Mónica García-Castro

Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain

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Publications (24)69.34 Total impact

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    ABSTRACT: Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events.
    Revista Espa de Cardiologia 07/2010; 63(7):856-9. · 3.20 Impact Factor
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    ABSTRACT: Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events.
    Revista Espanola De Cardiologia - REV ESPAN CARDIOL. 01/2010; 63(7):856-859.
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    ABSTRACT: Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor. The study included 316 patients with early onset MI (<55 years old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n=350) and compared the allele and genotype frequencies between groups. We found six common nucleotide changes: -1394 (T/G) and -974 C/A (promoter), +120 ins/del A (exon 1, 5' UTR), 568 A/G (exon 3, E106E), 844 G/T (exon 5, K198N), and 1617 T/C (exon 5, 3' UTR). No rare EDN1-variants specific to the MIpatients were found. None of the EDN1 polymorphisms were significantly associated with early-onset MI in our population. The two promoter polymorphisms were in linkage disequilibrium with K198N, but no haplotype was associated with MI risk. In our population, the EDN1 variation did not contribute to early-onset MI.
    Journal of atherosclerosis and thrombosis 09/2009; 16(4):388-95. · 2.93 Impact Factor
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    ABSTRACT: Gitelman's syndrome (GS) is caused by mutations in the SLC12A3. Most of the mutations are rare, making it difficult to establish a genotype-phenotype correlation. Although GS is a recessive disorder, some patients also have an affected parent, suggesting a dominant inheritance. We sequenced the 26 coding exons of SLC12A3 in a family in which the proband and her father had a late onset GS. We obtained cDNA of the 2 patients and analyzed the effect of a mutation on pre-mRNA splicing. The 2 patients were homozygous for a nucleotide change in the last nucleotide of exon 15: c.1925 G>A. The mother was a heterozygous carrier for this putative mutation. Amplification of cDNA with primers for exons 14-17 was negative, suggesting that this mutation affected the splicing and promoted mRNA degradation through nonsense-mediated decay. We report a family with 2 patients with late onset GS and homozygous for a mutation in the last nucleotide of exon 15. Our study shows that homozygosity for this mutation resulted in a significant loss of normal SLC12A3 transcript.
    American Journal of Nephrology 05/2009; 30(3):218-21. · 2.62 Impact Factor
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    ABSTRACT: Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.
    Revista Espa de Cardiologia 02/2009; 62(1):48-56. · 3.20 Impact Factor
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    ABSTRACT: Introduction and objectivesMutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy.MethodsWe used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated.ResultsIn total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1, and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had 2 mutations (ie, double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations.ConclusionsSome 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.Introducción y objetivosLas mutaciones en los genes sarcoméricos son la causa más frecuente de miocardiopatía hipertrófica. Para cada gen, la frecuencia de mutaciones varía entre los estudios, y las manifestaciones clínicas son muy heterogéneas, lo que dificulta el empleo de la información genética en la práctica clínica. Nuestro objetivo es determinar la frecuencia de mutaciones en los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en una serie de pacientes con miocardiopatía hipertrófica.MétodosSe analizaron las regiones codificantes de estos cinco genes mediante secuenciación en 120 pacientes (el 29% con antecedentes familiares), comparando el fenotipo según el gen mutado.ResultadosSe hallaron mutaciones en 32 pacientes; 10 y 20 tenían mutaciones en MYH7 (8%) y MYBPC3 (16%). Se hallaron mutaciones de TNNT2 y TPM1 en 2 y 1 pacientes, y ninguna de TNNI3. Dos pacientes tenían dos mutaciones (dobles mutantes). El 61% de las mutaciones no habían sido descritas previamente. No hallamos diferencias en la media de edad al diagnóstico o el tamaño de la hipertrofia entre los portadores de mutaciones en MYH7 y los de MYBPC3.ConclusionesEl 26% de los pacientes tenían mutaciones en alguno de los cinco genes estudiados. Más de la mitad de las mutaciones no habían sido descritas. El gen MYBPC3 fue el más mutado, seguido de MYH7. No se hallaron diferencias fenotípicas entre los pacientes según el gen mutado, lo que dificultaría el empleo de la información genética para estratificar el riesgo en estos pacientes.
    Revista Espanola de Cardiologia 01/2009; · 3.20 Impact Factor
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    ABSTRACT: Introduction and objectives Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. Methods We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. Results In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. Conclusions Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.
    Revista Espanola De Cardiologia - REV ESPAN CARDIOL. 01/2009; 62(1):48-56.
