clinical Chemistry. 2003;49:1279-1285.)
© 2003 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Hypertrophic Cardiomyopathy: Low Frequency of Mutations in the ß-Myosin Heavy Chain (MYH7) and Cardiac Troponin T (TNNT2) Genes among Spanish Patients

Mónica García-Castro1, Julián R. Reguero2, Alberto Batalla3, Beatriz Díaz-Molina2, Pelayo González1, Victoria Alvarez1, Arturo Cortina2, Gustavo I. Cubero2 and Eliecer Coto1,a

1 Genética Molecular-Instituto de Investigación Nefrológica (IRSIN-FRIAT) and
2 Servicio de Cardiología, Hospital Central de Asturias, 33006 Oviedo, Spain.

3 Servicio de Cardiología, Hospital de Cabueñes, 33394 Gijón, Spain.

aAddress correspondence to this author at: Genética Molecular, Hospital Central de Asturias (Maternidad), 33006 Oviedo, Spain. Fax 34-985-27-36-57; e-mail ecoto{at}hcas.sespa.es.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Mutations in the cardiac ß-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC). Although there are no mutational hotspots, most of the mutations are located in specific exons of the MYH7 and TNNT2 genes. Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy.

Methods: We sequenced exons 8, 9, 13–16, 19, 20, 22–24, and 30 of the MYH7 gene and exons 8, 9, 11, and 14–16 of the TNNT2 gene in 30 HC patients (18–60 years of age) from the region of Asturias (Northern Spain); 25 cases (80%) had a family history of the disease. Genomic DNA was amplified, and fragments were directly sequenced. Each DNA variant found in the patients was also analyzed in 200 healthy controls through single-strand conformation analysis.

Results: Four of the probands had nucleotide changes absent in the healthy controls. Two cases had mutations previously described in the MYH7 gene (exon 14, Arg453Cys) or the TNNT2 gene (exon 16, Arg278Cys). Two cases had new mutations (MYH7 exon 22, Met822Val; TNNT2 exon 14, Lys247Arg) not found among the healthy controls. We found MYH7 Met822Val in a woman with a severe form of HC; the mutation was absent in her parents, indicating a de novo mutation. MYH7 R453C was present in a woman with mild HC, mother of a son who died from SCD. TNNT2 R278C was present in a woman with severe HC, but a sister and a daughter were mutation carriers and did not have hypertrophy. A patient with severe HC was carrier of TNNT2 247Arg.

Conclusions:Mutations in the MYH7 and TNNT2 genes can be found in patients without a family history of HC. However, compared with other populations MYH7 or TNNT2 mutations were rare among our HC patients. This study illustrates the extreme phenotypic heterogeneity in carriers of MYH7 or TNNT2 mutations.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Hypertrophic cardiomyopathy (HC)1 is a cardiac disease characterized by a sarcomeric disarray that leads to cardiac muscle cell hypertrophy. The prevalence of HC has been estimated in 1 in 500 to 1000 persons, and HC is the most common cause of sudden death in the young (1). The hypertrophy is either primary (essential) or secondary to other clinicopathologic manifestations (such as hypertension or aortic stenosis) or environmental risk factors (such as physical exercise or the use of some drugs). The essential form of HC is frequently familial, transmitted as an autosomal dominant trait (2)(3). Because the clinical manifestations range from severe hypertrophy with sudden cardiac death (SCD) to a benign form (with mutation carriers remaining asymptomatic), it is difficult to identify the familial segregation in some cases. Moreover, the disease seems to be sporadic in ~50% of cases, but the incomplete penetrance of the phenotype in carriers of some mutations could lead to underestimation of the percentage of familial cases (4)(5)(6).

The genes involved in HC encode proteins of the sarcomere (5). The first HC locus was mapped to the long arm of chromosome 14 (14q1) (7). The gene encodes the ß-myosin heavy chain (MYH7) gene, and >50 different mutations have been identified worldwide (8)(9)(10)(11). Overall, MYH7 would be mutated in 10–30% of families, whereas the genes encoding cardiac troponin T (TNNT2) on chromosome 1q3, {alpha}-tropomyosin (TPMA) on chromosome 15q2, and myosin-binding protein C (MYBPC) on chromosome 11p11.2 are responsible for another 15–30% (12)(13)(14)(15)(16). Recently, mutations in other genes, such those that encode for the myosin essential and regulatory light chains, cardiac troponin I (TNNI3), and titin, have been identified in some HC patients (17)(18)(19).

