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1.
Mayr JA Haack TB Graf E Zimmermann FA Wieland T Haberberger B Superti-Furga A Kirschner J Steinmann B Baumgartner MR Moroni I Lamantea E Zeviani M Rodenburg RJ Smeitink J Strom TM Meitinger T Sperl W Prokisch H 《American journal of human genetics》2012,90(2):314-320
Exome sequencing of an individual with congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, all typical symptoms of Sengers syndrome, discovered two nonsense mutations in the gene encoding mitochondrial acylglycerol kinase (AGK). Mutation screening of AGK in further individuals with congenital cataracts and cardiomyopathy identified numerous loss-of-function mutations in an additional eight families, confirming the causal nature of AGK deficiency in Sengers syndrome. The loss of AGK led to a decrease of the adenine nucleotide translocator in the inner mitochondrial membrane in muscle, consistent with a role of AGK in driving the assembly of the translocator as a result of its effects on phospholipid metabolism in mitochondria. 相似文献
2.
Yu-Lin Ko Jin-Jer Chen Tang-K. Tang Ming-Sheng Teng Sheng-Yu Lin Peiliang Kuan Cheng-Wen Wu Wen-Pin Lien Choong-Chin Liew 《Human genetics》1996,97(4):457-461
To identify the disease locus of familial hypertrophic cardiomyopathy (FHC) in a Chinese family, a genetic linkage study
was performed using polymorphisms from various chromosomal regions. This family has eight affected members, including a case
with typical features of apical hypertrophic cardiomyopathy of the Japanese type. The results revealed significant evidence
of linkage of polymorphisms on chromosome 11p13–q13 and FHC in this family with a maximal lod score of 3.38 at θ = 0.00. Our data suggest that the locus responsible for FHC in this family maps to chromosome 11 and that the molecular basis
of FHC in the case of apical hypertrophic cardiomyopathy of the Japanese type might be similar to that of other affected members
in the same family. Further studies are needed to elucidate the whole spectrum of the genetic basis of apical hypertrophic
cardiomyopathy of the Japanese type.
Received: 15 June 1995 / Revised: 22 August 1995 相似文献
3.
CFC syndrome: a syndrome distinct from Noonan syndrome 总被引:2,自引:0,他引:2
A Verloes M Le Merrer D Soyeur J Kaplan C Pangalos J Rigo M L Briard 《Annales de génétique》1988,31(4):230-234
We report two children with a common pattern of birth defects. Both have very sparse, curly hair, nystagmus and mental retardation. The first one has Noonan syndrome habitus associated with keratosis plantaris and nystagmus; the second one has a slightly Noonan-like face, macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy. They represent the extreme of a spectrum of congenital defects recently reported independently as CFC syndrome by Reynolds and as "Noonan-like short stature syndrome with sparse hair" by Baraitser and Patton. The clinical features are reviewed and the autonomy of the syndrome with regards to Noonan syndrome, is disputed, since every sign seems to occur independently in Noonan syndrome. The father of the second case probably has a minor syndrome expression, pointing to probable autosomal dominant inheritance. 相似文献
4.
Liu Z Song Y Gu S He X Zhu X Shen Y Wu B Wang W Li S Jiang P Lu J Huang W Yan Q 《Gene》2012,506(2):339-343
Hypertrophic cardiomyopathy is a primary disorder characterized by asymmetric thickening of the septum and left ventricular wall, which affects 1 in 500 individuals in the general population. Mutations in mitochondrial DNA have been found to be one of the most important causes of hypertrophic cardiomyopathy. Here we report the clinical, genetic and molecular characterization of a Han Chinese family with a likely maternally transmitted hypertrophic cardiomyopathy. Four (2 men/2 women) of 5 matrilineal relatives in this 3-generation family exhibited the variable severity and age at onset of 44 to 79years old. Sequence analysis of the entire mitochondrial DNA in this pedigree identified the known homoplasmic ND5 12338T>C variant. This mitochondrial DNA haplogroup belongs to the Eastern Asian F2a. The 12338T>C variant, highly evolutionarily conserved, resulted in the replacement of the translation initiating methionine with a threonine, shortening the ND5 polypeptide by 2 amino acids. The occurrence of ND5 12338T>C variant exclusively in maternal members of this Chinese family suggested that the 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy. Our findings will provide theoretical basis for genetic counseling of maternally inherited hypertrophic cardiomyopathy. 相似文献
5.
