Gene/Protein Disease Symptom Drug Enzyme Compound
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Hypertrophic cardiomyopathy is associated with marked genetic and phenotypic heterogeneity. Pathogenic mutations in the 10 hypertrophic cardiomyopathy-associated sarcomeric genes cause autosomal dominant disease as a rule, although recessive disease has been reported. Cardiac hypertrophy is also a hallmark of Friedreich ataxia, an autosomal recessive disease caused by deficiency of the mitochondrial protein frataxin. We hypothesized that heterozygous mutations in frataxin may mimic or modify hypertrophic cardiomyopathy. Using DHPLC and DNA sequencing, we identified the novel R40C-frataxin mutation in a patient who also harbored a previously reported R810H-myosin binding protein C mutation. The R810H mutation is reported to cause hypertrophic cardiomyopathy only in the setting of homozygosity or compound heterozygosity with another sarcomeric mutation. Site-directed mutagenesis and in vitro and in vivo analysis enabled functional characterization of the mutant frataxin protein. R40C-frataxin protein is not cleaved to the mature form in vitro and shows delayed kinetics of cleavage by isolated mouse mitochondria. Yeast cells expressing R40C-frataxin demonstrated increased sensitivity to oxidative stress and abnormal accumulation of precursor frataxin protein. These data indicate that frataxin deficiency may have contributed to this patient's particular phenotype. Furthermore, these findings suggest that mutations altering myocyte energetics may act in synergy with sarcomeric mutations to cause hypertrophic cardiomyopathy.
Mol Genet Metab 2005 Aug
PMID:Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy. 1593 68

Hypertrophic cardiomyopathy (HCM) is one of the most common causes of sudden cardiac death in young adults and is a familial disease in at least 60% of cases. Causative mutations have been identified in several sarcomeric genes, including the myosin binding protein C (MYBPC3) gene. Although numerous causative mutations have been identified, the pathogenetic process is still poorly understood. A large animal model of familial HCM in the cat has been identified and may be used for additional study. As the first spontaneous large animal model of this familial disease, feline familial HCM provides a valuable model for investigators to evaluate pathophysiologic processes and therapeutic (pharmacologic or genetic) manipulations. The MYBPC3 gene was chosen as a candidate gene in this model after identifying a reduction in the protein in myocardium from affected cats in comparison to control cats (P<0.001). DNA sequencing was performed and sequence alterations were evaluated for evidence that they changed the amino acid produced, that the amino acid was conserved and that the protein structure was altered. We identified a single base pair change (G to C) in the feline MYBPC3 gene in affected cats that computationally alters the protein conformation of this gene and results in sarcomeric disorganization. We have identified a causative mutation in the feline MYBPC3 gene that results in the development of familial HCM. This is the first report of a spontaneous mutation causing HCM in a non-human species. It should provide a valuable model for evaluating pathophysiologic processes and therapeutic manipulations.
Hum Mol Genet 2005 Dec 01
PMID:A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. 1623 61

Hypertrophic cardiomyopathy is a relatively common genetic disease, affecting one person per 500 in the general population, and is clinically defined by the presence of unexplained left ventricular hypertrophy. Although recognized as the most common cause of sudden death in the young (especially in athletes), the cardiac expression of the disease is highly variable with respect to age at onset, degree of symptoms and risk of cardiac death. As a consequence, therapeutic strategies are diverse and must be adapted to the specific features of an individual. Recently, the molecular bases of the disease have been unraveled with the identification of a large number of mutations in genes encoding sarcomeric proteins. This review focuses on the impact of the molecular data on the understanding of the disease, and considers the emerging issues regarding the impact of molecular testing on the management of patients (or relatives) in clinical practice.
Expert Rev Mol Diagn 2006 Jan
PMID:Molecular genetics in hypertrophic cardiomyopathy: towards individualized management of the disease. 1635 68

Hypertrophic cardiomyopathy (HCM) is a disease of mutant sarcomeric proteins (except for phenocopy). Cardiac hypertrophy is the clinical diagnostic hallmark of HCM and a major determinant of morbidity and mortality in various cardiovascular diseases. However, there is remarkable variability in expression of hypertrophy, even among HCM patients with identical causal mutations. We hypothesized modifier genes are partly responsible for the variation in hypertrophic expressivity. To map the modifier loci, we typed 811 short-tandem repeat markers ( approximately 5 cMdense) in 100 members of an HCM family including 36 with the InsG791 mutation in MYBPC3. We performed oligogenic simultaneous segregation and linkage analyses using Markov Chain Monte Carlo methods and detected linkage on 3q26.2 (180 cM), 10p13 (41 cM), 17q24 (108 cM) with log of the posterior placement probability ratio (LOP) of 3.51, 4.86 and 4.17, respectively, and suggestive linkage (LOP of 2.40) on 16q12.2 (73 cM). The effect sizes varied according to the modifier locus, age and sex. It ranged from approximately 8 g shift in left ventricular mass for 10p13 locus heterozygosity for the common allele to approximately 90 g shift for 3q26.2 locus homozygosity for the uncommon allele. Refining the 10p13 locus restricted the candidate modifier genes to ITGA8, C10orf97 (CARP) and PTER. ITGA8 and CARP are biologically plausible candidates as they are implicated in cardiac fibrosis and apoptosis, respectively. Since cardiac hypertrophy is a major determinant of total and cardiovascular mortality and morbidity, regardless of the etiology, identification of the specific modifier genes could have significant prognostic and therapeutic implications for various cardiovascular diseases.
Hum Mol Genet 2007 Oct 15
PMID:Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. 1765 99