MYH7 is a large gene, expanding for ~25 kb of the genome, and contains 40 exons. The complete sequencing of MYH7 in HC patients suggests that most mutations are located in exons 8–24, which encode the globular head of the protein. Some of these mutations would be of prognostic significance. Thus, mutations Arg403Gln, Arg719Trp, and Arg453Cys are commonly associated with an unfavorable prognosis, and carriers have a high risk of sudden death with a reduced average lifespan. Carriers of other MYH7 mutations would have a normal (Gly256Glu, Val606Met, Leu908Val) or an intermediate (Arg249Gln, Glu930Lys) risk of premature sudden death (10)(20)(21)(22).

The cardiac troponin T protein links the troponin complex to tropomyosin in the sarcomere (23). The TNNT2 gene expands for ~25 kb of the genome and contains 15 exons. The complete sequencing of TNNT2 in HC patients suggests that most mutations are located in exons 8, 9, 11, and 14–16 (11), although the molecular mechanisms by which most of these mutations produce the HC phenotype remain to be elucidated. Some of the TNNT2 mutations were associated with an adverse prognosis, and this raised the possibility that the identification of mutations in this gene may identify individuals at high risk of SCD, who would benefit from the implantation of a cardioverter defibrillator. Because some of the TNNT2 mutations have been associated with a high incidence of SCD in spite of minimal hypertrophy, the analysis of this gene could be of special interest in asymptomatic individuals with a family history of SCD (22)(24)(26).

To establish the incidence of MYH7 and TNNT2 mutations in our population, we analyzed the most frequently mutated exons in 30 patients who had an essential form of myocardial hypertrophy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients and controls
A total of 30 unrelated patients were evaluated (16 males and 14 females; mean age at diagnosis, 44 years; range, 18–60 years). They were identified through the patient register of the Cardiology Department of Hospital Central Asturias, which is the reference center for the region of Asturias (Northern Spain; total population, 1 million). The main clinicopathologic findings of these patients are summarized in Table 1 . The diagnosis of HC was based on the presence of a maximal left ventricular wall thickness of at least 13 mm on two-dimensional echocardiography. The absence of other causes for ventricular hypertrophy, such as hypertension, aortic stenosis, physical exercise, or the use of some drugs, was confirmed in each patient. We also performed electrocardiographic and echocardiographic examinations on the available first-degree relatives of each patient. A total of 25 cases (80%) had at least one first-degree relative who was also diagnosed with HC and/or SCD. All individuals gave informed consent to participate in the study, which was approved by the Ethical Committee of Hospital Central Asturias.


View this table:
[in this window]
[in a new window]
  		Table 1. Main characteristics of the 30 patients with cardiac hypertrophy.

To confirm the absence of any new putative mutation in the MYH7 and TNNT2 in healthy individuals, we genotyped a total of 200 controls. These were blood bank donors and staff personnel of Hospital Central Asturias, younger than 60 years [mean (SD) age, 37 (15) years], and did not have a history of cardiovascular disease, including HC. However, they were not evaluated echocardiographically, and we can not discard the presence of asymptomatic HC in some of them.

myh7 and tnnt2 sequencing
Genomic DNA was prepared from peripheral blood leukocytes with use of a salting-out method (27). Exons 8, 9, 13–16, 19, 20, 22–24, and 30 of the MYH7 gene, as well as the corresponding intron-exon boundaries (numbered according to the GenBank sequence no. AJ238393), and exons 8, 9, 11, and 14–16 of the TNNT2 gene, as well as the corresponding exon-intron boundaries (GenBank sequence AY044273), were sequenced in the 30 patients. Genomic DNA was PCR-amplified with the primer pairs summarized in Tables 2 and 3 . Each amplification was performed in a total volume of 30 µL and consisted of 32 cycles of 30 s at 95 °C, 1 min at the annealing temperature (Tables 2 and 3 ), and 1 min at 72 °C. PCR products were electrophoresed on a 2% low-melting agarose gel, and the fragments were excised from the gel, purified with spin columns (DNA gel extraction Kit; Millipore), and subjected to direct sequencing on an ABI Prism 310 Genetic Analyzer. Both strands were sequenced using the PCR primers and ddRhodamine-Terminator Cycle Sequencing (PE Biosystems).