T. Germans W. P. Brouwer J. G. J. Groothuis A. M. Beek M. J. W. Götte A. C. van Rossum 《Netherlands heart journal》2010,18(3):135-143
The onset of sudden cardiac death and large inter- and intra-familial clinical variability of hypertrophic cardiomyopathy pose an important clinical challenge. Cardiac magnetic resonance imaging is a high-resolution imaging modality that has become increasingly available in the past decade and has the unique possibility to demonstrate the presence of fibrosis or scar using late gadolinium enhancement imaging. As a result, the diagnostic and prognostic potential of cardiac magnetic resonance imaging has been extensively explored in acute and chronic ischaemic cardiomyopathy, as well as in several nonischaemic cardiomyopathies. This review aims to provide a critical overview of recently published studies on hypertrophic cardiomyopathy and discusses the role of cardiac magnetic resonance imaging in differentiating underlying causes of hypertrophic cardiomyopathy, such as familial hypertrophic cardiomyopathy, cardiac involvement in systemic disease and left ventricular hypertrophy due to endurance sports. Also, it demonstrates the use of cardiac magnetic resonance in risk stratification for the onset of sudden cardiac death, and early identification of asymptomatic family members of hypertrophic cardiomyopathy patients who are at risk for the development of hypertrophic cardiomyopathy. (Neth Heart J 2010;18:135-43.) 相似文献
6.
MYBPC3 polymorphism is a modifier for expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy 总被引:6,自引:0,他引:6
Wang P Zou Y Fu C Zhou X Hui R 《Biochemical and biophysical research communications》2005,329(2):796-799
Clinical phenotype of hypertrophic cardiomyopathy exhibits significant inter- and intra-familial heterogeneities. To test if MYBPC3 polymorphism could modify the expression of cardiac hypertrophy, 226 patients with hypertrophic cardiomyopathy and 226 age- and sex-matched controls were recruited according to the diagnostic criteria of WHO. Genotyping was completed by using PCR, restrictive enzyme digestion, and sequencing. Three polymorphisms of MYBPC3 were studied, only the GG genotype at 18443 in exon 30 associated with thicker left ventricular wall (25.2+/-5.9 mm) in patient group, not the AA and AG genotypes (19.0+/-5.0mm, P<0.001). After multiple regression analysis for adjustment of age and sex, the association remained. No difference was found in the genotype distribution between control and patients. Our results point out that GG genotype of MYBPC3 might be a genetic risk factor for the expression of cardiac hypertrophic phenotype in the patients with hypertrophic cardiomyopathy. 相似文献
7.
Human familial hypertrophic cardiomyopathy is the most common Mendelian cardiovascular disease worldwide. Among the most severe presentations of the disease are those in families heterozygous for the mutation R403Q in β-cardiac myosin. Mice heterozygous for this mutation in the α-cardiac myosin isoform display typical familial hypertrophic cardiomyopathy pathology. Here, we study cardiomyocytes from heterozygous 403/+ mice. The effects of the R403Q mutation on force-generating capabilities and dynamics of cardiomyocytes were investigated using a dual carbon nanofiber technique to measure single-cell parameters. We demonstrate the Frank-Starling effect at the single cardiomyocyte level by showing that cell stretch causes an increase in amplitude of contraction. Mutant 403/+ cardiomyocytes exhibit higher end-diastolic and end-systolic stiffness than +/+ cardiomyocytes, whereas active force generation capabilities remain unchanged. Additionally, 403/+ cardiomyocytes show slowed relaxation dynamics. These phenotypes are consistent with increased end-diastolic and end-systolic chamber elastance, as well as diastolic dysfunction seen at the level of the whole heart. Our results show that these functional effects of the R403Q mutation are cell-intrinsic, a property that may be a general phenomenon in familial hypertrophic cardiomyopathy. 相似文献
8.
Shin-Ichi Haraguchi Masahisa Terasawa Hironori Toshima Isamu Matsumoto Tomiko Kuhara Toshihiro Shinka 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1982,230(1):7-14
Organic acids in the hearts of patients with idiopathic cardiomyopathy, obtained by biopsy, were studied using gas chromatography—mass spectrometry. The profiling of organic acids was compared among eight cases of hypertrophic cardiomyopathy, three cases of congestive cardiomyopathy, and nine cases of other heart diseases, which were regarded as controls.It was found that almost all organic acids, especially deoxyaldonic acids of 2-deoxytetronic acid, 2,3-dideoxypentonic acid, 3-deoxy-2-C-(hydroxymethyl)tetronic acid, 3-deoxyerythropentonic acid and 3-deoxy-2-C-(hydroxymethyl)erythropentonic acid, were accumulated in large amounts in the heart in congestive cardiomyopathy, while these acids were decreased in hypertrophic cardiomyopathy. It was therefore suggested that deoxyaldonic acid metabolism in the heart in congestive cardiomyopathy is quite different from that in hypertrophic cardiomyopathy. 相似文献
9.