Restrictive cardiomyopathy (RCM) is a debilitating disease characterized by impaired ventricular filling, reduced ventricular volumes, and severe diastolic dysfunction. Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy and heightened risk of premature sudden cardiac death. These cardiomyopathies can result from mutations in the same gene that encodes for cardiac troponin I (cTnI). Acute genetic engineering of adult rat cardiac myocytes was used to ascertain whether primary physiologic outcomes could distinguish between RCM and HCM alleles at the cellular level. Co-transduction of cardiac myocytes with wild-type (WT) cTnI and RCM/HCM linked mutants in cTnI's inhibitory region (IR) demonstrated that WT cTnI preferentially incorporated into the sarcomere over IR mutants. The cTnI IR mutants exhibited minor effects in single myocyte Ca(2+)-activated tension assays yet prolonged relaxation and Ca(2+) decay. In comparison RCM cTnI mutants in the helix-4/C-terminal region demonstrated a) hyper-sensitivity to Ca(2+) under loaded conditions, b) slowed myocyte mechanical relaxation and Ca(2+) transient decay, c) frequency-dependent Ca(2+)-independent diastolic tone, d) heightened myofilament incorporation and e) irreversible cellular contractile defects with acute diltiazem administration. For species comparison, a subset of cTnI mutants were tested in isolated adult rabbit cardiac myocytes. Here, RCM and HCM mutant cTnIs exerted similar effects of slowed myocyte relaxation and Ca(2+) transient decay but did not show variable phenotypes by cTnI region. This study highlights cellular contractile defects by cardiomyopathy mutant cTnIs that are allele and species dependent. The species dependent results in particular raise important issues toward elucidating a unifying mechanistic pathway underlying the inherited cardiomyopathies.
J Mol Cell Cardiol 2008 May
PMID:Allele and species dependent contractile defects by restrictive and hypertrophic cardiomyopathy-linked troponin I mutants. 1842 59

Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.
Hum Mol Genet 2008 Sep 15
PMID:Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. 1850 55

Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous disease, which suggests that a number of factors exist which modify disease outcome. Gender may be one such factor as more males present with the disease compared with females. The aim of the present study was to determine if an association exists between genetic variation in sex hormone receptors and the development of left ventricular hypertrophy in HCM. The study population included 200 unrelated individuals from an Australian HCM cohort. Clinical evaluation was performed. Genetic analysis of the androgen receptor (AR), estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and aromatase (CYP19A1) genes, was carried out in all patients. Fewer (CAG)n repeats within the AR gene were significantly associated with higher maximal left ventricular wall thickness (LVWT) in males (P=0.008), adjusting for age. Male carriers of the A allele at SNP rs6915267, located in the promoter region of ESR1, had an 11% decrease in mean LVWT compared to male GG homozygotes (P=0.047). We report for the first time that variation at the AR gene is associated with left ventricular hypertrophy in males with HCM. Understanding the impact of sex hormones on phenotype will be helpful in the risk stratification and clinical management of HCM patients.
J Mol Cell Cardiol 2008 Aug
PMID:Sex hormone receptor gene variation associated with phenotype in male hypertrophic cardiomyopathy patients. 1861 86

Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ss-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy.
J Mol Diagn 2009 Jan
PMID:The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. 1905 45

Hypertrophic cardiomyopathy (HCM) is associated with cardiac hypertrophy, diastolic dysfunction, and sudden death. Recently, it has been suggested that inefficient energy utilization could be a common molecular pathway of HCM-related mutations. We have previously generated transgenic Sprague-Dawley rats overexpressing a truncated cardiac troponin T (DEL-TNT) molecule, displaying typical features of HCM such as diastolic dysfunction and an increased susceptibility to ventricular arrhythmias. We now studied these rats using 31P magnetic resonance spectroscopy (MRS). MRS demonstrated that cardiac energy metabolism was markedly impaired, as indicated by a decreased phosphocreatine to ATP ratio (-31%, p < 0.05). In addition, we assessed contractility of isolated cardiomyocytes. While DEL-TNT and control cardiomyocytes showed no difference under baseline conditions, DEL-TNT cardiomyocytes selectively exhibited a decrease in fractional shortening by 28% after 1 h in glucose-deprived medium (p < 0.05). Moreover, significant decreases in contraction velocity and relaxation velocity were observed. To identify the underlying molecular pathways, we performed transcriptional profiling using real-time PCR. DEL-TNT hearts exhibited induction of several genes critical for cardiac energy supply, including CD36, CPT-1/-2, and PGC-1alpha. Finally, DEL-TNT rats and controls were studied by radiotelemetry after being stressed by isoproterenol, revealing a significantly increased frequency of arrhythmias in transgenic animals. In summary, we demonstrate profound energetic alterations in DEL-TNT hearts, supporting the notion that inefficient cellular ATP utilization contributes to the pathogenesis of HCM.
J Mol Med (Berl) 2009 Apr
PMID:Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy. 1918 74

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in cardiac sarcomeric proteins. Troponin I (TNNI3) and troponin T (TNNT2) are important parts of the sarcomere in heart muscle, and mutations in their genes are responsible for development of HCM. The prevalence of mutations in these two genes is low; hence, the data on clinical outcome are scarce. Yet, some of these mutations were shown to be malignant with a high incidence of sudden death. Here, we describe the disease course in three families affected with TNNI3 and one family with TNNT2 gene mutations. In TNNI3-HCM, the phenotypic manifestation ranged from clinically silent to sudden cardiac death with the worst prognosis observed in carriers of Ala157Val mutation in exon 7. In contrast, TNNT2-HCM was associated with favorable prognosis. Thus, the findings of the present study add evidence on the phenotypic presentation of this genetic disease.
Genet Test Mol Biomarkers 2009 Oct
PMID:Low prevalence and variable clinical presentation of troponin I and troponin T gene mutations in hypertrophic cardiomyopathy. 1964 27


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