View this table:
[in this window]
[in a new window]
  		Table 2. Primers and PCR conditions for analysis of the MYH7 gene.


View this table:
[in this window]
[in a new window]
  		Table 3. Primers and PCR conditions used for analysis of the TNNT2 exons.

myh7 and tnnt2 genotyping
Single-strand conformation analysis (SSCA) was used to genotype the putative mutations in all available relatives of each patient carrying the change, as well as in 200 healthy controls. In addition, the SSCA electrophoretic patterns corresponding to the 12 MYH7 exons and the 6 TNNT2 exons were analyzed in the 30 patients and in 30 healthy controls. Each genomic DNA was amplified in a final volume of 15 µL with the appropriate primer pairs (Tables 2Up and 3Up ). After 32 PCR cycles, each reaction was mixed with 30 µL of formamide and denatured at 95 °C; 5 µL of this mixture was then electrophoresed on 6% polyacrylamide gels (5.8% acrylamide-0.2% bisacrylamide; 50 cm in length) containing 100 mL/L glycerol. Electrophoresis was for 18 h at 20 W and room temperature. The gel was silver-stained, and the electrophoretic patterns were visualized to define each genotype.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We found a previously described MYH7 mutation in a 44-year-old woman with a mild form of HC, mother of a son who had died from sudden death at age 17 years. This mutation (9090 C>T; Arg453Cys) has previously been linked to HC in several families and was identified as an abnormal SSCA pattern in the patient, whereas the 200 healthy controls showed a wild-type electrophoretic pattern.

We found a previously reported TNNT2 mutation in a 60-year-old woman (patient 25) with a severe form of HC (concentric; with a septum of 22 mm). This mutation (19159 C>T; Arg278Cys) has previously been linked to HC. This patient was the only symptomatic patient in the family. However, the mutation was also present in a sister (55 years) and in the patient’s daughter (35 years), and the two did not have cardiac hypertrophy. Patient 25 had an abnormal SSCA electrophoretic pattern compared with the 200 healthy controls.

One patient had a mutation in the MYH7 gene not described previously. Patient 23 (a 28-year-old female) had severe cardiac hypertrophy and required a heart transplant. She had an A-to-G change at nucleotide 13103, a missense change at codon 822 (Val>Met) in exon 22 (Fig. 1 ). This patient was negative for mutations in the TNNT2 gene and did not have a family history of HC or SCD. The two parents and two brothers, the only available relatives, were healthy, and direct sequencing showed that they did not carry the mutation (paternity was confirmed through the analysis of 10 microsatellite markers; data not shown). SSCA showed an abnormal electrophoretic pattern in patient 23 and a wild-type pattern in the 200 healthy controls (Fig. 2 ). In this way, 822Met would be a de novo mutation linked to a severe form of HC.



View larger version (79K):
[in this window]
[in a new window]
  		Figure 1. Wild-type and mutated sequences in exon 22 of the MYH7 gene (A>G; Met822Val; A) and exon 14 of the TNNT2 gene (T>C; Lys247Arg; B).



View larger version (61K):
[in this window]
[in a new window]
  		Figure 2. SSCA of PCR fragments corresponding to MYH7 exon 22 (A) and TNNT2 exon 14 (B), showing the wild-type patterns and those corresponding to the presence of MYH7 822Val and TNNT2 247Arg (lanes 3 in A and B, respectively).

We also found patient with a new putative mutation in the TNNT2 gene: a 60-year-old woman with severe HC (23 mm septum) who had an A-to-G change at nucleotide 17085, a missense mutation at codon 247 (Lys>Arg) in exon 14 (Fig. 1Up ). SSCA identified this mutation as an abnormal electrophoretic pattern in the patient, whereas a wild-type pattern was observed in the 200 healthy controls (Fig. 2Up ). This patient was negative for mutations in the MYH7 gene, was the only available individual in the family, and did not have a recognized family history of cardiac hypertrophy or SCD.