Familial hypertrophic cardiomyopathy is a clinically and genetically diverse autosomal dominant disorder characterized by ventricular hypertrophy and myocyte disarray in the absence of known hypertrophic stimuli. It has been linked to many cardiac contractile proteins, including four point mutations in alpha-tropomyosin (Tm). Here we use adenoviral-mediated gene transfer into adult cardiac myocytes in vitro to show that all four hypertrophic cardiomyopathy alpha-Tm proteins can be expressed and incorporated into normal sarcomeric structures in cardiac myocytes at similar levels as normal alpha-Tm proteins after 5-6 days in culture. Isometric force recordings of single cardiac myocytes demonstrated inappropriate increased force output at submaximal calcium concentration with a specific mutant allele hierarchy. These data indicate that the severity of direct calcium-sensitizing effect of mutations in alpha-Tm may predict the clinical severity of mutant alpha-Tm-associated hypertrophic cardiomyopathy. 相似文献
10.
The outcome of 54 pregnancies in 23 patients with hypertrophic cardiomyopathy was analysed. No mother or infant died in the perinatal period. Six patients developed dyspnoea requiring treatment with diuretics. Beta-adrenergic blocking drugs were given in 18 pregnancies and three of the infants in this were small for dates and in two fetal bradycardia occurred. The results comfirmed that pregnancy is safe in patients with hypertrophic cardiomyopathy. A flexible approach should be adopted towards administering beta-adrenergic blocking drugs to pregnant women with hypertrophic cardiomyopathy. Many such patients do well without these drugs and can thus avoid the potential hazards--namely, small-for-dates babies and fetal bradycardia--that are associated with them. 相似文献
11.
Burhop J Rosol M Craig R Tobacman LS Lehman W 《The Journal of biological chemistry》2001,276(23):20788-20794
Familial hypertrophic cardiomyopathy (FHC) is caused by missense or premature truncation mutations in proteins of the cardiac contractile apparatus. Mutant proteins are incorporated into the thin filament or thick filament and eventually produce cardiomyopathy. However, it has been unclear how the several, genetically identified defects in protein structure translate into impaired protein and muscle function. We have studied the basis of FHC caused by premature truncation of the most frequently implicated thin filament target, troponin T. Electron microscope observations showed that the thin filament undergoes normal structural changes in response to Ca(2+) binding. On the other hand, solution studies showed that the mutation alters and destabilizes troponin binding to the thin filament to different extents in different regulatory states, thereby affecting the transitions among states that regulate myosin binding and muscle contraction. Development of hypertrophic cardiomyopathy can thus be traced to a defect in the primary mechanism controlling cardiac contraction, switching between different conformations of the thin filament. 相似文献
12.
Christine Schramm Michelle A. Edwards Maike Krenz 《The Journal of biological chemistry》2013,288(25):18335-18344
In LEOPARD syndrome (LS) patients, mutations in the protein tyrosine phosphatase Shp2 cause hypertrophic cardiomyopathy. The prohypertrophic effects of mutant Shp2 are mediated downstream by hyperactivation of mammalian target of rapamycin. Our goal was to further define the signaling cascade that is essential for the underlying pathomechanism, thus expanding the list of potential future therapeutic targets.Using cultured neonatal rat cardiomyocytes with adenoviral gene delivery and pharmacological inhibitors, we found that hypertrophy induced by a particularly aggressive LS mutation in Shp2 depends on hyperactivation of Akt and focal adhesion kinase as well as mammalian target of rapamycin. Dissecting domain-specific functions of Shp2 using double and truncation mutants, we determined that the hypertrophic effects of mutant Shp2 depend on the two SH2 domains and on an intact catalytic center. The latter finding prompted us to test the efficacy of a Shp2 inhibitor targeted directly at the catalytic pocket. This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS-associated cardiac hypertrophy. Of particular importance is the finding that intervention directly at the mutant Shp2 protein is effective because this would facilitate custom-tailored therapeutic approaches for patients carrying LS mutations in Shp2. 相似文献
13.