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    ABSTRACT: Familial hypertrophic cardiomyopathy (HCM) is an allelic cardiac disorder characterized by increased ventricular wall mass and sudden cardiac death. A variety of dominant single-gene mutations in sarcomeric genes have been identified, indicating a highly heterogeneous genetic etiology. MYOZ2 encodes for sarcomeric calsarcin-1 located in the myocardial z-disc, a focal point of HCM disease genes. Very recently mutations in MYOZ2 were reported as a cause for HCM. To assess the prevalence of MYOZ2 mutations among European HCM patients, coding exons weree analyzed for genetic variants in 438 patients. Four hundred thirty-eight patients with HCM in four European cardiovascular centers were recruited. The coding region of MYOZ2 was directly sequenced in all the HCM subjects. Two non-synonymous polymorphisms in exon 2 (rs17851524) and exon 5 (rs7687613) of MYOZ2 were identified in eight and twenty-two patients, respectively. However, no disease-causing mutations could be identified in this large cohort of HCM patients. Although a large cohort of more than 400 patients with familial HCM was screened, a disease-associated mutation in MYOZ2 was not identified. When these results are combined with previous reports, it can be concluded that MYOZ2 mutations are rare causes of familial HCM.
    Medical science monitor: international medical journal of experimental and clinical research 07/2008; 14(7):CR372-4. · 1.22 Impact Factor
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    ABSTRACT: The cyclophilin A (CypA)-cyclosporine (CsA) complex promotes immune response. The variation at the CypA gene could explain CsA-pharmacokinetics and clinical outcomes among CsA-treated patients. The study included 290 kidney transplanted patients (65% male; mean age 51 +/- 15 yr), treated with CsA. The five CypA- exons and the promoter region were analysed through single-strand conformation analysis, denaturing high performance liquid chromatography, and direct sequencing. The effect of a promoter polymorphism (-11 G/C) on gene expression was analysed in cell-cultures. We found two polymorphisms in the promoter (-11 G/C) and exon 1 (+36 G/A). Genotype frequencies did not differ between patients according to their pharmacokinetics status. In vitro studies showed that -11 G/C affected gene expression. The -11 G allele was significantly associated with clinical nephrotoxicity (p = 0.006). The strongest predictors for nephrotoxicity were a donor age > or =55 yr, and the promoter GG + GC genotypes. Our work suggests that a CypA-promoter polymorphism (-11 G/C) could be associated with clinical nephrotoxicity. Replication of this study in other populations is necessary to define the role of CypA-variants in the main clinical outcomes among CsA-treated kidney-transplanted patients.
    Clinical Transplantation 07/2008; 22(6):722-9. · 1.63 Impact Factor
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    ABSTRACT: Impaired mitochondrial function and an increased number of mutations in mitochondrial DNA (mtDNA) has been found in brains of patients with late-onset Alzheimer's disease (LOAD). The TFAM-gene encodes the mitochondrial transcription factor A, a protein that controls the transcription, replication, damage sensing, and repair of mtDNA. TFAM is on human chromosome region 10q21.1, where a locus for LOAD has been mapped. Our objective was to determine the role of TFAM-gene variation in the risk of LOAD. The seven TFAM coding exons were analysed through single strand conformation analysis and direct sequencing in a cohort of Spanish LOAD-patients and healthy controls. We found four common polymorphisms, two in the flanquing intronic and two in the coding sequences. Polymorphism rs1937 (+35 G/C) was the only missense change (S12T). Genotyping of this polymorphism in 300 LOAD-patients and 183 healthy controls showed a significantly higher frequency of GG-homozygotes in the patients (92% vs. 86%; p=0.04; OR=1.91, 95%CI=1.02-3.50). This suggests that S12 is a risk factor for LOAD in our population. In conclusion, rare variants (mutations) in the TFAM gene were not found in LOAD-patients, but the S12T polymorphism was a moderate risk factor for LOAD in our population.
    Journal of Alzheimer's disease: JAD 05/2008; 13(3):275-80. · 4.17 Impact Factor
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    ABSTRACT: We report the results of a study carried out in 825 young football club members, all of whom underwent screening for hypertrophic cardiomyopathy using a 12-lead ECG. Echocardiographic assessment was performed in only those with positive ECG results, as defined by the European Society of Cardiology. Echocardiography proved necessary in 61 (7%) individuals with positive ECG findings, of whom 7 had echocardiographic findings indicative of left ventricular hypertrophy: five were in the "gray zone", 1 was judged to have athlete's heart, and one had been diagnosed with hypertrophic cardiomyopathy. In all these cases, ECG showed repolarization abnormalities, and 4 satisfied criteria for left ventricular hypertrophy.