SSCA of the 12 MYH7 exons in the 30 patients and in 30 controls revealed three common polymorphisms: in exon 8 (6511 T/C; a silent change for Phe), exon 24 (14410 T/C; a silent change for Ile), and intron 19 (12215 T/A). Analysis of the six TNNT2 exons showed a common polymorphism in exon 9 (13150 T/C; a silent change for 106 Ile).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We sequenced 12 exons encoding the head and hinge regions of the MYH7 gene, as well as 6 exons in the TNNT2 gene, in 30 unrelated HC patients. According to previous reports, these exons would contain most of the MYH7 and TNNT2 mutations found in HC patients (4)(5)(6)(11). Exon 30 of MYH7 encodes amino acids in the rod-like domain and was included in the study because a previous report described a mutation in several patients with a mild form of HC (28). Because the 30 cases had an essential form of HC, not secondary to any other clinicopathologic condition, they would represent individuals predisposed to develop HC, likely carriers of mutations in any of the genes linked to this disease. A total of 25 cases had at least one affected relative, including 9 patients with a family history of sudden death, and only 5 cases did not have a recognized family history of HC or SCD.

Our work also illustrates the main difficulties in the genetic analysis of this disease. The mutations can be located in one of several very large genes, and most of the affected families do not have sufficient members to allow statistically significant chromosome linkage analysis. It is not currently possible to establish a correlation between the presence of a mutation in one of the sarcomeric genes and a particular phenotype (2)(5). Moreover, the same mutation can be found in individuals with different clinical manifestations (26). However, it is widely accepted that mutations in the MYH7 gene predispose to the development of severe HC, whereas mutations in the TNNT2 are frequently linked to a high risk of SCD in individuals with or without hypertrophy (2)(4).

One patient, a 28-year-old woman with severe HC, had a nonsilent change (Val822Met) in exon 22 of MYH7. This was the only individual affected in the family, and the two parents were healthy and did not have the mutation. This patient did not have TNNT2 mutations, and the MYH7 mutation was absent in 200 healthy controls. In addition, 822Val is conserved among the vertebrates, and a Val>Met mutation in codon 606 of MYH7 has been linked to the disease in several families (10)(29). These data suggest that this is a de novo mutation linked to a severe form of HC. De novo mutations in the MYH7 gene have previously been described in at least two patients (30)(31). In addition to this de novo mutation, we found a previously described mutation in a 44-year-old woman with a mild form of HC and a family history of sudden death. This mutation (Arg453Cys) has been linked to an unfavorable HC outcome (10). We also identified two TNNT2 mutations (Lys247Arg and Arg278Cys). One (K247R), a new putative mutation not previously described, was present in one patient and absent in the 200 healthy controls. The R278C mutation was found in a 60-year-old woman with severe hypertrophy, whereas her sister and her daughter were carriers and showed normal echocardiographic values. Functional analysis showed that this mutation increased the Ca2+ sensitivity of the myofibrillar ATPase activity (32). Watkins et al.(13) found the same mutation in a girl who was resuscitated after cardiac arrest at age 17, in spite of having normal ventricular wall measurements. These findings illustrate the dissociation between TNNT2 mutations and the severity of clinically demonstrable HC.

According to previous reports, mutations in the MYH7 exons analyzed in our study would be found in up to 40% of patients, whereas TNNT2 mutations would be responsible for another 10–15% of occurrences (5)(6). However, a very low rate of MYH7 mutations has also been found in other populations, such as a Finnish population (33). Most of the authors of these reports used SSCA to search for mutations in these genes. Approximately 20% of the nucleotide changes are not detected by this technique, and these studies could have underestimated the true incidence of MYH7 and TNNT2 mutations. Because our patients were analyzed through direct sequencing, we can conclude that mutations in the 12 MYH7 exons and in the 6 TNNT2 exons analyzed would be very rare in our patients and would explain <15% of the HC cases in our population. However, we analyzed individuals with a demonstrated hypertrophy, and TNNT2 mutations have been linked to a high risk of SCD without hypertrophy. It is thus possible that we underestimated the true incidence of TNNT2 mutations, which should be revealed through the analysis of genomic DNA from cases who have suffered SCD, even if they do not have a family history of hypertrophy or SCD.