F. J. ten Cate 《Netherlands heart journal》2009,17(12):456-457
The cardiomyopathies are defined as: ‘a myocardial disorder in which the heart is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension and congenital heart disease sufficient to cause the myocardial abnormality.’1 With the advent of molecular cardiology and cardiovascular imaging (including MRI and echocardiography) in the last decade, much insight has been gained into the different clinical presentations, its familial and genetic causes and pathophysiology in explaining left ventricular function and prognosis. This has been especially true for hypertrophic cardiomyopathy, but also for dilated cardiomyopathy (DCM) and RV cardiomyopathy. 相似文献
14.
H Nishi A Kimura H Harada H Toshima T Sasazuki 《Biochemical and biophysical research communications》1992,188(1):379-387
We have analyzed the exon 9, 13, 14, 15, and 16 of cardiac beta myosin heavy chain gene in 96 Japanese patients with hypertrophic cardiomyopathy by using PCR-DNA conformation polymorphism analysis. The analysis revealed a sequence variation of the exon 16 in one patient. The sequence variation of a G to C transversion with replacement of Asn by Lys at the codon 615 was confirmed by sequencing and by dot-blot hybridization with an allele-specific oligonucleotide probe. Because the missense mutation was found at the residue conserved through birds to humans, this mutation was suggested to be a cause of hypertrophic cardiomyopathy in the patient. This is the first report of a mutant cardiac beta myosin heavy chain gene in the Japanese population. 相似文献
15.
《Molecular medicine today》1996,2(9):387-393
Familial hypertrophic cardiomyopathy is the first primary cardiomyopathy to have yielded to the techniques of modern molecular genetics. In the past few years, four genes responsible for this disease have been identified, all of which code for sarcomeric structural proteins. In addition, structure—function analysis and genotype—phenotype correlation studies have shed significant light on the molecular basis of this disease. It is hoped that within the next few years the application of molecular genetic tools will not only facilitate the diagnosis of hypertrophic cardiomyopathy but will also provide prognostic and therapeutic stratification for more definitive therapy. 相似文献
16.
There are several hypotheses concerning the pathogenesis of hypertrophic cardiomyopathy (genetic, ischaemic, immune, inflammatory and apoptosis induction). We have studied three types of cardiomyopathy in order to observe the expression and assess the significance of different immunohistochemical markers (muscular actin, CD-31, proliferation cell nuclear antigen -PCNA-, Ki-67, and markers related with programmed cell death, bcl-2, p-53 and apopDETEC). We studied different microscopic (haematoxylin-eosin and Masson's thrichrome) and immunohistochemical parameters (streptavidin-biotin-peroxidase and "in situ" hybridisation) of forty cases: ten each of hypertensive hypertrophic cardiomyopathy, essential hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in patients treated with chemotherapy and morphologically "normal" hearts. Our findings point to an absence of structural marker expression (actin and CD-31) in cases of hypoxic damage. The distribution and intensity of apoptosis markers, a seen by "in situ" hybridisation were irregular, and the rest of the markers studied showed negative results, with the exception of acridin orange (a marker of hypoxic damage). In our opinion, the above immunohistochemical markers, especially actin and CD-31, could be used for differentiating hypoxic lesions in these three types of cardiomyopathy. Moreover, it is difficult to know the significance of the apoptosis markers, because the autolysis process produces cross reactions with false positive results. We think that there is a need for new studies on DNA breakdown processes during the post-mortem interval. To avoid autolysis problems the post-mortem material needs to be as fresh as possible. 相似文献
17.
The functional effects of two missense mutations in human cardiac troponin T, Phe110Ile and Glu244Asp, associated with familial hypertrophic cardiomyopathy were examined by exchanging the bacterially expressed and purified mutant troponin T into rabbit cardiac skinned muscle fibers. Both mutations significantly increased the maximum force without affecting the cooperativity. The Glu244Asp mutation also increased the Ca(2+) sensitivity of the force generation, as in the case of other mutations associated with a poor prognosis. On the other hand, the Phe110Ile mutation, associated with a favorable prognosis, had no effect on the Ca(2+) sensitivity. The results strongly support the hypothesis that increased Ca(2+) sensitivity is responsible for the pathogenesis of hypertrophic cardiomyopathy with a poor prognosis caused by mutations in troponin T. 相似文献
18.
Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency
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Burwinkel B Scott JW Bührer C van Landeghem FK Cox GF Wilson CJ Grahame Hardie D Kilimann MW 《American journal of human genetics》2005,76(6):1034-1049
Fatal congenital nonlysosomal cardiac glycogenosis has been attributed to a subtype of phosphorylase kinase deficiency, but the underlying genes and mutations have not been identified. Analyzing four sporadic, unrelated patients, we found no mutations either in the eight genes encoding phosphorylase kinase subunits or in the two genes encoding the muscle and brain isoforms of glycogen phosphorylase. However, in three of five patients, we identified identical heterozygous R531Q missense mutations of the PRKAG2 gene, which encodes the gamma 2-subunit of AMP-activated protein kinase, a key regulator of energy balance. Biochemical characterization of the recombinant R531Q mutant protein showed >100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity and increased phosphorylation of the alpha -subunit. Other PRKAG2 missense mutations were previously identified in patients with autosomal dominant hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome, characterized by juvenile-to-adult clinical onset, moderate cardiac glycogenosis, disturbed excitation conduction, risk of sudden cardiac death in midlife, and molecular perturbations that are similar to--but less severe than--those observed for the R531Q mutation. Thus, recurrent heterozygous R531Q missense mutations in PRKAG2 give rise to a massive nonlysosomal cardiac glycogenosis of fetal symptomatic onset and rapidly fatal course, constituting a genotypically and clinically distinct variant of hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome. R531Q and other PRKAG2 mutations enhance the basal activity and alpha -subunit phosphorylation of AMP-activated protein kinase, explaining the dominant nature of PRKAG2 disease mutations. Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal cardiac glycogenosis seems to be genetically heterogeneous. However, the existence of a heart-specific primary phosphorylase kinase deficiency is questionable, because no phosphorylase kinase mutations were found. 相似文献
19.
Tetsuo Konno Kenshi Hayashi Noboru Fujino Yoji Nagata Akihiko Hodatsu Eiichi Masuta Kenji Sakata Hiroyuki Nakamura Masa-aki Kawashiri Masakazu Yamagishi 《PloS one》2014,9(7)
Background
Myocardial scarring can be assessed by cardiac magnetic resonance imaging with late gadolinium enhancement and by endomyocardial biopsy. However, accuracy of late gadolinium enhancement for predicting microscopic myocardial scarring in biopsied specimens remains unknown in hypertrophic cardiomyopathy. We investigated whether late gadolinium enhancement in the whole heart reflects microscopic myocardial scarring in the small biopsied specimens in hypertrophic cardiomyopathy.Methods and Results
Twenty-one consecutive patients with hypertrophic cardiomyopathy who were examined both by cardiac magnetic resonance imaging and by endomyocardial biopsy were retrospectively studied. The right interventricular septum was the target site for endomyocardial biopsy in all patients. Late gadolinium enhancement in the ventricular septum had an excellent sensitivity (100%) with a low specificity (40%) for predicting microscopic myocardial scarring in biopsied specimens. The sensitivity of late gadolinium enhancement in the whole heart remained 100% with a specificity of 27% for predicting microscopic myocardial scarring in biopsied specimens. Quantitative assessments of fibrosis revealed that the extent of late gadolinium enhancement in the whole heart was the only independent variable related to the microscopic collagen fraction in biopsied specimens (β = 0.59, 95% confident interval: 0.15 – 1.0, p = 0.012).Conclusions
Although there was a compromise in the specificity, the sensitivity of late gadolinium enhancement was excellent for prediction of microscopic myocardial scarring in hypertrophic cardiomyopathy. Moreover, the severity of late gadolinium enhancement was independently associated with the quantitative collagen fraction in biopsied specimens in hypertrophic cardiomyopathy. These findings indicate that late gadolinium enhancement can reflect both the presence and the extent of microscopic myocardial scarring in the small biopsied specimens in hypertrophic cardiomyopathy. 相似文献20.
Carnitine is an essential cofactor for the beta-oxidation of fats. Both hypertrophic and congestive cardiomyopathies have been reported in primary and secondary carnitine deficiency. Conversely in avian cardiomyopathy models abnormally elevated plasma and tissue carnitine concentrations have been described. We measured plasma carnitine concentrations in 25 cardiomyopathy patients. In 14 patients with either hypertrophic or congestive cardiomyopathy plasma carnitine concentrations were abnormally elevated. Patients with secondary cardiomyopathies tended to have normal carnitine values. One patient with systemic carnitine deficiency was diagnosed. Her cardiac function normalized with L-carnitine replacement. Six of 14 patients with high plasma carnitine concentrations died. None of the 10 with low or normal plasma carnitine have died. Plasma carnitine determination may be a useful adjunct in the diagnostic evaluation of idiopathic cardiomyopathy. 相似文献