    Revista Espa de Cardiologia 05/2008; 61(4):426-9. · 3.20 Impact Factor
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    ABSTRACT: Cyclophilin A is secreted by vascular smooth muscle cells in response to inflammatory stimuli, and could thus contribute to atherosclerosis. We hypothesized that the genetic variation at the cyclophilin A gene (PPIA) could affect the risk for developing atherosclerosis and myocardial infarction. This study included 250 myocardial infarction patients (all male and < 60 years; 95% are smokers). All these cases had at least one atherosclerotic diseased coronary vessel. DNA was obtained from patients and from 250 healthy controls. The variation at the PPIA gene was determined in the patients through single-strand conformation analysis and direct sequencing of seven polymerase chain reaction fragments. Allele and genotype frequencies were compared between patients and controls. The effect of a promoter polymorphism (-11 G/C) on gene expression was in vitro analysed with luciferase-reporter assays. We found two common polymorphisms in the PPIA promoter (-11 G/C) and the 5' non-translated (+36 G/A) regions. Cells transfected with luciferase-plasmids containing the -11 G had significantly higher luciferase activity. Genotype frequencies for these polymorphisms did not differ between patients and controls. In conclusion, we reported a functional variant in the PPIA promoter. However, the PPIA variation did not significantly contribute to the risk of suffering from myocardial infarction among patients with atherosclerotic diseased vessels.
    International Journal of Immunogenetics 05/2008; 35(2):159-64. · 1.36 Impact Factor
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    ABSTRACT: Mitochondrial function is necessary to supply the energy required for cell metabolism. Mutations/polymorphisms in mitochondrial DNA (mtDNA) have been implicated in Parkinson's disease (PD). The mitochondrial transcription factor A (TFAM) controls the transcription of mtDNA and regulates the mtDNA-copy number, thus being important for maintaining ATP production. TFAM dysfunction may also be involved in PD, and TFAM gene mutations/polymorphisms could contribute to the risk of developing PD. We searched for gene variants in the seven TFAM-exons in a total of 250 PD-patients. We found five common polymorphisms, and only one was a missense change (S12T in exon 1). Genotype and allele frequencies did not differ between patients and healthy controls (n=225) for the five polymorphisms. Our work suggests that TFAM-variants did not contribute to the risk of developing PD.
    Neuroscience Letters 03/2008; 432(1):79-82. · 2.03 Impact Factor
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    ABSTRACT: We report the results of a study carried out in 825 young football club members, all of whom underwent screening for hypertrophic cardiomyopathy using a 12-lead ECG. Echocardiographic assessment was performed in only those with positive ECG results, as defined by the European Society of Cardiology. Echocardiography proved necessary in 61 (7%) individuals with positive ECG findings, of whom 7 had echocardiographic findings indicative of left ventricular hypertrophy: five were in the “gray zone”, 1 was judged to have athlete's heart, and one had been diagnosed with hypertrophic cardiomyopathy. In all these cases, ECG showed repolarization abnormalities, and 4 satisfied criteria for left ventricular hypertrophy.
    Revista Espanola De Cardiologia - REV ESPAN CARDIOL. 01/2008; 61(4):426-429.
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    ABSTRACT: We sequenced the coding exons of the cardiac troponins T (TNNT2) and I (TNNI3) genes in 115 Spanish HCM-patients (32% with a family history of the disease). Only two (2%) had mutations in the TNNT2 (Arg278>Cys and Arg92>Lys). These mutations were associated with variable clinical outcomes. No patient had TNNI3-mutation. We also genotyped these patients and 320 healthy controls for a 5 bp insertion/deletion (I/D) polymorphism in intron 3 of TNNT2. DD-homozygotes for the 5 bp I/D polymorphism were significantly more frequent among the patients (OR=1.83, 95% CI=2.10-5.16).
    International journal of cardiology 10/2007; 121(1):115-6. · 6.18 Impact Factor
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    ABSTRACT: Polymorphisms at different genes have been proposed as determinants of the risk for developing late-onset Alzheimer's disease (LOAD). Among the several candidate genes are those that encode proteins involved in neuronal degeneration/survival. Studies of primary neuronal cultures supported that members of the myocyte enhancing factor-2 (MEF2) family of transcription factors have an anti-apoptotic effect, regulating the expression of proteins involved in neuronal survival and differentiation. We analysed the MEF2A gene in a total of 357 patients (mean age 72 years, range 60-97 years). Among others, a Pro279Leu in exon 8 and a polyglutamine (CAG) repeat polymorphisms in exon 12 were found. These variants were also genotyped in 495 healthy controls (>50 years old), and the frequencies were statistically compared. Eight patients were 279L (six P/L and two L/L), compared to only one control (2% vs. 0.2%; p=0.004, OR=11.32). There was a significantly higher frequency of 279L-carriers among APOE epsilon4+ (7/154=4.5%), compared to epsilon4- (1/203) (p=0.02). In conclusion, our work suggests that the variation at the MEF2A gene could be involved in the risk of developing LOAD. Because MEF2 has been related with neuronal survival, and the 279L allele has been related with a reduction in the transcriptional activation activity of MEF2A, the effect of this allele could be mediated through a down-regulation of antiapoptotic genes.