Finally, we sequenced 12 MYH7 exons, representing ~3000 coding nucleotides, and 6 TNNT2 exons, representing ~1500 coding nucleotides. In addition to the patients, we also analyzed the 18 exons in 30 controls through SSCA. Thus, our data would indicate the degree of genetic variability in these regions of MYH7 and TNNT2 in our population. Interestingly, only three silent polymorphisms were identified, in exons 8 and 24 of the MYH7 gene and in exon 9 of the TNNT2 gene. This low variability suggests a strong selective pressure against nucleotide changes that could predispose to the development of HC and is in agreement with a previous report that described a very low incidence of sequence variation in MYH7 (34).

In conclusion, we describe two TNNT2 and two MYH7 mutations among 30 HC patients. Two of these were known mutations, and two were new (not previously described). One of them (MYH7; Val822Met) was a de novo mutation (not present in the parents of the affected patient). In addition, our study illustrates the extreme phenotypic heterogeneity in carriers of MYH7 or TNNT2 mutations and the difficulty in translating to the clinical practice data derived from the genetic analysis of sarcomeric genes.


   Acknowledgments
 
This work was supported in part by a grant from FICYT-Principado de Asturias (to E.C.) and the Spanish Fondo de Investigaciones Sanitarias-Red Temática de Centros (Genética). M.G.C. was the recipient of a fellowship from Sociedad Asturiana de Cardiología.