    Neuroscience Letters 01/2007; 411(1):47-51. · 2.03 Impact Factor
  • E Coto, M Menéndez, R Navarro, M García-Castro, V Alvarez
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    ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common hereditary forms of stroke, and migraine with aura, mood disorders, or dementia, are also frequently found in these patients. Missense mutations in the Notch3 gene that create or destroy cysteine residues, have been found in most cases with a family history of the disease, although a few sporadic cases harbouring Notch3 mutations have also been described. Here, we describe a 44-year-old patient with clinical features of CADASIL who was a carrier of a new Notch3 mutation: cys128-->gly. Both parents were alive and healthy, and negative for the mutation. This case illustrates the interest of analysing the Notch3 gene in cases with clinical features of CADASIL, even in the absence of a family history of the disease.
    European Journal of Neurology 07/2006; 13(6):628-31. · 4.16 Impact Factor
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    ABSTRACT: A myocyte enhancer factor 2A (MEF2A) mutation that segregated with coronary artery disease/myocardial infarction (CAD/MI) in a large family has recently been described. Missense mutations in sporadic coronary artery disease patients were also reported. These data suggest that mutations in exons 7 and 11 of MEF2A cause CAD/MI, though the association was refuted by another study. To analyse the genetic variation of exons 7 and 11 in a large cohort of Spanish CAD/MI patients and controls. A rare polymorphism, P279L, was detected both in patients and controls. Carriers of the 279Leu allele had a threefold risk of suffering CAD/MI compared with controls (p = 0.009; odds ratio = 3.06 (95% confidence interval, 1.17 to 8.06)). In the controls the allele was found only in those under 50 years of age. Exon 11 showed a high degree of heterogeneity caused by a polyglutamine (CAG)n polymorphism, but no significant differences in genotype or allelic frequencies were found. The 279Leu allele appears to be a genetic risk factor for CAD/MI in the population studied. This effect could be the result of a reduced transcriptional activity on MEF2A with 279Leu.
    Journal of Medical Genetics 03/2006; 43(2):167-9. · 5.70 Impact Factor
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    ABSTRACT: Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are responsible for up to 50% of familial cases with hypertrophic cardiomyopathy (HC). Compared to patients with mutations in other sarcomeric genes, patients with MYBPC3 mutations would have a milder form of the disease, with a lower incidence of sudden cardiac death. Because most of the mutations have been found in only one family, it is currently difficult to establish a correlation between a particular mutation and the HC phenotype. The aim of our study was to contribute to understanding of the role of MYBPC3 mutations in HC. We analysed the MYBPC3 exons and intron flanking regions in 10 patients from 10 families with at least two HC cases. After direct sequencing of polymerase chain reaction (PCR) fragments, we found three new mutations in three families (V771M, V342D, and A627V). These changes affected evolutionary conserved amino acids and were not found in 100 healthy controls. The Ala 627>Val was found homozygous in a 47-year-old patient with a severe form of HC, while his mother and a nephew were heterozygous carriers and asymptomatic. This fact suggests a dosage effect for mutations at the MYPBC3 gene.
    International Journal of Cardiology 08/2005; 102(3):501-7. · 6.18 Impact Factor
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    ABSTRACT: We determined the prevalence of mutations considered malignant in the genes for beta-myosin heavy chain (MYH7, 11 mutations) and troponin T (TNNT2, 5 mutations) in 30 patients with hypertrophic cardiomyopathy aged 18 to 60 years, 83% of whom had familial antecedents of hypertrophic myocardiopathy or sudden death. Mutations were identified with polymerase chain reaction followed by restriction enzyme digestion and agarose gel electrophoresis. Direct analysis identified 16 mutations in 2 of the 30 patients (7%): one women diagnosed at the age of 25 years as carrying the MYH7453cysteine mutation, and a 60-year-old women with the TNNT2278 cysteine mutation. These cases illustrate the considerable clinical heterogeneity that characterizes carriers of these mutations. Clinical manifestations can range from severe hypertrophy or early sudden death to the absence of symptoms up to advanced age.
    Revista Espa de Cardiologia 11/2003; 56(10):1022-5. · 3.20 Impact Factor