   Footnotes
 
1 Nonstandard abbreviations: HC, hypertrophic cardiomyopathy; SCD, sudden cardiac death; and SSCA, single-strand conformation analysis.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Circulation 1995;92:785-789.[Abstract/Free Full Text]
  2. Bachinski LL, Roberts R. Familial hypertrophic cardiomyopathy: diagnostic and therapeutic implications of recent genetic studies. Mol Med Today 1996;2:387-393.[ISI][Medline] [Order article via Infotrieve]
  3. Maron BJ, Nichols PF, III, Pickle LW, Wesley YE, Mulvihill JJ. Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography. Am J Cardiol 1984;53:1087-1094.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  4. Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532-540.[Free Full Text]
  5. Arad M, Seidman JG, Seidman CE. Phenotypic diversity in hypertrophic cardiomyopathy. Hum Mol Genet 2002;11:2499-2506.[Abstract/Free Full Text]
  6. Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336-1347.[Free Full Text]
  7. Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 1989;321:1372-1378.[Abstract]
  8. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, et al. A molecular basis for familial hypertrophic cardiomyopathy: a ß cardiac myosin heavy chain gene missense mutation. Cell 1990;62:999-1006.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  9. Epstein ND, Cohn GM, Cyran F, Fananapazir L. Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the ß-myosin heavy chain gene: a 906Leu-Val mutation and a 403Arg-Gln mutation. Circulation 1992;86:345-352.[Abstract/Free Full Text]
  10. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992;326:1108-1114.[Abstract]
  11. CardioGenomics home page.www.cardiogenomics.org (Accessed December 20, 2002)..
  12. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, et al. {alpha}-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994;77:701-712.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  13. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, 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;332:1058-1064.[Abstract/Free Full Text]
  14. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248-1257.[Abstract/Free Full Text]
  15. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, et al. Development of left ventricular hypertrophy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol 2001;38:315-321.[Abstract/Free Full Text]
  16. Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol 2001;33:655-670.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  17. Olson TM, Karst ML, Whitby FG, Driscoll DJ. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation 2002;105:2337-2340.[Abstract/Free Full Text]
  18. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002;105:446-451.[Abstract/Free Full Text]
  19. 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;30:201-204.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  20. Charron P, Dubourg O, Desnos M, Isnard R, Hagege A, Bonne G, et al. Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the ß-MHC genes. Eur Heart 1998;19:139-145.
  21. Havndrup O, Bundgaard H, Andersen PS, Larsen LA, Vuust J, Kjeldsen K, et al. A novel missense mutation, Leu390Val, in the cardiac ß-myosin heavy chain associated with pronounced septal hypertrophy in two families with hypertrophic cardiomyopathy. Scand Cardiovasc J 2000;34:558-563.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  22. Ackerman MJ, VanDriest SL, Ommen SR, Will ML, Nishimura RA, Tajik AJ, et al. Prevalence and age-dependence of malignant mutations in the ß-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy. A comprehensive outpatient perspective. J Am Coll Cardiol 2002;39:2042-2048.[Abstract/Free Full Text]
  23. Sweeney HL, Feng HS, Yang Z, Watkins H. Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function. Proc Natl Acad Sci U S A 1998;95:14406-14410.[Abstract/Free Full Text]
  24. Moolman JC, Corfield VA, Posen B, Ngumbela K, Seidman C, Brink PA, et al. Sudden death due to troponin T mutations. J Am Coll Cardiol 1997;29:549-555.[Abstract]
  25. Koga Y, Toshima H, Kimura A, Harada H, Koyanagi T, Nishi H, et al. Clinical manifestations of hypertrophic cardiomyopathy with mutations in the cardiac ß-myosin heavy chain or cardiac troponin T gene. J Card Fail 1996;2:97-103.
  26. Van driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, et al. Prevalence and severity of benign mutations in the ß-myosin heavy chain, cardiac troponin T, and {alpha}-tropomyosin genes in hypertrophic cardiomyopathy. Circulation 2002;106:3085-3090.[Abstract/Free Full Text]
  27. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.[Free Full Text]
  28. Blair E, Redwood C, de Jesus Oliveira M, Moolman-Smook JC, Brink P, Corfield VA, et al. Mutations of the light meromyosin domain of the ß-myosin heavy chain rod in hypertrophic cardiomyopathy. Circ Res 2002;90:263-269.[Abstract/Free Full Text]
  29. Havndrup O, Bundgaard H, Andersen PS, Larsen LA, Vuust J, Kjeldsen K, et al. The Val606Met mutation in the cardiac ß-myosin heavy chain gene in patients with familial hypertrophic cardiomyopathy is associated with a high risk of sudden death at young age. Am J Cardiol 2001;87:1315-1317.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  30. Watkins H, Thierfelder L, Hwang DS, McKenna W, Seidman JG, Seidman CE. Sporadic hypertrophic cardiomyopathy due to the novo myosin mutations. J Clin Invest 1992;92:1666-1671.
  31. Jeschke B, Uhl K, Weist B, Schroder D, Meitinger T, Dohlemann C, et al. A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mutated ß-myosin heavy chain genes. Hum Genet 1998;102:299-304.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  32. Morimoto S, Nakaura H, Yanaga F, Ohtsuki I. Functional consequences of a carboxyl terminal missense mutation Arg278Cys in human cardiac troponin T. Biochem Biophys Res Commun 1999;261:79-82.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  33. Jääskeläinen P, Soranta M, Miettinen R, Saarinen L, Pihlajamaki J, Silvennoinen K, et al. The cardiac ß-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population. J Am Coll Cardiol 1998;32:1709-1716.[Abstract/Free Full Text]
  34. Freeman K, Nakao K, Leinwand LA. Low sequence variation in the gene encoding the human ß-myosin heavy chain. Genomics 2001;76:73-80.[CrossRef][ISI][Medline] [Order article via Infotrieve]



The following articles in journals at HighWire Press have cited this article:


Home page
 J. Physiol.Home page
S. G. Sirenko, J. D. Potter, and B. C. Knollmann
Differential effect of troponin T mutations on the inotropic responsiveness of mouse hearts - role of myofilament Ca2+ sensitivity increase
J. Physiol., August 15, 2006; 575(1): 201 - 213.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
O. M. Hernandez, D. Szczesna-Cordary, B. C. Knollmann, T. Miller, M. Bell, J. Zhao, S. G. Sirenko, Z. Diaz, G. Guzman, Y. Xu, et al.
F110I and R278C Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy Affect Muscle Contraction in Transgenic Mice and Reconstituted Human Cardiac Fibers
J. Biol. Chem., November 4, 2005; 280(44): 37183 - 37194.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
A. V. GOMES and J. D. POTTER
Molecular and Cellular Aspects of Troponin Cardiomyopathies
Ann. N.Y. Acad. Sci., May 1, 2004; 1015(1): 214 - 224.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (20)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by García-Castro, M.
Right arrow Articles by Coto, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by García-Castro, M.
Right arrow Articles by Coto, E.
Related Collections
Right arrow Molecular Diagnostics and Genetics

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS