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Sample records for cardiomyopathy mutations affect

  1. Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain.

    PubMed

    Huang, Wenrui; Liang, Jingsheng; Yuan, Chen-Ching; Kazmierczak, Katarzyna; Zhou, Zhiqun; Morales, Ana; McBride, Kim L; Fitzgerald-Butt, Sara M; Hershberger, Ray E; Szczesna-Cordary, Danuta

    2015-06-01

    Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by left ventricular dilatation and diminished contractile function. Here we describe a novel DCM mutation in the myosin regulatory light chain (RLC), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first-degree relatives who met formal criteria for idiopathic DCM. To obtain insight into the functional significance of this pathogenic MYL2 variant, we cloned and purified the human ventricular RLC wild-type (WT) and D94A mutant proteins, and performed in vitro experiments using RLC-mutant or WT-reconstituted porcine cardiac preparations. The mutation induced a reduction in the α-helical content of the RLC, and imposed intra-molecular rearrangements. The phosphorylation of RLC by Ca²⁺/calmodulin-activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of RLC to the myosin heavy chain, and its incorporation into RLC-depleted porcine myosin. The actin-activated ATPase activity of mutant-reconstituted porcine cardiac myosin was significantly higher compared with ATPase of wild-type. No changes in the myofibrillar ATPase-pCa relationship were observed in wild-type- or D94A-reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross-section of muscle, with no change in the calcium sensitivity of force in D94A-reconstituted skinned porcine papillary muscle strips compared with wild-type. Our data indicate that subtle structural rearrangements in the RLC molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the DCM phenotype. PMID:25825243

  2. Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

    PubMed Central

    Haywood, Natalie J.; Wolny, Marcin; Rogers, Brendan; Trinh, Chi H.; Shuping, Yu; Edwards, Thomas A.; Peckham, Michelle

    2016-01-01

    α-Actinin-2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients, A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain (ABD) of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease. PMID:27287556

  3. Missense mutations in Desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro

    PubMed Central

    Beffagna, Giorgia; De Bortoli, Marzia; Nava, Andrea; Salamon, Michela; Lorenzon, Alessandra; Zaccolo, Manuela; Mancuso, Luisa; Sigalotti, Luca; Bauce, Barbara; Occhi, Gianluca; Basso, Cristina; Lanfranchi, Gerolamo; Towbin, Jeffrey A; Thiene, Gaetano; Danieli, Gian Antonio; Rampazzo, Alessandra

    2007-01-01

    Background Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement. We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue. Methods Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing. To evaluate the pathogenic potentials of the DSC2 mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells. Results We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions. In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm. Conclusion The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling. PMID:17963498

  4. Inherited cardiomyopathies caused by troponin mutations

    PubMed Central

    Lu, Qun-Wei; Wu, Xiao-Yan; Morimoto, Sachio

    2013-01-01

    Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy. PMID:23610579

  5. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.

    PubMed

    Boyden, Lynn M; Kam, Chen Y; Hernández-Martín, Angela; Zhou, Jing; Craiglow, Brittany G; Sidbury, Robert; Mathes, Erin F; Maguiness, Sheilagh M; Crumrine, Debra A; Williams, Mary L; Hu, Ronghua; Lifton, Richard P; Elias, Peter M; Green, Kathleen J; Choate, Keith A

    2016-01-15

    Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. PMID:26604139

  6. [Hereditary amyloid cardiomyopathy related to a mutation at transthyretin protein number 111. A clinical, genetic and echocardiographic study of an affected Danish family].

    PubMed

    Svendsen, I H; Steensgaard-Hansen, F; Nordvåg, B Y

    1999-09-01

    Amyloidosis is a group of diseases characterized by amyloid deposition in various tissues. The diseases can roughly be divided into hereditary and non-hereditary forms. The hereditary forms are related to a mutation in the serum protein transthyretin which is produced mainly in the liver. The inheritance is autosomal dominant. A family in Denmark has earlier been described as having inherited cardiac amyloidosis with a mutation at amino acid number 111 in the transthyretin protein. The family now has been re-examined because of new diagnostic and therapeutic possibilities. The aims of the study were to identify carriers and non-carriers of the mutant transthyretin methionine 111 linked familial amyloid disease, to detect early signs of the restrictive cardiomyopathy and other clinical manifestations of this disease. Clinical, echocardiographic and genetic examination was carried out. Out of 125 living family members, 99 were available for examination. Twenty-five persons were heterozygous carriers of the mutant transthyretin methionine 111 genotype, while 74 were non-carriers. Eight carriers, all above the age of 35, showed echocardiographic abnormalities suggestive of developing or manifest restrictive cardiomyopathy. Nine carriers had carpal tunnel syndrome as opposed to none of the non-carriers. It is concluded that for early detection of familial amyloid cardiomyopathy, echocardiography is the investigation of choice. The first sign is diastolic dysfunction detected as an abnormal relaxation pattern. Carpal tunnel syndrome appears to be the earliest presenting clinical symptom. Early liver transplantation seems to be curative. PMID:10489791

  7. Arrhythmogenic Cardiomyopathy in a Patient With a Rare Loss‐of‐Function KCNQ1 Mutation

    PubMed Central

    Xiong, Qinmei; Cao, Qing; Zhou, Qiongqiong; Xie, Jinyan; Shen, Yang; Wan, Rong; Yu, Jianhua; Yan, Sujuan; Marian, Ali J.; Hong, Kui

    2015-01-01

    Background Ventricular tachycardia (VT) is a common manifestation of advanced cardiomyopathies. In a subset of patients with dilated cardiomyopathy, VT is the initial and the cardinal manifestation of the disease. The molecular genetic basis of this subset of dilated cardiomyopathy is largely unknown. Methods and Results We identified 10 patients with dilated cardiomyopathy who presented with VT and sequenced 14 common causal genes for cardiomyopathies and arrhythmias. Functional studies included cellular patch clamp, confocal microscopy, and immunoblotting. We identified nonsynonymous variants in 4 patients, including a rare missense p.R397Q mutation in the KCNQ1 gene in a 60‐year‐old man who presented with incessant VT and had mild cardiac dysfunction. The p.R397Q mutation was absent in an ethnically matched control group, affected a conserved amino acid, and was predicted by multiple algorithms to be pathogenic. Co‐expression of the mutant KCNQ1 with its partner unit KCNE1 was associated with reduced tail current density of slowly activating delayed rectifier K+ current (IKs). The mutation reduced membrane localization of the protein. Conclusions Dilated cardiomyopathy with an initial presentation of VT may be a forme fruste of arrhythmogenic cardiomyopathy caused by mutations in genes encoding the ion channels. The findings implicate KCNQ1 as a possible causal gene for arrhythmogenic cardiomyopathy. PMID:25616976

  8. Unclassifiable arrhythmic cardiomyopathy associated with Emery-Dreifuss caused by a mutation in FHL1.

    PubMed

    San Román, I; Navarro, M; Martínez, F; Albert, L; Polo, L; Guardiola, J; García-Molina, E; Muñoz-Esparza, C; López-Ayala, J M; Sabater-Molina, M; Gimeno, J R

    2016-08-01

    Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non-dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL-1 disorder in X-linked cardiomyopathy. PMID:26857240

  9. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss.

    PubMed

    Schönberger, Jost; Wang, Libin; Shin, Jordan T; Kim, Sang Do; Depreux, Frederic F S; Zhu, Hao; Zon, Leonard; Pizard, Anne; Kim, Jae B; Macrae, Calum A; Mungall, Andy J; Seidman, J G; Seidman, Christine E

    2005-04-01

    We identified a human mutation that causes dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (SNHL). Unlike previously described mutations causing dilated cardiomyopathy that affect structural proteins, this mutation deletes 4,846 bp of the human transcriptional coactivator gene EYA4. To elucidate the roles of eya4 in heart function, we studied zebrafish embryos injected with antisense morpholino oligonucleotides. Attenuated eya4 transcript levels produced morphologic and hemodynamic features of heart failure. To determine why previously described mutated EYA4 alleles cause SNHL without heart disease, we examined biochemical interactions of mutant Eya4 peptides. Eya4 peptides associated with SNHL, but not the shortened 193-amino acid peptide associated with dilated cardiomyopathy and SNHL, bound wild-type Eya4 and associated with Six proteins. These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function. PMID:15735644

  10. Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.

    PubMed

    Brodehl, Andreas; Ferrier, Raechel A; Hamilton, Sara J; Greenway, Steven C; Brundler, Marie-Anne; Yu, Weiming; Gibson, William T; McKinnon, Margaret L; McGillivray, Barbara; Alvarez, Nanette; Giuffre, Michael; Schwartzentruber, Jeremy; Gerull, Brenda

    2016-03-01

    Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies. PMID:26666891

  11. The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms

    PubMed Central

    Gollapudi, Sampath K.; Tardiff, Jil C.

    2015-01-01

    Given the differential impact of α- and β-myosin heavy chain (MHC) isoforms on how troponin T (TnT) modulates contractile dynamics, we hypothesized that the effects of dilated cardiomyopathy (DCM) mutations in TnT would be altered differently by α- and β-MHC. We characterized dynamic contractile features of normal (α-MHC) and transgenic (β-MHC) mouse cardiac muscle fibers reconstituted with a mouse TnT analog (TnTR144W) of the human DCM R141W mutation. TnTR144W did not alter maximal tension but attenuated myofilament Ca2+ sensitivity (pCa50) to a similar extent in α- and β-MHC fibers. TnTR144W attenuated the speed of cross-bridge (XB) distortion dynamics (c) by 24% and the speed of XB recruitment dynamics (b) by 17% in α-MHC fibers; however, both b and c remained unaltered in β-MHC fibers. Likewise, TnTR144W attenuated the rates of XB detachment (g) and tension redevelopment (ktr) only in α-MHC fibers. TnTR144W also decreased the impact of strained XBs on the recruitment of new XBs (γ) by 30% only in α-MHC fibers. Because c, b, g, ktr, and γ are strongly influenced by thin filament-based cooperative mechanisms, we conclude that the TnTR144W- and β-MHC-mediated changes in the thin filament interact to produce a less severe functional phenotype, compared with that brought about by TnTR144W and α-MHC. These observations provide a basis for lower mortality rates of humans (β-MHC) harboring the TnTR141W mutant compared with transgenic mouse studies. Our findings strongly suggest that some caution is necessary when extrapolating data from transgenic mouse studies to human hearts. PMID:25681424

  12. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

    PubMed Central

    Wessels, Marja W; Herkert, Johanna C; Frohn-Mulder, Ingrid M; Dalinghaus, Michiel; van den Wijngaard, Arthur; de Krijger, Ronald R; Michels, Michelle; de Coo, Irenaeus FM; Hoedemaekers, Yvonne M; Dooijes, Dennis

    2015-01-01

    Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients. PMID:25335496

  13. Exome Sequencing Identifies Mitochondrial Alanyl-tRNA Synthetase Mutations in Infantile Mitochondrial Cardiomyopathy

    PubMed Central

    Götz, Alexandra; Tyynismaa, Henna; Euro, Liliya; Ellonen, Pekka; Hyötyläinen, Tuulia; Ojala, Tiina; Hämäläinen, Riikka H.; Tommiska, Johanna; Raivio, Taneli; Oresic, Matej; Karikoski, Riitta; Tammela, Outi; Simola, Kalle O.J.; Paetau, Anders; Tyni, Tiina; Suomalainen, Anu

    2011-01-01

    Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure. PMID:21549344

  14. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.

    PubMed

    Du, Cheng-Kun; Morimoto, Sachio; Nishii, Kiyomasa; Minakami, Reiko; Ohta, Mika; Tadano, Naoto; Lu, Qun-Wei; Wang, Yuan-Yuan; Zhan, Dong-Yun; Mochizuki, Misato; Kita, Satomi; Miwa, Yoshikazu; Takahashi-Yanaga, Fumi; Iwamoto, Takahiro; Ohtsuki, Iwao; Sasaguri, Toshiyuki

    2007-07-20

    We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca(2+) sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca(2+) transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca(2+) transient was augmented to compensate for decreased myofilament Ca(2+) sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca(2+) sensitivity could not be fully compensated by only increasing the intracellular Ca(2+) transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca(2+) sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca(2+) desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca(2+) sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations. PMID:17556660

  15. Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations.

    PubMed

    Huang, Wenrui; Szczesna-Cordary, Danuta

    2015-12-01

    We discuss here the potential mechanisms of action associated with hypertrophic (HCM) or dilated (DCM) cardiomyopathy causing mutations in the myosin regulatory (RLC) and essential (ELC) light chains. Specifically, we focus on four HCM mutations: RLC-A13T, RLC-K104E, ELC-A57G and ELC-M173V, and one DCM RLC-D94A mutation shown by population studies to cause different cardiomyopathy phenotypes in humans. Our studies indicate that RLC and ELC mutations lead to heart disease through different mechanisms with RLC mutations triggering alterations of the secondary structure of the RLC which further affect the structure and function of the lever arm domain and impose changes in the cross bridge cycling rates and myosin force generation ability. The ELC mutations exert their detrimental effects through changes in the interaction of the N-terminus of ELC with actin altering the cross talk between the thick and thin filaments and ultimately resulting in an altered force-pCa relationship. We also discuss the effect of mutations on myosin light chain phosphorylation. Exogenous myosin light chain phosphorylation and/or pseudo-phosphorylation were explored as potential rescue tools to treat hypertrophy-related cardiac phenotypes. PMID:26385864

  16. Cardiomyopathy

    MedlinePlus

    ... page from the NHLBI on Twitter. What Is Cardiomyopathy? Cardiomyopathy refers to diseases of the heart muscle. These ... many causes, signs and symptoms, and treatments. In cardiomyopathy, the heart muscle becomes enlarged, thick, or rigid. ...

  17. Cardiomyopathy

    MedlinePlus

    ... or surgeries may also be used, including: A defibrillator that sends an electrical pulse to stop life- ... failure - overview Heart transplant Hypertrophic cardiomyopathy Implantable cardioverter-defibrillator Peripartum cardiomyopathy Restrictive cardiomyopathy Patient Instructions Heart failure - ...

  18. Molecular diagnosis of the transthyretin (TTR) Met111 mutation in familial amyloid cardiomyopathy of Danish origin.

    PubMed

    Nordvåg, B Y; Husby, G; Ranløv, I; el-Gewely, M R

    1992-06-01

    Familial amyloid cardiomyopathy in a Danish kindred is associated with a specific mutation (Met for Leu111) in the transthyretin (TTR) gene, causing the loss of a recognition site for the restriction enzyme DdeI in the gene. We describe a diagnostic test for the molecular detection of this mutation. A sequence of the TTR gene containing the mutation was amplified by the polymerase chain reaction from isolated genomic DNA of two affected patients and several controls. DdeI digestion of the amplified DNA from the patients revealed 3 bands by gel-electrophoresis, whereas amplified DNA of the controls showed only 2 bands, consistent with complete digestion. Thus, the assumed heterozygous TTR Met111 mutation was confirmed in the affected patients. PMID:1618497

  19. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation

    PubMed Central

    Spiegel, Ronen; Saada, Ann; Flannery, Padraig J; Burté, Florence; Soiferman, Devorah; Khayat, Morad; Eisner, Verónica; Vladovski, Eugene; Taylor, Robert W; Bindoff, Laurence A; Shaag, Avraham; Mandel, Hanna; Schuler-Furman, Ora; Shalev, Stavit A; Elpeleg, Orly; Yu-Wai-Man, Patrick

    2016-01-01

    Background Infantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes. Objective To identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. Methods We describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy. Results Both affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients’ muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion. Conclusions We have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association

  20. Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies

    PubMed Central

    Tomasov, Pavol; Villard, Eric; Faludi, Reka; Melacini, Paola; Lossie, Janine; Lohmann, Nadine; Richard, Pascale; De Bortoli, Marzia; Angelini, Annalisa; Varga-Szemes, Akos; Sperling, Silke R.; Simor, Tamás; Veselka, Josef; Özcelik, Cemil; Charron, Philippe

    2016-01-01

    Introduction Transgenic mice overexpressing mutated NEBL, encoding the cardiac-specific Z-disk protein nebulette, develop severe cardiac phenotypes. Since cardiomyopathies are commonly familial and because mutations in a single gene may result in variable phenotypes, we tested the hypothesis that NEBL mutations are associated with cardiomyopathy. Material and methods We analyzed 389 patients, including cohorts of patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction cardiomyopathy (LVNC). The 28 coding exons of the NEBL gene were sequenced. Further bioinformatic analysis was used to distinguish variants. Results In total, we identified six very rare heterozygous missense mutations in NEBL in 7 different patients (frequency 1.8%) in highly conserved codons. The mutations were not detectable in 320 Caucasian sex-matched unrelated individuals without cardiomyopathy and 192 Caucasian sex-matched blood donors without heart disease. Known cardiomyopathy genes were excluded in these patients. The mutations p.H171R and p.I652L were found in 2 HCM patients. Further, p.Q581R and p.S747L were detected in 2 DCM patients, while the mutation p.A175T was identified independently in two unrelated patients with DCM. One LVNC patient carried the mutation p.P916L. All HCM and DCM related mutations were located in the nebulin-like repeats, domains responsible for actin binding. Interestingly, the mutation associated with LVNC was located in the C-terminal serine-rich linker region. Conclusions Our data suggest that NEBL mutations may cause various cardiomyopathies. We herein describe the first NEBL mutations in HCM and LVNC. Our findings underline the notion that the cardiomyopathies are true allelic diseases. PMID:27186169

  1. Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise

    PubMed Central

    Kapplinger, Jamie D.; Landstrom, Andrew P.; Bos, J. Martijn; Salisbury, Benjamin A.; Callis, Thomas E.; Ackerman, Michael J.

    2014-01-01

    Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the Hypertrophic Cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the “Gold Standard” Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly over-represented in disease, a background rate as high as ~5% among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test. PMID:24510615

  2. Rare variant mutations identified in pediatric patients with dilated cardiomyopathy.

    PubMed

    Rampersaud, Evadnie; Siegfried, Jill D; Norton, Nadine; Li, Duanxiang; Martin, Eden; Hershberger, Ray E

    2011-01-01

    Dilated cardiomyopathy (DCM) in infants and children can be partially explained by genetic cause but the catalogue of known genes is limited. We reviewed our database of 41 cases diagnosed with DCM before 18 years of age who underwent detailed clinical and genetic evaluation, and summarize here the evidence for mutations causing DCM in these cases from 15 genes (PSEN1, PSEN2, CSRP3, LBD3, MYH7, SCN5A, TCAP, TNNT2, LMNA, MYBPC3, MYH6, TNNC1, TNNI3, TPM1, and RBM20). Thirty-five of the 41 pediatric cases had relatives with adult-onset DCM. More males (66%) were found among children diagnosed after 1 year of age with DCM. Nineteen mutations in 9 genes were identified among 15 out of 41 patients; 3 patients (diagnosed at ages 2 weeks, 9 and 13 years) had multiple mutations. Of the 19 mutations identified in 12 families, mutations in TPM1 (32%) and TNNT2 (21%) were the most commonly found. Of the 6 patients diagnosed before 1 year of age, 3 had mutations in TPM1 (including a set of identical twins), 1 in TNNT2, 1 in MYH7, and 1 with multiple mutations (MYH7 and TNNC1). Most DCM was accompanied by advanced heart failure and need for cardiac transplantation. We conclude that in some cases pediatric DCM has a genetic basis, which is complicated by allelic and locus heterogeneity as seen in adult-onset DCM. We suggest that future prospective comprehensive family-based genetic studies of pediatric DCM are indicated to further define mutation frequencies in known genes and to discover novel genetic cause. PMID:21483645

  3. Rare variant mutations identified in pediatric patients with dilated cardiomyopathy

    PubMed Central

    Rampersaud, Evadnie; Siegfried, Jill D; Norton, Nadine; Li, Duanxiang; Martin, Eden; Hershberger, Ray E

    2010-01-01

    Dilated cardiomyopathy (DCM) in infants and children can be partially explained by genetic cause but the catalogue of known genes is limited. We reviewed our database of 41 cases diagnosed with DCM before 18 years of age who underwent detailed clinical and genetic evaluation, and summarize here the evidence for mutations causing DCM in these cases from 15 genes (PSEN1, PSEN2, CSRP3, LBD3, MYH7, SCN5A, TCAP, TNNT2, LMNA, MYBPC3, MYH6, TNNC1, TNNI3, TPM1, and RBM20). Thirty-five of the 41 pediatric cases had relatives with adult-onset DCM. More males (66%) were found among children diagnosed after 1 year of age with DCM. Nineteen mutations in 9 genes were identified among 15 out of 41 patients; 3 patients (diagnosed at ages 2 weeks, 9 and 13 years) had multiple mutations. Of the 19 mutations identified in 12 families, mutations in TPM1 (32%) and TNNT2 (21%) were the most commonly found. Of the 6 patients diagnosed before 1 year of age, 3 had mutations in TPM1 (including a set of identical twins), 1 in TNNT2, 1 in MYH7, and 1 with multiple mutations (MYH7 and TNNC1). Most DCM was accompanied by advanced heart failure and need for cardiac transplantation. We conclude that in some cases pediatric DCM has a genetic basis, which is complicated by allelic and locus heterogeneity as seen in adult-onset DCM. We suggest that future prospective comprehensive family-based genetic studies of pediatric DCM are indicated to further define mutation frequencies in known genes and to discover novel genetic cause. PMID:21483645

  4. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy.

    PubMed Central

    Anan, R; Greve, G; Thierfelder, L; Watkins, H; McKenna, W J; Solomon, S; Vecchio, C; Shono, H; Nakao, S; Tanaka, H

    1994-01-01

    Three novel beta cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change. Images PMID:8282798

  5. The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy

    PubMed Central

    Heliö, Tiina; Jääskeläinen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S.; Laakso, Markku; Hyötyläinen, Tuulia; Orešič, Matej; Kuusisto, Johanna

    2015-01-01

    Aims Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters. Methods and Results 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Conclusions Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle. PMID:26267065

  6. Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy.

    PubMed

    Pigors, Manuela; Schwieger-Briel, Agnes; Cosgarea, Rodica; Diaconeasa, Adriana; Bruckner-Tuderman, Leena; Fleck, Thilo; Has, Cristina

    2015-03-01

    Mutations in genes encoding for desmosomal components are associated with a broad spectrum of phenotypes comprising skin and hair abnormalities and account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy. Today, more than 120 dominant and recessive desmoplakin (DSP) gene mutations have been reported to be associated with skin, hair and/or heart defects. Here we report on 3 cases with yet unreported DSP mutations, c.7566_7567delAAinsC, p.R2522Sfs*39, c.7756C>T, p.R2586*, c.2131_2132delAG and c.1067C>A, p.T356K, that were associated with variable woolly hair or hypotrichosis, palmoplantar keratoderma, and cardiac manifestations. In addition, we review and summarise the clinical features and DSP mutations of the patients described in the literature, which illustrates the complexity of this group of disorders and of their genotype-phenotype correlations, which cannot be easily predicted. Early diagnosis is crucial and cardiac examinations have to be performed on a regular basis. PMID:25227139

  7. Cardiomyopathy

    MedlinePlus

    ... and the most common reason for needing a heart transplant. Cardiomyopathy is so dangerous because it often goes ... damaged by ischemic cardiomyopathy, doctors may recommend a heart transplant. Arrhythmogenic Right Ventricular Dysplasia Arrhythmogenic right ventricular dysplasia ( ...

  8. Cardiomyopathy

    MedlinePlus

    Cardiomyopathy is the name for diseases of the heart muscle. These diseases enlarge your heart muscle or ... tissue. Some people live long, healthy lives with cardiomyopathy. Some people don't even realize they have ...

  9. Cardiomyopathy

    MedlinePlus

    Cardiomyopathy is disease in which the heart muscle becomes weakened, stretched, or has another structural problem. It ... cannot pump or function well. Most people with cardiomyopathy have heart failure .

  10. HCN4 mutation as a molecular explanation on patients with bradycardia and non-compaction cardiomyopathy.

    PubMed

    Millat, Gilles; Janin, Alexandre; de Tauriac, Olivier; Roux, Antoine; Dauphin, Claire

    2015-09-01

    A very recent study suggested that HCN4 mutations could be associated with sinusal bradycardia and myocardial non compaction. A French family with 3 affected sisters presenting the same clinical phenotype (sinus bradycardia in combination with non compaction cardiomyopathy (NCCM)) have benefited both from a systematic cardiovascular exploration and molecular investigations. The molecular analysis, performed by NGS sequencing, led to identify only one likely-disease causing variation: p.Gly482Arg on HCN4 gene. Our results confirm the genetic evidence for the involvement of the HCN4 mutations in the combined bradycardia-NCCM phenotype and illustrates that, in front of this combined clinical phenotype, HCN4 mutations has to be suspected. PMID:26206080

  11. Prediction of Sarcomere Mutations in Subclinical Hypertrophic Cardiomyopathy

    PubMed Central

    Captur, Gabriella; Lopes, Luis R.; Mohun, Timothy J.; Patel, Vimal; Li, Chunming; Bassett, Paul; Finocchiaro, Gherardo; Ferreira, Vanessa M.; Esteban, Maite Tome; Muthurangu, Vivek; Sherrid, Mark V.; Day, Sharlene M.; Canter, Charles E.; McKenna, William J.; Seidman, Christine E.; Bluemke, David A.; Elliott, Perry M.; Ho, Carolyn Y.; Moon, James C.

    2014-01-01

    Background Sarcomere protein mutations in hypertrophic cardiomyopathy (HCM) induce subtle cardiac structural changes prior to the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic HCM pre-LVH (G+LVH−). Methods and Results A multi-centre case-control study investigated crypts and 22 other cardiovascular magnetic resonance (CMR) parameters in subclinical HCM to determine their strength of association with sarcomere gene mutation carriage. The G+LVH− sample (n=73) was 29±13 years old and 51% male. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5, 95% confidence interval [CI] 0.5-4.4, p=0.014; for ≥2 crypts, β=3.0, 95%CI 0.8-7.9, p=0.004). In combination with 3 other parameters: anterior mitral valve leaflet (AMVL) elongation (β=2.1, 95%CI 1.7-3.1, p<0.001), abnormal LV apical trabeculae (β=1.6, 95%CI 0.8-2.5, p<0.001), and smaller LV end-systolic volumes (β=1.4, 95%CI 0.5-2.3, p=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95%CI 0.8-0.9). In this G+LVH− population cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared to the other combined mutations (47 vs. 23%; odds ratio, 2.9; 95%CI 1.1–7.9; p=0.045). Conclusions The subclinical HCM phenotype measured by CMR in a multi-center environment and consisting of crypts (particularly multiple), AMVL elongation, abnormal trabeculae and smaller LV systolic cavity, is indicative of the presence of sarcomere gene mutations and highlights the need for further study. PMID:25228707

  12. Deception in simplicity: hereditary phospholamban mutations in dilated cardiomyopathy.

    PubMed

    Young, Howard S; Ceholski, Delaine K; Trieber, Catharine A

    2015-02-01

    The sarcoplasmic reticulum (SR) calcium pump (SERCA) and its regulator phospholamban are required for cardiovascular function. Phospholamban alters the apparent calcium affinity of SERCA in a process that is modulated by phosphorylation via the β-adrenergic pathway. This regulatory axis allows for the dynamic control of SR calcium stores and cardiac contractility. Herein we focus on hereditary mutants of phospholamban that are associated with heart failure, such as Arg(9)-Cys, Arg(9)-Leu, Arg(9)-His, and Arg(14)-deletion. Each mutant has a distinct effect on PLN function and SR calcium homeostasis. Arg(9)-Cys and Arg(9)-Leu do not inhibit SERCA, Arg(14)-deletion is a partial inhibitor, and Arg(9)-His is comparable to wild-type. While the mutants have distinct functional effects on SERCA, they have in common that they cannot be phosphorylated by protein kinase A (PKA). Arg(9) and Arg(14) are required for PKA recognition and phosphorylation of PLN. Thus, mutations at these positions eliminate β-adrenergic control and dynamic cardiac contractility. Hydrophobic mutations of Arg(9) cause more complex changes in function, including loss of PLN function and dominant negative interaction with SERCA in heterozygous individuals. In addition, aberrant interaction with PKA may prevent phosphorylation of wild-type PLN and sequester PKA from other local subcellular targets. Herein we consider what is known about each mutant and how the synergistic changes in SR calcium homeostasis lead to impaired cardiac contractility and dilated cardiomyopathy. PMID:25563649

  13. A Mutation in C2orf64 Causes Impaired Cytochrome c Oxidase Assembly and Mitochondrial Cardiomyopathy

    PubMed Central

    Huigsloot, Merei; Nijtmans, Leo G.; Szklarczyk, Radek; Baars, Marieke J.H.; van den Brand, Mariël A.M.; HendriksFranssen, Marthe G.M.; van den Heuvel, Lambertus P.; Smeitink, Jan A.M.; Huynen, Martijn A.; Rodenburg, Richard J.T.

    2011-01-01

    The assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase) involves the coordinated action of several assembly chaperones. In Saccharomyces cerevisiae, at least 30 different assembly chaperones have been identified. To date, pathogenic mutations leading to a mitochondrial disorder have been identified in only seven of the corresponding human genes. One of the genes for which the relevance to human pathology is unknown is C2orf64, an ortholog of the S. cerevisiae gene PET191. This gene has previously been shown to be a complex IV assembly factor in yeast, although its exact role is still unknown. Previous research in a large cohort of complex IV deficient patients did not support an etiological role of C2orf64 in complex IV deficiency. In this report, a homozygous mutation in C2orf64 is described in two siblings affected by fatal neonatal cardiomyopathy. Pathogenicity of the mutation is supported by the results of a complementation experiment, showing that complex IV activity can be fully restored by retroviral transduction of wild-type C2orf64 in patient-derived fibroblasts. Detailed analysis of complex IV assembly intermediates in patient fibroblasts by 2D-BN PAGE revealed the accumulation of a small assembly intermediate containing subunit COX1 but not the COX2, COX4, or COX5b subunits, indicating that C2orf64 is involved in an early step of the complex IV assembly process. The results of this study demonstrate that C2orf64 is essential for human complex IV assembly and that C2orf64 mutational analysis should be considered for complex IV deficient patients, in particular those with hypertrophic cardiomyopathy. PMID:21457908

  14. Relevance of truncating titin mutations in dilated cardiomyopathy.

    PubMed

    Akinrinade, O; Alastalo, T-P; Koskenvuo, J W

    2016-07-01

    Dilated cardiomyopathy (DCM), a genetically heterogeneous cardiac disease characterized by left ventricular dilatation and systolic dysfunction, is caused majorly by truncations of titin (TTN), especially in A-band region. Clinical interpretation of TTN-truncating variants (TTNtv) has been challenged by the existing inaccurate variant assessment strategies and uncertainty in the true frequency of TTNtv across the general population. We aggregated TTNtv identified in 1788 DCM patients and compared the variants with those reported in over 60,000 Exome Aggregation Consortium reference population. We implemented our current variant assessment strategy that prioritizes TTNtv affecting all transcripts of the gene, and observed a decline in the prevalence of TTNtv in DCM. Despite this decline, TTNtv are more prevalent in DCM patients compared with reference population (p = 4.1 × 10(-295) ). Moreover, our extended analyses confirmed the enrichment of TTNtv not only in the A-band but also in the I/A-band junction of TTN. We estimated the probability of pathogenicity of TTNtv affecting all transcripts of TTN, identified in unselected DCM patients to be 97.8% (likelihood ratio (LR) = 42.2). We emphasize that identifying a TTNtv, especially in the A-band region, has a higher risk of being disease-causing than previously anticipated, and recommend prioritizing TTNtv affecting at least five transcripts of the gene. PMID:26777568

  15. Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle.

    PubMed

    Juan-Mateu, J; Paradas, C; Olivé, M; Verdura, E; Rivas, E; González-Quereda, L; Rodríguez, M J; Baiget, M; Gallano, P

    2012-12-01

    X-linked dilated cardiomyopathy is a pure cardiac dystrophinopathy phenotype mainly caused by DMD mutations that present a specific transcription effect in cardiac tissue. We report a 26-year-old male who presented with severe dilated cardiomyopathy and high creatine kinase. The patient did not complain of skeletal muscle weakness. A muscle biopsy showed mild dystrophic changes and a low proportion of dystrophin-negative fibres. A molecular study identified a nonsense DMD mutation (p.Arg2098X) in somatic mosaicism. The ratio of mutant versus normal allele in blood and skeletal muscle suggests selective pressure against mutant muscle cells, a process known as genetic normalization. We hypothesize that this process may have mitigated skeletal muscle symptoms in this patient. This is the second report of a DMD somatic mosaic with evidence of genetic normalization in muscle. Somatic DMD mutations should be considered in patients presenting with idiopathic dilated cardiomyopathy. PMID:22092019

  16. Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies.

    PubMed

    Fish, Maryam; Shaboodien, Gasnat; Kraus, Sarah; Sliwa, Karen; Seidman, Christine E; Burke, Michael A; Crotti, Lia; Schwartz, Peter J; Mayosi, Bongani M

    2016-01-01

    Cardiomyopathy is an important cause of heart failure in Sub-Saharan Africa, accounting for up to 30% of adult heart failure hospitalisations. This high prevalence poses a challenge in societies without access to resources and interventions essential for disease management. Over 80 genes have been implicated as a cause of cardiomyopathy. Mutations in the phospholamban (PLN) gene are associated with dilated cardiomyopathy (DCM) and severe heart failure. In Africa, the prevalence of PLN mutations in cardiomyopathy patients is unknown. Our aim was to screen 315 patients with arrhythmogenic right ventricular cardiomyopathy (n = 111), DCM (n = 95), hypertrophic cardiomyopathy (n = 40) and peripartum cardiomyopathy (n = 69) for disease-causing PLN mutations by high resolution melt analysis and DNA sequencing. We detected the previously reported PLN c.25C > T (p.R9C) mutation in a South African family with severe autosomal dominant DCM. Haplotype analysis revealed that this mutation occurred against a different haplotype background to that of the original North American family and was therefore unlikely to have been inherited from a common ancestor. No other mutations in PLN were detected (mutation prevalence = 0.2%). We conclude that PLN is a rare cause of cardiomyopathy in African patients. The PLN p.R9C mutation is not well-tolerated, emphasising the importance of this gene in cardiac function. PMID:26917049

  17. Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies

    PubMed Central

    Fish, Maryam; Shaboodien, Gasnat; Kraus, Sarah; Sliwa, Karen; Seidman, Christine E.; Burke, Michael A.; Crotti, Lia; Schwartz, Peter J.; Mayosi, Bongani M.

    2016-01-01

    Cardiomyopathy is an important cause of heart failure in Sub-Saharan Africa, accounting for up to 30% of adult heart failure hospitalisations. This high prevalence poses a challenge in societies without access to resources and interventions essential for disease management. Over 80 genes have been implicated as a cause of cardiomyopathy. Mutations in the phospholamban (PLN) gene are associated with dilated cardiomyopathy (DCM) and severe heart failure. In Africa, the prevalence of PLN mutations in cardiomyopathy patients is unknown. Our aim was to screen 315 patients with arrhythmogenic right ventricular cardiomyopathy (n = 111), DCM (n = 95), hypertrophic cardiomyopathy (n = 40) and peripartum cardiomyopathy (n = 69) for disease-causing PLN mutations by high resolution melt analysis and DNA sequencing. We detected the previously reported PLN c.25C > T (p.R9C) mutation in a South African family with severe autosomal dominant DCM. Haplotype analysis revealed that this mutation occurred against a different haplotype background to that of the original North American family and was therefore unlikely to have been inherited from a common ancestor. No other mutations in PLN were detected (mutation prevalence = 0.2%). We conclude that PLN is a rare cause of cardiomyopathy in African patients. The PLN p.R9C mutation is not well-tolerated, emphasising the importance of this gene in cardiac function. PMID:26917049

  18. Malalignment of the sarcomeric filaments in hypertrophic cardiomyopathy with cardiac myosin heavy chain gene mutation

    PubMed Central

    Muraishi, A; Kai, H; Adachi, K; Nishi, H; Imaizumi, T

    1999-01-01

    OBJECTIVE—To investigate changes in the alignment of the sarcomeric filaments in hypertrophic cardiomyopathy and the effects of cardiac β myosin heavy chain (β-MHC) mutation on the sarcomeric ultrastructure.
DESIGN—A retrospective analysis.
PATIENTS—Endomyocardial biopsy samples were examined by transmission electron microscopy in seven patients with hypertrophic cardiomyopathy and β-MHC mutation, six with hypertrophic cardiomyopathy but without the mutation, and five controls (with chest pain syndromes).
MAIN OUTCOME MEASURE—Alignment of the sarcomeric filaments and the distance between neighbouring thick myosin filaments.
RESULTS—In controls, cross sections of the sarcomere at the A band showed a highly organised orthohexagonal array with 6 thin actin filaments surrounding one thick myosin filament, whereas in hypertrophic cardiomyopathy the alignment of the sarcomeric filaments was sparse and disrupted. In hypertrophic cardiomyopathy with a mutation, the distance between neighbouring thick myosin filaments was greater than in controls (mean (SD) 45.3 (4.7) v 38.5 (3.5) nm, p < 0.05), and the variance of the distance was greater than in controls (8.0 (0.7) v 4.8 (1.0) nm, p < 0.001) or in patients with hypertrophic cardiomyopathy without a mutation (6.7 (0.6) nm, p < 0.05). In the latter, the variance of the distance was also greater than in the controls (p < 0.01). A significant correlation was found between the grade of the myocyte hypertrophy and the variance of the distance (r = 0.654; p < 0.01).
CONCLUSIONS—The alignment of the sarcomeric filaments is disrupted in hypertrophic cardiomyopathy, particularly when there is β-MHC mutation.


Keywords: hypertrophic cardiomyopathy; β myosin heavy chain; myosin filament; sarcomere PMID:10525522

  19. A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy

    PubMed Central

    Ashrafian, Houman; Docherty, Louise; Leo, Vincenzo; Towlson, Christopher; Neilan, Monica; Steeples, Violetta; Lygate, Craig A.; Hough, Tertius; Townsend, Stuart; Williams, Debbie; Wells, Sara; Norris, Dominic; Glyn-Jones, Sarah; Land, John; Barbaric, Ivana; Lalanne, Zuzanne; Denny, Paul; Szumska, Dorota; Bhattacharya, Shoumo; Griffin, Julian L.; Hargreaves, Iain; Fernandez-Fuentes, Narcis; Cheeseman, Michael; Watkins, Hugh; Dear, T. Neil

    2010-01-01

    Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease. PMID:20585624

  20. The search of 'novel' mtDNA mutations in hypertrophic cardiomyopathy: MITOMAPping as a risk factor.

    PubMed

    Bandelt, Hans-Jürgen; Yao, Yong-Gang; Salas, Antonio

    2008-06-01

    MITOMAP is by far the most frequently cited Web resource that is referred to in substantiating novelty of an mtDNA mutation. This database, as is now known, has quite an incomplete coverage of the mtDNA mutations from the literature. This circumstance has seduced many scholars of medical genetics in the past to claim novelty of rather 'worn-out' mtDNA mutations. What is, however, really novel in the field is that researchers take advantage of this situation and deliberately suppress information from other sources, as it appears to have occurred in two recently published cases of hypertrophic cardiomyopathy. PMID:17482693

  1. Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy

    PubMed Central

    Kopajtich, Robert; Nicholls, Thomas J.; Rorbach, Joanna; Metodiev, Metodi D.; Freisinger, Peter; Mandel, Hanna; Vanlander, Arnaud; Ghezzi, Daniele; Carrozzo, Rosalba; Taylor, Robert W.; Marquard, Klaus; Murayama, Kei; Wieland, Thomas; Schwarzmayr, Thomas; Mayr, Johannes A.; Pearce, Sarah F.; Powell, Christopher A.; Saada, Ann; Ohtake, Akira; Invernizzi, Federica; Lamantea, Eleonora; Sommerville, Ewen W.; Pyle, Angela; Chinnery, Patrick F.; Crushell, Ellen; Okazaki, Yasushi; Kohda, Masakazu; Kishita, Yoshihito; Tokuzawa, Yoshimi; Assouline, Zahra; Rio, Marlène; Feillet, François; Mousson de Camaret, Bénédict; Chretien, Dominique; Munnich, Arnold; Menten, Björn; Sante, Tom; Smet, Joél; Régal, Luc; Lorber, Abraham; Khoury, Asaad; Zeviani, Massimo; Strom, Tim M.; Meitinger, Thomas; Bertini, Enrico S.; Van Coster, Rudy; Klopstock, Thomas; Rötig, Agnès; Haack, Tobias B.; Minczuk, Michal; Prokisch, Holger

    2014-01-01

    Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm5U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function. PMID:25434004

  2. The role of mutations in the SCN5A gene in cardiomyopathies.

    PubMed

    Zaklyazminskaya, Elena; Dzemeshkevich, Sergei

    2016-07-01

    The SCN5A gene encodes the alpha-subunit of the Nav1.5 ion channel protein, which is responsible for the sodium inward current (INa). Since 1995 several hundred mutations in this gene have been found to be causative for inherited arrhythmias including Long QT syndrome, Brugada syndrome, cardiac conduction disease, sudden infant death syndrome, etc. As expected these syndromes are primarily electrical heart diseases leading to life-threatening arrhythmias with an "apparently normal heart". In 2003 a new form of dilated cardiomyopathy was identified associated with mutations in the SCN5A gene. Recently mutations have been also found in patients with arrhythmogenic right ventricular cardiomyopathy and atrial standstill. The purpose of this review is to outline and analyze the following four topics: 1) SCN5A genetic variants linked to different cardiomyopathies; 2) clinical manifestations of the known mutations; 3) possible molecular mechanisms of myocardial remodeling; and 4) the potential implications of gene-specific treatment for those disorders. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID:26916278

  3. Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy

    PubMed Central

    Prajapati, Chandra; Pölönen, Risto-Pekka; Rajala, Kristiina; Pekkanen-Mattila, Mari; Rasku, Jyrki; Larsson, Kim; Aalto-Setälä, Katriina

    2016-01-01

    Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) and α-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn mutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca2+ handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well. PMID:27057166

  4. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy.

    PubMed

    Galant, Damien; Gaborit, Bénédicte; Desgrouas, Camille; Abdesselam, Ines; Bernard, Monique; Levy, Nicolas; Merono, Françoise; Coirault, Catherine; Roll, Patrice; Lagarde, Arnaud; Bonello-Palot, Nathalie; Bourgeois, Patrice; Dutour, Anne; Badens, Catherine

    2016-01-01

    ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient. PMID:27120622

  5. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

    PubMed Central

    Galant, Damien; Gaborit, Bénédicte; Desgrouas, Camille; Abdesselam, Ines; Bernard, Monique; Levy, Nicolas; Merono, Françoise; Coirault, Catherine; Roll, Patrice; Lagarde, Arnaud; Bonello-Palot, Nathalie; Bourgeois, Patrice; Dutour, Anne; Badens, Catherine

    2016-01-01

    ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient. PMID:27120622

  6. A mutation in the {beta}-myosin rod associated with hypertrophic cardiomyopathy has an unexpected molecular phenotype

    SciTech Connect

    Armel, Thomas Z.; Leinwand, Leslie A.

    2010-01-01

    Hypertrophic cardiomyopathy (HCM) is a common, autosomal dominant disorder primarily characterized by left ventricular hypertrophy and is the leading cause of sudden cardiac death in youth. HCM is caused by mutations in several sarcomeric proteins, with mutations in MYH7, encoding {beta}-MyHC, being the most common. While many mutations in the globular head region of the protein have been reported and studied, analysis of HCM-causing mutations in the {beta}-MyHC rod domain has not yet been reported. To address this question, we performed an array of biochemical and biophysical assays to determine how the HCM-causing E1356K mutation affects the structure, stability, and function of the {beta}-MyHC rod. Surprisingly, the E1356K mutation appears to thermodynamically destabilize the protein, rather than alter the charge profile know to be essential for muscle filament assembly. This thermodynamic instability appears to be responsible for the decreased ability of the protein to form filaments and may be responsible for the HCM phenotype seen in patients.

  7. Delineation of Molecular Pathways Involved in Cardiomyopathies Caused by Troponin T Mutations.

    PubMed

    Gilda, Jennifer E; Lai, Xianyin; Witzmann, Frank A; Gomes, Aldrin V

    2016-06-01

    Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca(2+) sensitivity of the myofilament; however, the R278C mutation does not alter Ca(2+) sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism

  8. Targeted Next-Generation Sequencing Reveals Hot Spots and Doubly Heterozygous Mutations in Chinese Patients with Familial Cardiomyopathy

    PubMed Central

    Zhao, Yue; Feng, Yue; Zhang, Yun-Mei; Ding, Xiao-Xue; Song, Yu-Zhu; Zhang, A-Mei; Liu, Li; Zhang, Hong; Ding, Jia-Huan; Xia, Xue-Shan

    2015-01-01

    As a common cardiac disease mainly caused by gene mutations in sarcomeric cytoskeletal, calcium-handling, nuclear envelope, desmosomal, and transcription factor genes, inherited cardiomyopathy is becoming one of the major etiological factors of sudden cardiac death (SCD) and heart failure (HF). This disease is characterized by remarkable genetic heterogeneity, which makes it difficult to screen for pathogenic mutations using Sanger sequencing. In the present study, three probands, one with familial hypertrophic cardiomyopathy (FHCM) and two with familial dilated cardiomyopathy (FDCM), were recruited together with their respective family members. Using next-generation sequencing technology (NGS), 24 genes frequently known to be related to inherited cardiomyopathy were screened. Two hot spots (TNNI3-p.Arg145Gly, and LMNA-p.Arg190Trp) and double (LMNA-p.Arg190Trp plus MYH7-p.Arg1045His) heterozygous mutations were found to be highly correlated with familial cardiomyopathy. FDCM patients with doubly heterozygous mutations show a notably severe phenotype as we could confirm in our study; this indicates that the double mutations had a dose effect. In addition, it is proposed that genetic testing using NGS technology can be used as a cost-effective screening tool and help guide the treatment of patients with familial cardiomyopathy particularly regarding the risk of family members who are clinically asymptomatic. PMID:26199943

  9. Three siblings of familial amyloid cardiomyopathy with isoleucine-50 transthyretin mutation.

    PubMed

    Sadamatsu, K; Hayashi, Y; Nakamura, M

    1997-09-19

    We herein describe three siblings with familial amyloid cardiomyopathy in a Japanese family, who demonstrated an Ile-50 mutation in the transthyretin gene. In their clinical course, the symptoms started at from 50 to 55 years of age, and two cases died within 5 years. However, one case is still alive seven years after onset probably due to either the implantation of a pacemaker for a complete atrio-ventricular block or the administration of dimethylsulphoxide. Based on our findings, some differences were observed not only in the mutation of the transthyretin gene but also in the clinical course between our cases and the previously reported cases. PMID:9314208

  10. Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy

    PubMed Central

    2011-01-01

    Background The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. Methods Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated. Results Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. Conclusions Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM. PMID:21689390

  11. A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.

    PubMed

    Alston, Charlotte L; Ceccatelli Berti, Camilla; Blakely, Emma L; Oláhová, Monika; He, Langping; McMahon, Colin J; Olpin, Simon E; Hargreaves, Iain P; Nolli, Cecilia; McFarland, Robert; Goffrini, Paola; O'Sullivan, Maureen J; Taylor, Robert W

    2015-08-01

    Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be recessively inherited through segregation studies. The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma. By introducing both mutations into Saccharomyces cerevisiae, we were able to confirm that the p.(Asp92Gly) mutation causes a more severe oxidative growth phenotype than the p.(Asp92Tyr) mutant, and provides functional evidence to support the pathogenicity of the patient's SDHD mutation. This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency. PMID:26008905

  12. Titin Mutations in iPS cells Define Sarcomere Insufficiency as a Cause of Dilated Cardiomyopathy

    PubMed Central

    Hinson, John T.; Chopra, Anant; Nafissi, Navid; Polacheck, William J.; Benson, Craig C.; Swist, Sandra; Gorham, Joshua; Yang, Luhan; Schafer, Sebastian; Sheng, Calvin C.; Haghighi, Alireza; Homsy, Jason; Hubner, Norbert; Church, George; Cook, Stuart A.; Linke, Wolfgang A.; Chen, Christopher S.; Seidman, J. G.; Seidman, Christine E.

    2015-01-01

    Human mutations that truncate the massive sarcomere protein titin (TTNtv) are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtv, diminish contractile performance and are pathogenic. By combining functional analyses with RNAseq, we explain why truncations in the A-band domain of TTN cause DCM while truncations in the I-band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS-cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodelling. PMID:26315439

  13. De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy.

    PubMed

    Long, Pamela A; Zimmermann, Michael T; Kim, Maengjo; Evans, Jared M; Xu, Xiaolei; Olson, Timothy M

    2016-08-01

    Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder with variable age-dependent penetrance. We sought to identify the genetic underpinnings of syndromic, sporadic DCM in a newborn female diagnosed in utero. Postnatal evaluation revealed ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms. Comprehensive metabolic and genetic testing, including chromosomal microarray, mitochondrial DNA and targeted RASopathy gene sequencing, and clinical whole exome sequencing for known cardiomyopathy genes was non-diagnostic. Following exclusion of asymptomatic DCM in the parents, trio-based whole exome sequencing was carried out on a research basis, filtering for rare, predicted deleterious de novo and recessive variants. An unreported de novo S75Y mutation was discovered in RRAGC, encoding Ras-related GTP binding C, an essential GTPase in nutrient-activated mechanistic target of rapamycin complex 1 (mTORC1) signaling. In silico protein modeling and molecular dynamics simulation predicted the mutation to disrupt ligand interactions and increase the GDP-bound state. Overexpression of RagC(S75Y) rendered AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC. These findings implicate mTORC1 dysregulation through a gain-of-function mutation in RagC as a novel molecular basis for syndromic forms of pediatric heart failure, and expand genotype-phenotype correlation in RASopathy-related syndromes. PMID:27234373

  14. Whole mitochondrial genome analysis in two families with dilated mitochondrial cardiomyopathy: detection of mutations in MT-ND2 and MT-TL1 genes.

    PubMed

    Alila, Olfa Fersi; Rebai, Emna Mkaouar; Tabebi, Mouna; Tej, Amel; Chamkha, Imen; Tlili, Abdelaziz; Bouguila, Jihene; Tilouche, Samia; Soyah, Nejla; Boughamoura, Lamia; Fakhfakh, Faiza

    2016-07-01

    Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. These mutations were described in the mt-tRNA genes and in the mitochondrial protein-coding genes. The aim of this study was to identify the genetic defect in two patients belonging to two families with cardiac dysfunction associated to a wide spectrum of clinical phenotypes. The sequencing analysis of the whole mitochondrial DNA in the two patients and their parents revealed the presence of known polymorphisms associated to cardiomyopathy and two pathogenic mutations in DNA extracted from blood leucocytes: the heteroplasmic m.3243A > G mutation in the MT-TL1 gene in patient A; and the homoplasmic m.5182C > T mutation in the ND2 gene in patient B. Secondary structure analysis of the ND2 protein further supported the deleterious role of the m.5182C > T mutation, as it was found to be involved an extended imbalance in its hydrophobicity and affect its function. In addition, the mitochondrial variants identified in patients A and B classify both of them in the same haplogroup H2a2a1. PMID:26258512

  15. Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect

    SciTech Connect

    Wang Hu; Wang Jizheng; Zheng Weiyue; Wang Xiaojian; Wang Shuxia; Song Lei; Zou Yubao; Yao Yan; Hui Rutai . E-mail: huirutai@sglab.org

    2006-05-26

    Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. The mutations in lamin A/C gene have been linked to dilated cardiomyopathy. We screened genetic mutations in a large Chinese family of 50 members including members with dilated cardiomyopathy and found a Glu82Lys substitution mutation in the rod domain of the lamin A/C protein in eight family members, three of them have been diagnosed as dilated cardiomyopathy, one presented with heart dilation. The pathogenic mechanism of lamin A/C gene defect is poorly understood. Glu82Lys mutated lamin A/C and wild type protein was transfected into HEK293 cells. The mutated protein was not properly localized at the inner nuclear membrane and the emerin protein, which interacts with lamin A/C, was also aberrantly distributed. The nuclear membrane structure was disrupted and heterochromatin was aggregated aberrantly in the nucleus of the HEK293 cells stably transfected with mutated lamin A/C gene as determined by transmission electron microscopy.

  16. Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy

    PubMed Central

    ZHAO, YUE; FENG, YUE; ZHANG, YUN-MEI; DING, XIAO-XUE; SONG, YU-ZHU; ZHANG, A-MEI; LIU, LI; ZHANG, HONG; DING, JIA-HUAN; XIA, XUE-SHAN

    2015-01-01

    Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death and heart failure, and it is characterized by genetic and clinical heterogeneity, even for some patients with a very poor clinical prognosis; in the majority of cases, DCM necessitates a heart transplant. Genetic mutations have long been considered to be associated with this disease. At present, mutations in over 50 genes related to DCM have been documented. This study was carried out to elucidate the characteristics of gene mutations in patients with DCM. The candidate genes that may cause DCM include MYBPC3, MYH6, MYH7, LMNA, TNNT2, TNNI3, MYPN, MYL3, TPM1, SCN5A, DES, ACTC1 and RBM20. Using next-generation sequencing (NGS) and subsequent mutation confirmation with traditional capillary Sanger sequencing analysis, possible causative non-synonymous mutations were identified in ~57% (12/21) of patients with DCM. As a result, 7 novel mutations (MYPN, p.E630K; TNNT2, p.G180A; MYH6, p.R1047C; TNNC1, p.D3V; DES, p.R386H; MYBPC3, p.C1124F; and MYL3, p.D126G), 3 variants of uncertain significance (RBM20, p.R1182H; MYH6, p.T1253M; and VCL, p.M209L), and 2 known mutations (MYH7, p.A26V and MYBPC3, p.R160W) were revealed to be associated with DCM. The mutations were most frequently found in the sarcomere (MYH6, MYBPC3, MYH7, TNNC1, TNNT2 and MYL3) and cytoskeletal (MYPN, DES and VCL) genes. As genetic testing is a useful tool in the clinical management of disease, testing for pathogenic mutations is beneficial to the treatment of patients with DCM and may assist in predicting disease risk for their family members before the onset of symptoms. PMID:26458567

  17. A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

    PubMed

    Jonckheere, An I; Hogeveen, Marije; Nijtmans, Leo; van den Brand, Mariel; Janssen, Antoon; Diepstra, Heleen; van den Brandt, Frans; van den Heuvel, Bert; Hol, Frans; Hofste, Tom; Kapusta, Livia; Dillmann, U; Shamdeen, M; Smeitink, J; Smeitink, J; Rodenburg, Richard

    2009-01-01

    To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G→A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme. PMID:21686774

  18. Identification of novel mutations including a double mutation in patients with inherited cardiomyopathy by a targeted sequencing approach using the Ion Torrent PGM system

    PubMed Central

    ZHAO, YUE; CAO, HONG; SONG, YINDI; FENG, YUE; DING, XIAOXUE; PANG, MINGJIE; ZHANG, YUNMEI; ZHANG, HONG; DING, JIAHUAN; XIA, XUESHAN

    2016-01-01

    Inherited cardiomyopathy is the major cause of sudden cardiac death (SCD) and heart failure (HF). The disease is associated with extensive genetic heterogeneity; pathogenic mutations in cardiac sarcomere protein genes, cytoskeletal protein genes and nuclear envelope protein genes have been linked to its etiology. Early diagnosis is conducive to clinical monitoring and allows for presymptomatic interventions as needed. In the present study, the entire coding sequences and flanking regions of 12 major disease (cardiomyopathy)-related genes [namely myosin, heavy chain 7, cardiac muscle, β (MYH7); myosin binding protein C, cardiac (MYBPC3); lamin A/C (LMNA); troponin I type 3 (cardiac) (TNNI3); troponin T type 2 (cardiac) (TNNT2); actin, α, cardiac muscle 1 (ACTC1); tropomyosin 1 (α) (TPM1); sodium channel, voltage gated, type V alpha subunit (SCN5A); myosin, light chain 2, regulatory, cardiac, slow (MYL2); myosin, heavy chain 6, cardiac muscle, α (MYH6); myosin, light chain 3, alkali, ventricular, skeletal, slow (MYL3); and protein kinase, AMP-activated, gamma 2 non-catalytic subunit (PRKAG2)] in 8 patients with dilated cardiomyopathy (DCM) and in 8 patients with hypertrophic cardiomyopathy (HCM) were amplified and then sequenced using the Ion Torrent Personal Genome Machine (PGM) system. As a result, a novel heterozygous mutation (MYH7, p.Asn885Thr) and a variant of uncertain significance (TNNT2, p.Arg296His) were identified in 2 patients with HCM. These 2 missense mutations, which were absent in the samples obtained from the 200 healthy control subjects, altered the amino acid that was evolutionarily conserved among a number of vertebrate species; this illustrates that these 2 non-synonymous mutations play a role in the pathogenesis of HCM. Moreover, a double heterozygous mutation (PRKAG2, p.Gly100Ser plus MYH7, p.Arg719Trp) was identified in a patient with severe familial HCM, for the first time to the best of our knowledge. This patient provided us with more

  19. "Myo-cardiomyopathy" is commonly associated with the A8344G "MERRF" mutation.

    PubMed

    Catteruccia, Michela; Sauchelli, Donato; Della Marca, Giacomo; Primiano, Guido; Cuccagna, Cristina; Bernardo, Daniela; Leo, Milena; Camporeale, Antonella; Sanna, Tommaso; Cianfoni, Alessandro; Servidei, Serenella

    2015-03-01

    The objective of the study was to better characterize the clinical phenotype associated with the A8344G "MERRF" mutation of mitochondrial DNA. Fifteen mutated patients were extensively investigated. The frequency of main clinical features was: exercise intolerance and/or muscle weakness 67 %, respiratory involvement 67 %, lactic acidosis 67 %, cardiac abnormalities 53 %, peripheral neuropathy 47 %, myoclonus 40 %, epilepsy 40 %, ataxia 13 %. A restrictive respiratory insufficiency requiring ventilatory support was observed in about half of our patients. One patient developed a severe and rapidly progressive cardiomyopathy requiring cardioverter-defibrillator implantation. Five patients died of overwhelming, intractable lactic acidosis. Serial muscle MRIs identified a consistent pattern of muscle involvement and progression. Cardiac MRI showed non-ischemic late gadolinium enhancement in the left ventricle inferolateral part as early sign of myocardial involvement. Brain spectroscopy demonstrated increased peak of choline and reduction of N-acetylaspartate. Lactate was never detected in brain areas, while it could be documented in ventricles. We confirm that muscle involvement is the most frequent clinical feature associated with A8443G mutation. In contrast with previous reports, however, about half of our patients did not develop signs of CNS involvement even in later stages of the disease. The difference may be related to the infrequent investigation of A8344G mutation in 'pure' mitochondrial myo-cardiomyopathy, representing a bias and a possible cause of syndrome's underestimation. Our study highlights the importance of lactic acidosis and respiratory muscle insufficiency as critical prognostic factors. Muscle and cardiac MRI and brain spectroscopy may be useful tools in diagnosis and follow-up of MERRF. PMID:25559684

  20. Functional characterization of putative novel splicing mutations in the cardiomyopathy-causing genes.

    PubMed

    Millat, Gilles; Lafont, Estèle; Nony, Séverine; Rouvet, Isabelle; Bozon, Dominique

    2015-07-01

    Molecular diagnosis of cardiomyopathies remains difficult not only because of the large number of causative genes and the high rate of private mutations but also due to the large number of unclassified variants (UVs) found in patients' DNA. This study reports the functional splicing impact of nine novel genomic variations previously identified in unrelated patients with cardiomyopathies. To identify splice variants among these UVs, a combination of in silico and in vitro hybrid minigene tools was used as transcript is not available. Using this two-step approach, these UVs were reclassified as splicing mutations (MYBPC3-c.655-25A>G, MYBPC3-c.1790G>A (p.Arg597Gln), MYBPC3-c.2414-36G>T) or as mutations with a majority of abnormally spliced transcripts (MYBPC3-c.1182C>A, TNNT2-c.460G>A (p.Glu154Lys), and TNNT2-c.822-3C>A) or as variations with a weak splicing effect (TNNT2-c.1000-38C>A). For the two remaining variations in intron 11 of the TNNT2 gene in the vicinity of the acceptor splice site (c.571-7G>A, c.571-29G>A), a minigene assay was inconclusive as exon 12 is neither recognized as an exon by HeLa nor by H9c2 cells. Our study highlights the importance of the combined use of in silico and in vitro splicing assays to improve the prediction of the functional splicing impact of identified genetic variants if the RNA sample from the patient is not easily available. PMID:25849606

  1. Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy

    PubMed Central

    Arndt, Anne-Karin; Schafer, Sebastian; Drenckhahn, Jorg-Detlef; Sabeh, M. Khaled; Plovie, Eva R.; Caliebe, Almuth; Klopocki, Eva; Musso, Gabriel; Werdich, Andreas A.; Kalwa, Hermann; Heinig, Matthias; Padera, Robert F.; Wassilew, Katharina; Bluhm, Julia; Harnack, Christine; Martitz, Janine; Barton, Paul J.; Greutmann, Matthias; Berger, Felix; Hubner, Norbert; Siebert, Reiner; Kramer, Hans-Heiner; Cook, Stuart A.; MacRae, Calum A.; Klaassen, Sabine

    2013-01-01

    Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM. PMID:23768516

  2. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.

    PubMed

    Arndt, Anne-Karin; Schafer, Sebastian; Drenckhahn, Jorg-Detlef; Sabeh, M Khaled; Plovie, Eva R; Caliebe, Almuth; Klopocki, Eva; Musso, Gabriel; Werdich, Andreas A; Kalwa, Hermann; Heinig, Matthias; Padera, Robert F; Wassilew, Katharina; Bluhm, Julia; Harnack, Christine; Martitz, Janine; Barton, Paul J; Greutmann, Matthias; Berger, Felix; Hubner, Norbert; Siebert, Reiner; Kramer, Hans-Heiner; Cook, Stuart A; MacRae, Calum A; Klaassen, Sabine

    2013-07-11

    Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM. PMID:23768516

  3. Mutation in Human Desmoplakin Domain Binding to Plakoglobin Causes a Dominant Form of Arrhythmogenic Right Ventricular Cardiomyopathy

    PubMed Central

    Rampazzo, Alessandra; Nava, Andrea; Malacrida, Sandro; Beffagna, Giorgia; Bauce, Barbara; Rossi, Valeria; Zimbello, Rosanna; Simionati, Barbara; Basso, Cristina; Thiene, Gaetano; Towbin, Jeffrey A.; Danieli, Gian A.

    2002-01-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVD/C) is a genetically heterogeneous disease characterized by progressive degeneration of the right ventricular myocardium and increased risk of sudden death. Here, we report on a genome scan in one Italian family in which the disease appeared unlinked to any of the six different ARVD loci reported so far; we identify a mutation (S299R) in exon 7 of desmoplakin (DSP), which modifies a putative phosphorylation site in the N-terminal domain binding plakoglobin. It is interesting that a nonsense DSP mutation was reported elsewhere in the literature, inherited as a recessive trait and causing a biventricular dilative cardiomyopathy associated with palmoplantar keratoderma and woolly hairs. Therefore, different DSP mutations might produce different clinical phenotypes, with different modes of inheritance. PMID:12373648

  4. An in silico analysis of troponin I mutations in hypertrophic cardiomyopathy of Indian origin.

    PubMed

    Ramachandran, Gayatri; Kumar, Manoj; Selvi Rani, Deepa; Annanthapur, Venkateshwari; Calambur, Narasimhan; Nallari, Pratibha; Kaur, Punit

    2013-01-01

    Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases. PMID:23967088

  5. Dystrophin-Deficient Cardiomyopathy.

    PubMed

    Kamdar, Forum; Garry, Daniel J

    2016-05-31

    Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophinopathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient. PMID:27230049

  6. Restrictive cardiomyopathy

    MedlinePlus

    ... blood returns from the body (diastole). When the disease progresses, the heart may not pump blood strongly. The abnormal heart function can affect the lungs, liver, and other body systems. Restrictive cardiomyopathy may affect either or both of the ...

  7. Restrictive cardiomyopathy

    MedlinePlus

    ... blood returns from the body (diastole). When the disease progresses, the heart may not pump blood strongly. The abnormal heart function can affect the lungs, liver, and other body systems. Restrictive cardiomyopathy may affect ...

  8. Mitochondrial Cardiomyopathies

    PubMed Central

    El-Hattab, Ayman W.; Scaglia, Fernando

    2016-01-01

    Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20–40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia. PMID:27504452

  9. Mitochondrial Cardiomyopathies.

    PubMed

    El-Hattab, Ayman W; Scaglia, Fernando

    2016-01-01

    Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20-40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia. PMID:27504452

  10. The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

    SciTech Connect

    Mezghani, Najla; Mnif, Mouna; Mkaouar-Rebai, Emna; Kallel, Nozha; Salem, Ikhlass Haj; Charfi, Nadia; Abid, Mohamed; Fakhfakh, Faiza

    2011-07-29

    Highlights: {yields} We reported a patient with Wolfram syndrome and dilated cardiomyopathy. {yields} We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). {yields} Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. {yields} The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

  11. Identification of arrhythmogenic right ventricular cardiomyopathy-causing gene mutations in young sudden unexpected death autopsy cases.

    PubMed

    Sato, Takako; Nishio, Hajime; Suzuki, Koichi

    2015-03-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) results in an increased risk of sudden death. We sought mutations of desmoglein-2 (DSG2), desmoplakin (DSP), and plakophilin-2 (PKP2) in 15 cases of sudden death whose causes of death could not be determined at autopsy. In three victims, mutations were identified in DSP. Two of these mutations were novel; one had previously been reported in a patient with ARVC that had been diagnosed clinically. Histological findings were not typical of ARVC; however, it was notable that these mutations were present in three of 15 cases, a relatively high proportion. The causal relationship between the mutations and ARVC is unclear, but the mutations might have been associated with faulty desmosomal proteins resulting in fatal arrhythmia. Combining information gathered by the traditional means of gross and histological examination with postmortem genetic analysis of young victims would assist in identifying their cause of death. PMID:25693453

  12. Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.

    PubMed

    Siggs, Owen M; Stockenhuber, Alexander; Deobagkar-Lele, Mukta; Bull, Katherine R; Crockford, Tanya L; Kingston, Bethany L; Crawford, Greg; Anzilotti, Consuelo; Steeples, Violetta; Ghaffari, Sahar; Czibik, Gabor; Bellahcene, Mohamed; Watkins, Hugh; Ashrafian, Houman; Davies, Benjamin; Woods, Angela; Carling, David; Yavari, Arash; Beutler, Bruce; Cornall, Richard J

    2016-06-28

    Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt-Hogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive loss-of-function variant of Fnip1 Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK. Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51-like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK. PMID:27303042

  13. Identification of novel mutations including a double mutation in patients with inherited cardiomyopathy by a targeted sequencing approach using the Ion Torrent PGM system.

    PubMed

    Zhao, Yue; Cao, Hong; Song, Yindi; Feng, Yue; Ding, Xiaoxue; Pang, Mingjie; Zhang, Yunmei; Zhang, Hong; Ding, Jiahuan; Xia, Xueshan

    2016-06-01

    Inherited cardiomyopathy is the major cause of sudden cardiac death (SCD) and heart failure (HF). The disease is associated with extensive genetic heterogeneity; pathogenic mutations in cardiac sarcomere protein genes, cytoskeletal protein genes and nuclear envelope protein genes have been linked to its etiology. Early diagnosis is conducive to clinical monitoring and allows for presymptomatic interventions as needed. In the present study, the entire coding sequences and flanking regions of 12 major disease (cardiomyopathy)-related genes [namely myosin, heavy chain 7, cardiac muscle, β (MYH7); myosin binding protein C, cardiac (MYBPC3); lamin A/C (LMNA); troponin I type 3 (cardiac) (TNNI3); troponin T type 2 (cardiac) (TNNT2); actin, α, cardiac muscle 1 (ACTC1); tropomyosin 1 (α) (TPM1); sodium channel, voltage gated, type V alpha subunit (SCN5A); myosin, light chain 2, regulatory, cardiac, slow (MYL2); myosin, heavy chain 6, cardiac muscle, α (MYH6); myosin, light chain 3, alkali, ventricular, skeletal, slow (MYL3); and protein kinase, AMP-activated, gamma 2 non-catalytic subunit  (PRKAG2)] in 8 patients with dilated cardiomyopathy (DCM) and in 8 patients with hypertrophic cardiomyopathy (HCM) were amplified and then sequenced using the Ion Torrent Personal Genome Machine (PGM) system. As a result, a novel heterozygous mutation (MYH7, p.Asn885Thr) and a variant of uncertain significance (TNNT2, p.Arg296His) were identified in 2 patients with HCM. These 2 missense mutations, which were absent in the samples obtained from the 200 healthy control subjects, altered the amino acid that was evolutionarily conserved among a number of vertebrate species; this illustrates that these 2 non-synonymous mutations play a role in the pathogenesis of HCM. Moreover, a double heterozygous mutation (PRKAG2, p.Gly100Ser plus MYH7, p.Arg719Trp) was identified in a patient with severe familial HCM, for the first time to the best of our

  14. Arrhythmogenic cardiomyopathy.

    PubMed

    Pilichou, Kalliopi; Thiene, Gaetano; Bauce, Barbara; Rigato, Ilaria; Lazzarini, Elisabetta; Migliore, Federico; Perazzolo Marra, Martina; Rizzo, Stefania; Zorzi, Alessandro; Daliento, Luciano; Corrado, Domenico; Basso, Cristina

    2016-01-01

    Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50% of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis.AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC.Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho

  15. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy.

    PubMed

    Karakikes, Ioannis; Stillitano, Francesca; Nonnenmacher, Mathieu; Tzimas, Christos; Sanoudou, Despina; Termglinchan, Vittavat; Kong, Chi-Wing; Rushing, Stephanie; Hansen, Jens; Ceholski, Delaine; Kolokathis, Fotis; Kremastinos, Dimitrios; Katoulis, Alexandros; Ren, Lihuan; Cohen, Ninette; Gho, Johannes M I H; Tsiapras, Dimitrios; Vink, Aryan; Wu, Joseph C; Asselbergs, Folkert W; Li, Ronald A; Hulot, Jean-Sebastien; Kranias, Evangelia G; Hajjar, Roger J

    2015-01-01

    A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca(2+) handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies. PMID:25923014

  16. Gene expression patterns in transgenic mouse models of hypertrophic cardiomyopathy caused by mutations in myosin regulatory light chain.

    PubMed

    Huang, Wenrui; Kazmierczak, Katarzyna; Zhou, Zhiqun; Aguiar-Pulido, Vanessa; Narasimhan, Giri; Szczesna-Cordary, Danuta

    2016-07-01

    Using microarray and bioinformatics, we examined the gene expression profiles in transgenic mouse hearts expressing mutations in the myosin regulatory light chain shown to cause hypertrophic cardiomyopathy (HCM). We focused on two malignant RLC-mutations, Arginine 58→Glutamine (R58Q) and Aspartic Acid 166 → Valine (D166V), and one benign, Lysine 104 → Glutamic Acid (K104E)-mutation. Datasets of differentially expressed genes for each of three mutants were compared to those observed in wild-type (WT) hearts. The changes in the mutant vs. WT samples were shown as fold-change (FC), with stringency FC ≥ 2. Based on the gene profiles, we have identified the major signaling pathways that underlie the R58Q-, D166V- and K104E-HCM phenotypes. The correlations between different genotypes were also studied using network-based algorithms. Genes with strong correlations were clustered into one group and the central gene networks were identified for each HCM mutant. The overall gene expression patterns in all mutants were distinct from the WT profiles. Both malignant mutations shared certain classes of genes that were up or downregulated, but most similarities were noted between D166V and K104E mice, with R58Q hearts showing a distinct gene expression pattern. Our data suggest that all three HCM mice lead to cardiomyopathy in a mutation-specific manner and thus develop HCM through diverse mechanisms. PMID:26906074

  17. The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy

    PubMed Central

    De Bortoli, Marzia; Beffagna, Giorgia; Bauce, Barbara; Lorenzon, Alessandra; Smaniotto, Gessica; Rigato, Ilaria; Calore, Martina; Li Mura, Ilena E A; Basso, Cristina; Thiene, Gaetano; Lanfranchi, Gerolamo; Danieli, Gian Antonio; Nava, Andrea; Rampazzo, Alessandra

    2010-01-01

    Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), an autosomal-dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement. We screened 112 ARVC/D probands for mutations in desmocollin-2 (DSC2) gene and detected two different amino-acid substitutions (p.E102K, p.I345T) and a frameshift variation (p.A897KfsX4) in 7 (6.2%) patients. DSC2a variant p.A897KfsX4, previously reported as a p.E896fsX900 mutation, was identified in five unrelated probands. Four of them were found to carry one or two mutations in different ARVC/D genes. Unexpectedly, p.A897KfsX4 variation was also found in 6 (1.5%) out of 400 control chromosomes. In vitro functional studies showed that, unlike wild-type DSC2a, this C-terminal mutated protein was localised in the cytoplasm. p.A897KfsX4 variation affects the last five amino acids of the DSC2a isoform but not of DSC2b. In contrast with what we found in other human tissues, in the heart DSC2b is more expressed than DSC2a, suggesting that relative deficiency of DSC2a might be compensated by isoform b. In conclusion, DSC2 gene mutations are not frequently involved in ARVC/D. The p.A897KfsX4 variation, identified in several Italian healthy control subjects, which affects only one of the two DSC2 isoforms, may be considered a rare variant, though possibly affecting phenotypic expression of concomitant ARVC/D mutations. PMID:20197793

  18. Retrospective molecular detection of Transthyretin Met 111 mutation in a Danish kindred with familial amyloid cardiomyopathy, using DNA from formalin-fixed and paraffin-embedded tissues.

    PubMed

    Nordvåg, B Y; Ranløv, I; Riise, H M; Husby, G; el-Gewely, M R

    1993-10-01

    Severe familial amyloid cardiomyopathy (FAC) in a Danish kindred is associated with a specific mutation (Met for Leu 111) in the transthyretin (TTR) gene. The mutation causes the loss of a DdeI restriction site in the gene, allowing molecular diagnostic studies. We studied formalin-fixed, paraffin-embedded tissues, up to 39 years old, from 29 family members of this kindred. DNA was partially purified from deparaffinized tissue sections and a DNA sequence of the TTR gene flanking the mutation site was amplified by the polymerase chain reaction (PCR), followed by restriction enzyme analysis. Amplified DNA was obtained from tissues representing 23 of the 29 persons. Ten out of the 23 family members were found to carry the TTR Met 111 mutation, whereas 13 were not affected. The results were consistent with known clinical data and with corresponding serum TTR examinations. This retrospective study shows that archival tissues can be used to confirm the diagnosis and disease pattern in members of families affected by hereditary diseases. PMID:8406434

  19. Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing

    PubMed Central

    Liu, Xuxia; Jiang, Tengyong; Piao, Chunmei; Li, Xiaoyan; Guo, Jun; Zheng, Shuai; Zhang, Xiaoping; Cai, Tao; Du, Jie

    2015-01-01

    Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death. Mutations in the MYBPC3 gene represent the cause of HCM in ~35% of patients with HCM. However, genetic testing in clinic setting has been limited due to the cost and relatively time-consuming by Sanger sequencing. Here, we developed a HCM Molecular Diagnostic Kit enabling ultra-low-cost targeted gene resequencing in a large cohort and investigated the mutation spectrum of MYBPC3. In a cohort of 114 patients with HCM, a total of 20 different mutations (8 novel and 12 known mutations) of MYBPC3 were identified from 25 patients (21.9%). We demonstrated that the power of targeted resequencing in a cohort of HCM patients, and found that MYBPC3 is a common HCM-causing gene in Chinese patients. Phenotype-genotype analyses showed that the patients with double mutations (n = 2) or premature termination codon mutations (n = 12) showed more severe manifestations, compared with patients with missense mutations (n = 11). Particularly, we identified a recurrent truncation mutation (p.Y842X) in four unrelated cases (4/25, 16%), who showed severe phenotypes, and suggest that the p.Y842X is a frequent mutation in Chinese HCM patients with severe phenotypes. PMID:26090888

  20. Mutation of mitochondrial DNA G13513A presenting with Leigh syndrome, Wolff-Parkinson-White syndrome and cardiomyopathy.

    PubMed

    Wang, Shi-Bing; Weng, Wen-Chin; Lee, Ni-Chung; Hwu, Wuh-Liang; Fan, Pi-Chuan; Lee, Wang-Tso

    2008-08-01

    Mutation of mitochondrial DNA (mtDNA) G13513A, encoding the ND5 subunit of respiratory chain complex I, can cause mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) and Leigh syndrome. Wolff-Parkinson-White (WPW) syndrome and optic atrophy were reported in a high proportion of patients with this mutation. We report an 18-month-old girl, with an 11-month history of psychomotor regression who was diagnosed with WPW syndrome and hypertrophic cardiomyopathy, in association with Leigh syndrome. Supplementation with coenzyme Q10, thiamine and carnitine prevented further regression in gross motor function but the patient's heart function deteriorated and dilated cardiomyopathy developed 11 months later. She was found to have a mutation of mtDNA G13513A. We suggest that mtDNA G13513A mutation is an important factor in patients with Leigh syndrome associated with WPW syndrome and/or optic atrophy, and serial heart function monitoring by echocardiography is recommended in this group of patients. PMID:19054921

  1. Mitochondrial 12S ribosomal RNA A1555G mutation associated with cardiomyopathy and hearing loss following high-dose chemotherapy and repeated aminoglycoside exposure.

    PubMed

    Skou, Anne-Sofie; Tranebjærg, Lisbeth; Jensen, Tim; Hasle, Henrik

    2014-02-01

    A 19-month-old girl with the A1555G mitochondrial mutation in the 12S ribosomal RNA gene and acute myelogenous leukemia developed dilated cardiomyopathy and bilateral sensorineural hearing loss before undergoing allogeneic stem cell transplantation. She had received gentamicin during episodes of febrile neutropenia. Testing for the A1555G mutation is recommended in patients frequently treated with aminoglycosides. PMID:24252789

  2. A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress.

    PubMed

    Wilkinson, Ross; Song, Weihua; Smoktunowicz, Natalia; Marston, Steven

    2015-12-01

    We investigated cardiac contractility in the ACTC E361G transgenic mouse model of dilated cardiomyopathy (DCM). No differences in cardiac dimensions or systolic function were observed in young mice, whereas young adult mice exhibited only mild diastolic abnormalities. Dobutamine had an inotropic and lusitropic effect on the mouse heart. In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was only reduced 10% at 10 Hz. Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response. The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min. Mice were treated with high doses of ANG II for 4 wk. The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG. There was a significant reduction in rates of pressure increase and decrease, as well as reduced end-systolic pressure and increased volume. Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM. In vitro DCM-causing mutations uncouple the relationship between Ca(2+) sensitivity and troponin I phosphorylation. We conclude that this leads to the observed, reduced response to β1 agonists and reduced cardiac reserve that predisposes the heart to DCM under conditions of chronic stress. PMID:26432839

  3. A Failure to Communicate: MYOSIN RESIDUES INVOLVED IN HYPERTROPHIC CARDIOMYOPATHY AFFECT INTER-DOMAIN INTERACTION.

    PubMed

    Kronert, William A; Melkani, Girish C; Melkani, Anju; Bernstein, Sanford I

    2015-12-01

    Our molecular modeling studies suggest a charge-dependent interaction between residues Glu-497 in the relay domain and Arg-712 in the converter domain of human β-cardiac myosin. To test the significance of this putative interaction, we generated transgenic Drosophila expressing indirect flight muscle myosin with charge reversal mutations in the relay (E496R) or converter (R713E). Each mutation yielded dramatic reductions in myosin Ca-ATPase activity (~80%) as well as in basal (~67%) and actin-activated (~84%) Mg-ATPase activity. E496R myosin-induced in vitro actin-sliding velocity was reduced by 71% and R713E myosin permitted no actin motility. Indirect flight muscles of late pupae from each mutant displayed disrupted myofibril assembly, with adults having severely abnormal myofibrils and no flight ability. To understand the molecular basis of these defects, we constructed a putative compensatory mutant that expresses myosin with both E496R and R713E. Intriguingly, ATPase values were restored to ~73% of wild-type and actin-sliding velocity increased to 40%. The double mutation suppresses myofibril assembly defects in pupal indirect flight muscles and dramatically reduces myofibril disruption in young adults. Although sarcomere organization is not sustained in older flies and flight ability is not restored in homozygotes, young heterozygotes fly well. Our results indicate that this charge-dependent interaction between the myosin relay and converter domains is essential to the mechanochemical cycle and sarcomere assembly. Furthermore, the same inter-domain interaction is disrupted when modeling human β-cardiac myosin heavy chain cardiomyopathy mutations E497D or R712L, implying that abolishing this salt bridge is one cause of the human disease. PMID:26446785

  4. High Resolution Systematic Digital Histological Quantification of Cardiac Fibrosis and Adipose Tissue in Phospholamban p.Arg14del Mutation Associated Cardiomyopathy

    PubMed Central

    Gho, Johannes M. I. H.; van Es, René; Stathonikos, Nikolas; Harakalova, Magdalena; te Rijdt, Wouter P.; Suurmeijer, Albert J. H.; van der Heijden, Jeroen F.; de Jonge, Nicolaas; Chamuleau, Steven A. J.; de Weger, Roel A.; Asselbergs, Folkert W.; Vink, Aryan

    2014-01-01

    Myocardial fibrosis can lead to heart failure and act as a substrate for cardiac arrhythmias. In dilated cardiomyopathy diffuse interstitial reactive fibrosis can be observed, whereas arrhythmogenic cardiomyopathy is characterized by fibrofatty replacement in predominantly the right ventricle. The p.Arg14del mutation in the phospholamban (PLN) gene has been associated with dilated cardiomyopathy and recently also with arrhythmogenic cardiomyopathy. Aim of the present study is to determine the exact pattern of fibrosis and fatty replacement in PLN p.Arg14del mutation positive patients, with a novel method for high resolution systematic digital histological quantification of fibrosis and fatty tissue in cardiac tissue. Transversal mid-ventricular slices (n = 8) from whole hearts were collected from patients with the PLN p.Arg14del mutation (age 48±16 years; 4 (50%) male). An in-house developed open source MATLAB script was used for digital analysis of Masson's trichrome stained slides (http://sourceforge.net/projects/fibroquant/). Slides were divided into trabecular, inner and outer compact myocardium. Per region the percentage of connective tissue, cardiomyocytes and fatty tissue was quantified. In PLN p.Arg14del mutation associated cardiomyopathy, myocardial fibrosis is predominantly present in the left posterolateral wall and to a lesser extent in the right ventricular wall, whereas fatty changes are more pronounced in the right ventricular wall. No difference in distribution pattern of fibrosis and adipocytes was observed between patients with a clinical predominantly dilated and arrhythmogenic cardiomyopathy phenotype. In the future, this novel method for quantifying fibrosis and fatty tissue can be used to assess cardiac fibrosis and fatty tissue in animal models and a broad range of human cardiomyopathies. PMID:24732829

  5. A family with a dystrophin gene mutation specifically affecting dystrophin expression in the heart

    SciTech Connect

    Muntoni, F.; Davies, K.; Dubowitz, V.

    1994-09-01

    We recently described a family with X-linked dilated cardiomyopathy where a large deletion in the muscle promoter region of the dystrophin gene was associated with a severe dilated cardiomyopathy in absence of clinical skeletal muscle involvement. The deletion removed the entire muscle promoter region, the first muscle exon and part of intron 1. The brain and Purkinje cell promoters were not affected by the deletion. Despite the lack of both the muscle promoter and the first muscle exon, dystrophin was detected immunocytochemically in relative high levels in the skeletal muscle of the affected males. We have now found that both the brain and Purkinje cell promoters were transcribed at high levels in the skeletal muscle of these individuals. This phenomenon, that does not occur in normal skeletal muscle, indicates that these two isoforms, physiologically expressed mainly in the central nervous system, can be transcribed and be functionally active in skeletal muscle under specific circumstances. Contrary to what is observed in skeletal muscle, dystrophin was not detected in the heart of one affected male using immunocytochemistry and an entire panel of anti-dystrophin antibodies. This was most likely the cause for the pronounced cardiac fibrosis observed and eventually responsible for the severe cardiac involvement invariably seen in seven affected males. In conclusion, the mutation of the muscle promoter, first muscle exon and part of intron 1 specifically affected expression of dystrophin in the heart. We believe that this deletion removes sequences involved in regulation of dystrophin expression in the heart and are at the moment characterizing other families with X-linked cardiomyopathy secondary to a dystrophinopathy.

  6. Novel m.15434C>A (p.230L>I) Mitochondrial Cytb Gene Missense Mutation Associated with Dilated Cardiomyopathy

    PubMed Central

    Zarrouk Mahjoub, Sinda; Mehri, Sounira; Ourda, Fatma; Finsterer, Josef; Ben Arab, Saïda

    2012-01-01

    Background. Previously it has been shown that various types of hypertrophic and dilative cardiomyopathy (hCMP, dCMP) can be attributed to disturbed mitochondrial oxidative energy metabolism. Several studies described mutations in mitochondrial DNA-located genes encoding for subunits of respiratory chain complexes, including the cytochrome b gene (MT-CYB), causing CMPs. Methods and Results. In the present study the MT-CYB gene was analysed in 30 patients with hCMP, 40 patients with dCMP, and 50 controls for alterations. Altogether, 27 MT-CYB variants were detected. Twenty-four of them were single nucleotide polymorphisms defining common haplogroups. The variant m.15434C>A was found in a single patient with severe dCMP and assessed as novel mutation, since it was not found in healthy controls or available data sets, and was nonhaplogroup associated with Phylotree. This variant altered an amino acid (L230I) with a high interspecific amino acid conservation index (CI = 97.7%) indicative of the functional importance of the residue. Conclusions. Though the L230I mutation seems to play a causative role for dCMP, prospective studies on yeast or transgenic mice models with defined mutation are warranted to study the pathogenetic impact of this mutation. PMID:22811935

  7. Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility.

    PubMed

    Cheng, Yuanhua; Regnier, Michael

    2016-07-01

    Cardiac troponin (cTn) acts as a pivotal regulator of muscle contraction and relaxation and is composed of three distinct subunits (cTnC: a highly conserved Ca(2+) binding subunit, cTnI: an actomyosin ATPase inhibitory subunit, and cTnT: a tropomyosin binding subunit). In this mini-review, we briefly summarize the structure-function relationship of cTn and its subunits, its modulation by PKA-mediated phosphorylation of cTnI, and what is known about how these properties are altered by hypertrophic cardiomyopathy (HCM) associated mutations of cTnI. This includes recent work using computational modeling approaches to understand the atomic-based structural level basis of disease-associated mutations. We propose a viewpoint that it is alteration of cTnC-cTnI interaction (rather than the Ca(2+) binding properties of cTn) per se that disrupt the ability of PKA-mediated phosphorylation at cTnI Ser-23/24 to alter contraction and relaxation in at least some HCM-associated mutations. The combination of state of the art biophysical approaches can provide new insight on the structure-function mechanisms of contractile dysfunction resulting cTnI mutations and exciting new avenues for the diagnosis, prevention, and even treatment of heart diseases. PMID:26851561

  8. Hypertrophic Cardiomyopathy: A Review

    PubMed Central

    Houston, Brian A; Stevens, Gerin R

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is a global disease with cases reported in all continents, affecting people of both genders and of various racial and ethnic origins. Widely accepted as a monogenic disease caused by a mutation in 1 of 13 or more sarcomeric genes, HCM can present catastrophically with sudden cardiac death (SCD) or ventricular arrhythmias or insidiously with symptoms of heart failure. Given the velocity of progress in both the fields of heart failure and HCM, we present a review of the approach to patients with HCM, with particular attention to those with HCM and the clinical syndrome of heart failure. PMID:25657602

  9. Exome sequencing identified mutations in CASK and MYBPC3 as the cause of a complex dilated cardiomyopathy phenotype.

    PubMed

    Reinstein, Eyal; Tzur, Shay; Bormans, Concetta; Behar, Doron M

    2016-01-01

    Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families. PMID:27173948

  10. Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease

    PubMed Central

    Yu, B; Sawyer, N A; Caramins, M; Yuan, Z G; Saunderson, R B; Pamphlett, R; Richmond, D R; Jeremy, R W; Trent, R J

    2005-01-01

    Aims: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) as a high throughput tool in: (1) DNA mutation detection in familial hypertrophic cardiomyopathy (FHC), and (2) single nucleotide polymorphism (SNP) discovery and validation in sporadic motor neurone disease (MND). Methods: The coding sequence and intron–exon boundaries of the cardiac β myosin heavy chain gene (MYH7) were screened by DHPLC for mutation identification in 150 unrelated patients diagnosed with FHC. One hundred and forty patients with sporadic MND were genotyped for the A67T SNP in the poliovirus receptor gene. All DHPLC positive signals were confirmed by conventional methods. Results: Mutation screening of MYH7 covered 10 kb with a total of 5700 amplicons, and more than 6750 DHPLC injections were completed within 35 days. The causative mutation was identified in 14% of FHC cases, including seven novel missense mutations (L227V, E328G, K351E, V411I, M435T, E894G, and E927K). Genotyping of the A67T SNP was performed at two different temperatures both in MND cases and 280 controls. This coding SNP was found more frequently in MND cases (13.6%) than in controls (6.8%). Furthermore, 19 and two SNPs were identified in MYH7 and the poliovirus receptor gene, respectively, during DHPLC screening. Conclusions: DHPLC is a high throughput, sensitive, specific, and robust platform for the detection of DNA variants, such as disease causing mutations or SNPs. It enables rapid and accurate screening of large genomic regions. PMID:15858117

  11. Genetic Analysis of 63 Mutations Affecting Maize Kernel Development Isolated from Mutator Stocks

    PubMed Central

    Scanlon, M. J.; Stinard, P. S.; James, M. G.; Myers, A. M.; Robertson, D. S.

    1994-01-01

    Sixty-three mutations affecting development of the maize kernel were isolated from active Robertson's Mutator (Mu) stocks. At least 14 previously undescribed maize gene loci were defined by mutations in this collection. Genetic mapping located 53 of these defective kernel (dek) mutations to particular chromosome arms, and more precise map determinations were made for 21 of the mutations. Genetic analyses identified 20 instances of allelism between one of the novel mutations and a previously described dek mutation, or between new dek mutations identified in this study; phenotypic variability was observed in three of the allelic series. Viability testing of homozygous mutant kernels identified numerous dek mutations with various pleiotropic effects on seedling and plant development. The mutations described here presumably arose by insertion of a Mu transposon within a dek gene; thus, many of the affected loci are expected to be accessible to molecular cloning via transposon-tagging. PMID:8138165

  12. PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction.

    PubMed

    Muhammad, Emad; Levitas, Aviva; Singh, Sonia R; Braiman, Alex; Ofir, Rivka; Etzion, Sharon; Sheffield, Val C; Etzion, Yoram; Carrier, Lucie; Parvari, Ruti

    2015-12-20

    Gene mutations, mostly segregating with a dominant mode of inheritance, are important causes of dilated cardiomyopathy (DCM), a disease characterized by enlarged ventricular dimensions, impaired cardiac function, heart failure and high risk of death. Another myocardial abnormality often linked to gene mutations is left ventricular noncompaction (LVNC) characterized by a typical diffuse spongy appearance of the left ventricle. Here, we describe a large Bedouin family presenting with a severe recessive DCM and LVNC. Homozygosity mapping and exome sequencing identified a single gene variant that segregated as expected and was neither reported in databases nor in Bedouin population controls. The PLEKHM2 cDNA2156_2157delAG variant causes the frameshift p.Lys645AlafsTer12 and/or the skipping of exon 11 that results in deletion of 30 highly conserved amino acids. PLEKHM2 is known to interact with several Rabs and with kinesin-1, affecting endosomal trafficking. Accordingly, patients' primary fibroblasts exhibited abnormal subcellular distribution of endosomes marked by Rab5, Rab7 and Rab9, as well as the Golgi apparatus. In addition, lysosomes appeared to be concentrated in the perinuclear region, and autophagy flux was impaired. Transfection of wild-type PLEKHM2 cDNA into patient's fibroblasts corrected the subcellular distribution of the lysosomes, supporting the causal effect of PLEKHM2 mutation. PLEKHM2 joins LAMP-2 and BAG3 as a disease gene altering autophagy resulting in an isolated cardiac phenotype. The association of PLEKHM2 mutation with DCM and LVNC supports the importance of autophagy for normal cardiac function. PMID:26464484

  13. D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.

    PubMed

    Levitas, Aviva; Konstantino, Yuval; Muhammad, Emad; Afawi, Zaid; Marc Weinstein, Jean; Amit, Guy; Etzion, Yoram; Parvari, Ruti

    2016-05-01

    Dilated cardiomyopathy (DCM) and malignant ventricular arrhythmias are important causes of congestive heart failure, heart transplantation, and sudden cardiac death in young patients. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line that has a pivotal role in maintaining adult cardiac structure and function. The putative mutation p.(D117N) in Cypher/ZASP has been suggested to cause systolic dysfunction, dilated left ventricle with hypertrabeculated myocardium, and intraventricular conduction disturbance, based on two reported sporadic cases. In two unrelated Bedouin families, one with pediatric DCM and the other with DCM and ventricular arrhythmias at young adulthood searching for the causative mutation by exome sequencing we identified the p.(D117N) variant in Cypher/ZASP. However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations. Furthermore, the carrier frequency in the Bedouin population of origin is estimated to be 5.2%, which is much higher than the incidence of idiopathic DCM in this population. Thus, our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation in the families tested by us. The results also indicates that at least in some cases, the p.(D117N) in Cypher/ZASP is not a causative mutation and the role of D117N in Cypher/ZASP in cardiac pathologies should be further clarified and re-evaluated. PMID:26419279

  14. Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability.

    PubMed

    Campbell, Matthew D; Witcher, Marc; Gopal, Anoop; Michele, Daniel E

    2016-05-01

    Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM. PMID:26968544

  15. The structural and functional effects of the familial hypertrophic cardiomyopathy-linked cardiac troponin C mutation, L29Q

    PubMed Central

    Robertson, Ian M.; Sevrieva, Ivanka; Li, Monica X.; Irving, Malcolm; Sun, Yin-Biao; Sykes, Brian D.

    2015-01-01

    Familial hypertrophic cardiomyopathy (FHC) is characterized by severe abnormal cardiac muscle growth. The traditional view of disease progression in FHC is that an increase in the Ca2 +-sensitivity of cardiac muscle contraction ultimately leads to pathogenic myocardial remodeling, though recent studies suggest this may be an oversimplification. For example, FHC may be developed through altered signaling that prevents downstream regulation of contraction. The mutation L29Q, found in the Ca2 +-binding regulatory protein in heart muscle, cardiac troponin C (cTnC), has been linked to cardiac hypertrophy. However, reports on the functional effects of this mutation are conflicting, and our goal was to combine in vitro and in situ structural and functional data to elucidate its mechanism of action. We used nuclear magnetic resonance and circular dichroism to solve the structure and characterize the backbone dynamics and stability of the regulatory domain of cTnC with the L29Q mutation. The overall structure and dynamics of cTnC were unperturbed, although a slight rearrangement of site 1, an increase in backbone flexibility, and a small decrease in protein stability were observed. The structure and function of cTnC was also assessed in demembranated ventricular trabeculae using fluorescence for in situ structure. L29Q reduced the cooperativity of the Ca2 +-dependent structural change in cTnC in trabeculae under basal conditions and abolished the effect of force-generating myosin cross-bridges on this structural change. These effects could contribute to the pathogenesis of this mutation. PMID:26341255

  16. Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy

    PubMed Central

    McConnell, Bradley K.; Singh, Sonal; Fan, Qiying; Hernandez, Adriana; Portillo, Jesus P.; Reiser, Peter J.; Tikunova, Svetlana B.

    2015-01-01

    The physiological consequences of aberrant Ca2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients) in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was 12 weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction (EF) and fractional shortening (FS), were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM). In conclusion, our results suggest that decreasing Ca2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM. PMID:26379556

  17. TMEM43 Mutation p.S358L Alters Intercalated Disc Protein Expression and Reduces Conduction Velocity in Arrhythmogenic Right Ventricular Cardiomyopathy

    PubMed Central

    Siragam, Vinayakumar; Cui, Xuezhi; Masse, Stephane; Ackerley, Cameron; Aafaqi, Shabana; Strandberg, Linn; Tropak, Michael; Fridman, Michael D.; Nanthakumar, Kumaraswamy; Liu, Jun; Sun, Yu; Su, Bin; Wang, Caroline; Liu, Xiaoru; Yan, Yuqing; Mendlowitz, Ariel; Hamilton, Robert M.

    2014-01-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of myocardium in the right ventricular free wall and frequently results in life-threatening ventricular arrhythmias and sudden cardiac death. A heterozygous missense mutation in the transmembrane protein 43 (TMEM43) gene, p.S358L, has been genetically identified to cause autosomal dominant ARVC type 5 in a founder population from the island of Newfoundland, Canada. Little is known about the function of the TMEM43 protein or how it leads to the pathogenesis of ARVC. We sought to determine the distribution of TMEM43 and the effect of the p.S358L mutation on the expression and distribution of various intercalated (IC) disc proteins as well as functional effects on IC disc gap junction dye transfer and conduction velocity in cell culture. Through Western blot analysis, transmission electron microscopy (TEM), immunofluorescence (IF), and electrophysiological analysis, our results showed that the stable expression of p.S358L mutation in the HL-1 cardiac cell line resulted in decreased Zonula Occludens (ZO-1) expression and the loss of ZO-1 localization to cell-cell junctions. Junctional Plakoglobin (JUP) and α-catenin proteins were redistributed to the cytoplasm with decreased localization to cell-cell junctions. Connexin-43 (Cx43) phosphorylation was altered, and there was reduced gap junction dye transfer and conduction velocity in mutant TMEM43-transfected cells. These observations suggest that expression of the p.S358L mutant of TMEM43 found in ARVC type 5 may affect localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue. PMID:25343256

  18. Point Mutations in Human β Cardiac Myosin Heavy Chain Have Differential Effects on Sarcomeric Structure and Assembly: An ATP Binding Site Change Disrupts Both Thick and Thin Filaments, Whereas Hypertrophic Cardiomyopathy Mutations Display Normal Assembly

    PubMed Central

    Becker, K. David; Gottshall, Kim R.; Hickey, Reed; Perriard, Jean-Claude; Chien, Kenneth R.

    1997-01-01

    Hypertrophic cardiomyopathy is a human heart disease characterized by increased ventricular mass, focal areas of fibrosis, myocyte, and myofibrillar disorganization. This genetically dominant disease can be caused by mutations in any one of several contractile proteins, including β cardiac myosin heavy chain (βMHC). To determine whether point mutations in human βMHC have direct effects on interfering with filament assembly and sarcomeric structure, full-length wild-type and mutant human βMHC cDNAs were cloned and expressed in primary cultures of neonatal rat ventricular cardiomyocytes (NRC) under conditions that promote myofibrillogenesis. A lysine to arginine change at amino acid 184 in the consensus ATP binding sequence of human βMHC resulted in abnormal subcellular localization and disrupted both thick and thin filament structure in transfected NRC. Diffuse βMHC K184R protein appeared to colocalize with actin throughout the myocyte, suggesting a tight interaction of these two proteins. Human βMHC with S472V mutation assembled normally into thick filaments and did not affect sarcomeric structure. Two mutant myosins previously described as causing human hypertrophic cardiomyopathy, R249Q and R403Q, were competent to assemble into thick filaments producing myofibrils with well defined I bands, A bands, and H zones. Coexpression and detection of wild-type βMHC and either R249Q or R403Q proteins in the same myocyte showed these proteins are equally able to assemble into the sarcomere and provided no discernible differences in subcellular localization. Thus, human βMHC R249Q and R403Q mutant proteins were readily incorporated into NRC sarcomeres and did not disrupt myofilament formation. This study indicates that the phenotype of myofibrillar disarray seen in HCM patients which harbor either of these two mutations may not be directly due to the failure of the mutant myosin heavy chain protein to assemble and form normal sarcomeres, but may rather be a

  19. The Cardiomyopathy Mutation, R146G Troponin I, Stabilizes the Intermediate "C" State of Regulated Actin under High- and Low-Free Ca(2+) Conditions.

    PubMed

    Johnson, Dylan; Mathur, Mohit C; Kobayashi, Tomoyoshi; Chalovich, Joseph M

    2016-08-16

    The R146G mutation of troponin I (TnI) is associated with hypertrophic cardiomyopathy in humans. Earlier data pointed to stabilization of the intermediate, C state, of actin-tropomyosin-troponin by this mutant. Because cardiac disorders appear to be linked to changes in regulated actin distributions, we determined the extent to which the R146G TnI mutant alters the distribution of states at low and high Ca(2+) concentrations. We show, from measurements of the kcat for actin-activated ATPase activity at saturating Ca(2+) concentrations, that R146G TnI reduced the population of the active, M, state to 25% of the wild-type level. Together with acrylodan-tropomyosin fluorescence measurements of the B state, it appeared that the C state was populated at ∼91% of the total for the R146G TnI-containing actin filaments. The C state was also more heavily populated at low Ca(2+) concentrations. Acrylodan-tropomyosin fluorescence changes showed a large diminution in the inactive state value relative to the wild-type value without a comparable increase in the active state. Furthermore, the rate of binding of rigor S1 to pyrene-labeled actin filaments containing R146G TnI was faster than the rate of binding to wild-type filaments at low free Ca(2+) concentrations. These results indicate that the inhibitory region of TnI affects the B-C and M-C equilibria of actin-tropomyosin-troponin. The observation that a mutation in the inhibitory region affects the M-C equilibrium may point to a novel regulatory interaction. PMID:27454189

  20. Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice.

    PubMed

    Huang, Wenrui; Liang, Jingsheng; Kazmierczak, Katarzyna; Muthu, Priya; Duggal, Divya; Farman, Gerrie P; Sorensen, Lars; Pozios, Iraklis; Abraham, Theodore P; Moore, Jeffrey R; Borejdo, Julian; Szczesna-Cordary, Danuta

    2014-09-01

    We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)-associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results were compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >13months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5 to 6month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype. PMID:24992035

  1. Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

    PubMed Central

    Kazmierczak, Katarzyna; Paulino, Ellena C.; Huang, Wenrui; Muthu, Priya; Liang, Jingsheng; Yuan, Chen-Ching; Rojas, Ana I.; Hare, Joshua M.

    2013-01-01

    The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca2+ sensitivity of force (ΔpCa50 ≅ 0.1) and an ∼1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca2+ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling. PMID:23748425

  2. Computational Characterization of Mutations in Cardiac Troponin T Known to Cause Familial Hypertrophic Cardiomyopathy

    PubMed Central

    Guinto, Pia J.; Manning, Edward P.; Schwartz, Steven D.; Tardiff, Jil C.

    2015-01-01

    Cardiac Troponin T (cTnT) is a central modulator of thin filament regulation of myofilament activation. The lack of structural data for the TNT1 tail domain, a proposed α-helical region, makes the functional implications of the FHC mutations difficult to determine. Studies have suggested that flexibility of TNT1 is important in normal protein-protein interactions within the thin filament. Our groups have previously shown through Molecular Dynamics (MD) simulations that some FHC mutations, Arg92Leu(R92L) and Arg92Trp(R92W), result in increased flexibility at a critical hinge region 12 residues distant from the mutation. To explain this distant effect and its implications for FHC mutations, we characterized the dynamics of wild type and mutational segments of cTnT using MD. Our data shows an opening of the helix between residues 105–110 in mutants. Consequently, the dihedral angles of these residues correspond to non-α-helical regions on Ramachandran plots. We hypothesize the removal of a charged residue decreases electrostatic repulsion between the point mutation and surrounding residues resulting in local helical compaction. Constrained ends of the helix and localized compaction results in expansion within the nearest non-polar helical turn from the mutation site, residues 105–109. PMID:26500385

  3. A Restrictive Cardiomyopathy Mutation in an Invariant Proline at the Myosin Head/Rod Junction Enhances Head Flexibility and Function, Yielding Muscle Defects in Drosophila.

    PubMed

    Achal, Madhulika; Trujillo, Adriana S; Melkani, Girish C; Farman, Gerrie P; Ocorr, Karen; Viswanathan, Meera C; Kaushik, Gaurav; Newhard, Christopher S; Glasheen, Bernadette M; Melkani, Anju; Suggs, Jennifer A; Moore, Jeffrey R; Swank, Douglas M; Bodmer, Rolf; Cammarato, Anthony; Bernstein, Sanford I

    2016-06-01

    An "invariant proline" separates the myosin S1 head from its S2 tail and is proposed to be critical for orienting S1 during its interaction with actin, a process that leads to muscle contraction. Mutation of the invariant proline to leucine (P838L) caused dominant restrictive cardiomyopathy in a pediatric patient (Karam et al., Congenit. Heart Dis. 3:138-43, 2008). Here, we use Drosophila melanogaster to model this mutation and dissect its effects on the biochemical and biophysical properties of myosin, as well as on the structure and physiology of skeletal and cardiac muscles. P838L mutant myosin isolated from indirect flight muscles of transgenic Drosophila showed elevated ATPase and actin sliding velocity in vitro. Furthermore, the mutant heads exhibited increased rotational flexibility, and there was an increase in the average angle between the two heads. Indirect flight muscle myofibril assembly was minimally affected in mutant homozygotes, and isolated fibers displayed normal mechanical properties. However, myofibrils degraded during aging, correlating with reduced flight abilities. In contrast, hearts from homozygotes and heterozygotes showed normal morphology, myofibrillar arrays, and contractile parameters. When P838L was placed in trans to Mhc(5), an allele known to cause cardiac restriction in flies, it did not yield the constricted phenotype. Overall, our studies suggest that increased rotational flexibility of myosin S1 enhances myosin ATPase and actin sliding. Moreover, instability of P838L myofibrils leads to decreased function during aging of Drosophila skeletal muscle, but not cardiac muscle, despite the strong evolutionary conservation of the P838 residue. PMID:27107639

  4. Identification of mutations in Colombian patients affected with Fabry disease.

    PubMed

    Uribe, Alfredo; Mateus, Heidi Eliana; Prieto, Juan Carlos; Palacios, Maria Fernanda; Ospina, Sandra Yaneth; Pasqualim, Gabriela; da Silveira Matte, Ursula; Giugliani, Roberto

    2015-12-15

    Fabry Disease (FD) is an X-linked inborn error of glycosphingolipid catabolism, caused by a deficiency of the lisosomal α-galactosidase A (AGAL). The disorder leads to a vascular disease secondary to the involvement of kidney, heart and the central nervous system. The mutation analysis is a valuable tool for diagnosis and genetic counseling. Although more than 600 mutations have been identified, most mutations are private. Our objective was to describe the analysis of nine Colombian patients with Fabry disease by automated sequencing of the seven exons of the GLA gene. Two novel mutations were identified in two patients affected with the classical subtype of FD, in addition to other 6 mutations previously reported. The present study confirms the heterogeneity of mutations in Fabry disease and the importance of molecular analysis for genetic counseling, female heterozygotes detection as well as therapeutic decisions. PMID:26297554

  5. Facilitated Cross-Bridge Interactions with Thin Filaments by Familial Hypertrophic Cardiomyopathy Mutations in α-Tropomyosin

    PubMed Central

    Wang, Fang; Brunet, Nicolas M.; Grubich, Justin R.; Bienkiewicz, Ewa A.; Asbury, Thomas M.; Compton, Lisa A.; Mihajlović, Goran; Miller, Victor F.; Chase, P. Bryant

    2011-01-01

    Familial hypertrophic cardiomyopathy (FHC) is a disease of cardiac sarcomeres. To identify molecular mechanisms underlying FHC pathology, functional and structural differences in three FHC-related mutations in recombinant α-Tm (V95A, D175N, and E180G) were characterized using both conventional and modified in vitro motility assays and circular dichroism spectroscopy. Mutant Tm's exhibited reduced α-helical structure and increased unordered structure. When thin filaments were fully occupied by regulatory proteins, little or no motion was detected at pCa 9, and maximum speed (pCa 5) was similar for all tropomyosins. Ca2+-responsiveness of filament sliding speed was increased either by increased pCa50 (V95A), reduced cooperativity n (D175N), or both (E180G). When temperature was increased, thin filaments with E180G exhibited dysregulation at temperatures ~10°C lower, and much closer to body temperature, than WT. When HMM density was reduced, thin filaments with D175N required fewer motors to initiate sliding or achieve maximum sliding speed. PMID:22187526

  6. Analysis of Dominant Mutations Affecting Muscle Excitation in Caenorhabditis Elegans

    PubMed Central

    Reiner, D. J.; Weinshenker, D.; Thomas, J. H.

    1995-01-01

    We examined mutations that disrupt muscle activation in Caenorhabditis elegans. Fifteen of 17 of these genes were identified previously and we describe new mutations in three of them. We also describe mutations in two new genes, exp-3 and exp-4. We assessed the degree of defect in pharyngeal, body-wall, egg-laying, and enteric muscle activation in animals mutant for each gene. Mutations in all 17 genes are semidominant and, in cases that could be tested, appear to be gain-of-function. Based on their phenotypes, the genes fall into three broad categories: mutations in 11 genes cause defective muscle activation, mutations in four genes cause hyperactivated muscle, and mutations in two genes cause defective activation in some muscle types and hyperactivation in others. In all testable cases, the mutations blocked response to pharmacological activators of egg laying, but did not block muscle activation by irradiation with a laser microbeam. The data suggest that these mutations affect muscle excitation, but not the capacity of the muscle fibers to contract. For most of the genes, apparent loss-of-function mutants have a grossly wild-type phenotype. These observations suggest that there is a large group of genes that function in muscle excitation that can be identified primarily by dominant mutations. PMID:8582640

  7. A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death

    PubMed Central

    2012-01-01

    Background Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation. Methods HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A>G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test. Results Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A>G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century. We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups. Conclusion A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and

  8. LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues.

    PubMed

    Chardon, Jodi Warman; Smith, A C; Woulfe, J; Pena, E; Rakhra, K; Dennie, C; Beaulieu, C; Huang, Lijia; Schwartzentruber, J; Hawkins, C; Harms, M B; Dojeiji, S; Zhang, M; Majewski, J; Bulman, D E; Boycott, K M; Dyment, D A

    2015-12-01

    Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders leading to progressive muscle degeneration and often associated with cardiac complications. We present two adult siblings with childhood-onset of weakness progressing to a severe quadriparesis with the additional features of triangular tongues and biventricular cardiac dysfunction. Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2. Biopsy of skeletal muscle demonstrated disrupted immunostaining of LIMS2. This is the first report of mutations in LIMS2 and resulting disruption of the integrin linked kinase (ILK)-LIMS-parvin complex associated with LGMD. PMID:25589244

  9. A Novel Mutation in the CYP11B1 Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy.

    PubMed

    Alqahtani, Mohammad A; Shati, Ayed A; Zou, Minjing; Alsuheel, Ali M; Alhayani, Abdullah A; Al-Qahtani, Saleh M; Gilban, Hessa M; Meyer, Brain F; Shi, Yufei

    2015-01-01

    Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260 (∗) ) was reported in a patient with papillary thyroid cancer (COSMIC database). In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment. PMID:26265915

  10. Unexpectedly Low Mutation Rates in Beta-Myosin Heavy Chain and Cardiac Myosin Binding Protein Genes in Italian Patients With Hypertrophic Cardiomyopathy

    PubMed Central

    Roncarati, Roberta; Latronico, Michael VG; Musumeci, Beatrice; Aurino, Stefania; Torella, Annalaura; Bang, Marie-Louise; Jotti, Gloria Saccani; Puca, Annibale A; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

    2011-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. J. Cell. Physiol. 226: 2894–2900, 2011. © 2011 Wiley-Liss, Inc. PMID:21302287

  11. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher.

    PubMed

    Meurs, Kathryn M; Lahmers, Sunshine; Keene, Bruce W; White, Stephen N; Oyama, Mark A; Mauceli, Evan; Lindblad-Toh, Kerstin

    2012-08-01

    Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog. PMID:22447147

  12. Autosomal Mutations Affecting Adhesion between Wing Surfaces in Drosophila Melanogaster

    PubMed Central

    Prout, M.; Damania, Z.; Soong, J.; Fristrom, D.; Fristrom, J. W.

    1997-01-01

    Integrins are evolutionarily conserved transmembrane α,β heterodimeric receptors involved in cell-to-matrix and cell-to-cell adhesions. In Drosophila the position-specific (PS) integrins mediate the formation and maintenance of junctions between muscle and epidermis and between the two epidermal wing surfaces. Besides integrins, other proteins are implicated in integrin-dependent adhesion. In Drosophila, somatic clones of mutations in PS integrin genes disrupt adhesion between wing surfaces to produce wing blisters. To identify other genes whose products function in adhesion between wing surfaces, we conducted a screen for autosomal mutations that produce blisters in somatic wing clones. We isolated 76 independent mutations in 25 complementation groups, 15 of which contain more than one allele. Chromosomal sites were determined by deficiency mapping, and genetic interactions with mutations in the β(PS) integrin gene myospheroid were investigated. Mutations in four known genes (blistered, Delta, dumpy and mastermind) were isolated. Mutations were isolated in three new genes (piopio, rhea and steamer duck) that affect myo-epidermal junctions or muscle function in embryos. Mutations in three other genes (kakapo, kiwi and moa) may also affect cell adhesion or muscle function at hatching. These new mutants provide valuable material for the study of integrin-dependent cell-to-cell adhesion. PMID:9136017

  13. A Mitochondrial DNA A8701G Mutation Associated with Maternally Inherited Hypertension and Dilated Cardiomyopathy in a Chinese Pedigree of a Consanguineous Marriage

    PubMed Central

    Zhu, Ye; Gu, Xiang; Xu, Chao

    2016-01-01

    Background: Cardiovascular diseases, including dilated cardiomyopathy (DCM) and hypertension, are the leading cause of death worldwide. The role of mitochondrial DNA (mtDNA) in the pathogenesis of these diseases has not been completely clarified. In this study, we evaluate whether A8701G mutation is associated with maternally inherited hypertension and DCM in a Chinese pedigree of a consanguineous marriage. Methods: Fourteen subjects in a three-generation Han Chinese family with hypertension and DCM, in which consanguineous marriage was present in the parental generation, were interviewed. We divided all the family members into case (7 maternal members) and control group (7 nonmaternal members) for comparison. Clinical evaluations and sequence analysis of mtDNA were obtained from all participants. Frequency differences between maternal and nonmaternal members were tested to locate the disease-associated mutations. Results: The majority of the family members presented with a maternal inheritance of hypertension and DCM. Sequence analysis of mtDNA in this pedigree identified eight mtDNA mutations. Among the mutations identified, there was only one significant mutation: A8701G (P = 0.005), which is a homoplasmic mitochondrial missense mutation in all the matrilineal relatives. There was no clear evidence for any synergistic effects between A8701G and other mutations. Conclusions: A8701G mutation may act as an inherited risk factor for the matrilineal transmission of hypertension and DCM in conjunction with genetic disorders caused by consanguineous marriage. PMID:26831225

  14. GENETIC CAUSES OF DILATED CARDIOMYOPATHY

    PubMed Central

    Mestroni, Luisa; Brun, Francesca; Spezzacatene, Anita; Sinagra, Gianfranco; Taylor, Matthew RG

    2014-01-01

    Dilated cardiomyopathy is a disease of the myocardium characterized by left ventricular dilatation and/or dysfunction, affecting both adult and pediatric populations. Almost half of cases are genetically determined with an autosomal pattern of inheritance. Up to 40 genes have been identified affecting proteins of a wide variety of cellular structures such as the sarcomere, the nuclear envelope, the cytoskeleton, the sarcolemma and the intercellular junction. Novel gene mutations have been recently identified thanks to advances in next-generation sequencing technologies. Genetic screening is an essential tool for early diagnosis, risk assessment, prognostic stratification and, possibly, adoption of primary preventive measures in affected patients and their asymptomatic relatives. The purpose of this article is to review the genetic basis of DCM, the known genotype-phenotype correlations, the role of current genetic sequencing techniques in the discovery of novel pathogenic gene mutations and new therapeutic perspectives. PMID:25584016

  15. The Dilated Cardiomyopathy-Causing Mutation ACTC E361G in Cardiac Muscle Myofibrils Specifically Abolishes Modulation of Ca2+ Regulation by Phosphorylation of Troponin I

    PubMed Central

    Vikhorev, Petr G.; Song, Weihua; Wilkinson, Ross; Copeland, O’Neal; Messer, Andrew E.; Ferenczi, Michael A.; Marston, Steven B.

    2014-01-01

    Phosphorylation of troponin I by protein kinase A (PKA) reduces Ca2+ sensitivity and increases the rate of Ca2+ release from troponin C and the rate of relaxation in cardiac muscle. In vitro experiments indicate that mutations that cause dilated cardiomyopathy (DCM) uncouple this modulation, but this has not been demonstrated in an intact contractile system. Using a Ca2+-jump protocol, we measured the effect of the DCM-causing mutation ACTC E361G on the equilibrium and kinetic parameters of Ca2+ regulation of contractility in single transgenic mouse heart myofibrils. We used propranolol treatment of mice to reduce the level of troponin I and myosin binding protein C (MyBP-C) phosphorylation in their hearts before isolating the myofibrils. In nontransgenic mouse myofibrils, the Ca2+ sensitivity of force was increased, the fast relaxation phase rate constant, kREL, was reduced, and the length of the slow linear phase, tLIN, was increased when the troponin I phosphorylation level was reduced from 1.02 to 0.3 molPi/TnI (EC50 P/unP = 1.8 ± 0.2, p < 0.001). Native myofibrils from ACTC E361G transgenic mice had a 2.4-fold higher Ca2+ sensitivity than nontransgenic mouse myofibrils. Strikingly, the Ca2+ sensitivity and relaxation parameters of ACTC E361G myofibrils did not depend on the troponin I phosphorylation level (EC50 P/unP = 0.88 ± 0.17, p = 0.39). Nevertheless, modulation of the Ca2+ sensitivity of ACTC E361G myofibrils by sarcomere length or EMD57033 was indistinguishable from that of nontransgenic myofibrils. Overall, EC50 measured in different conditions varied over a 7-fold range. The time course of relaxation, as defined by tLIN and kREL, was correlated with EC50 but varied by just 2.7- and 3.3-fold, respectively. Our results confirm that troponin I phosphorylation specifically alters the Ca2+ sensitivity of isometric tension and the time course of relaxation in cardiac muscle myofibrils. Moreover, the DCM-causing mutation ACTC E361G blunts this

  16. Genetics of inherited cardiomyopathy

    PubMed Central

    Jacoby, Daniel; McKenna, William J.

    2012-01-01

    During the past two decades, numerous disease-causing genes for different cardiomyopathies have been identified. These discoveries have led to better understanding of disease pathogenesis and initial steps in the application of mutation analysis in the evaluation of affected individuals and their family members. As knowledge of the genetic abnormalities, and insight into cellular and organ biology has grown, so has appreciation of the level of complexity of interaction between genotype and phenotype across disease states. What were initially thought to be one-to-one gene-disease correlates have turned out to display important relational plasticity dependent in large part on the genetic and environmental backgrounds into which the genes of interest express. The current state of knowledge with regard to genetics of cardiomyopathy represents a starting point to address the biology of disease, but is not yet developed sufficiently to supplant clinically based classification systems or, in most cases, to guide therapy to any significant extent. Future work will of necessity be directed towards elucidation of the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype–phenotype relationship with the ultimate goal of furthering our ability to identify, diagnose, risk stratify, and treat this group of disorders which cause heart failure and sudden death in the young. PMID:21810862

  17. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA{sup Lys} gene (G8363A)

    SciTech Connect

    Santorelli, F.M.; Mak, Suk-Chun; El-Schahawi, M.

    1996-05-01

    A novel G8363A mutation in the mtDNA tRNA{sup Lys} gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% {plus_minus} 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome c oxidase-negative fibers than in cytochrome c oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity. 23 refs., 3 figs., 1 tab.

  18. Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents

    PubMed Central

    Moreau, Adrien; Gosselin-Badaroudine, Pascal; Boutjdir, Mohamed; Chahine, Mohamed

    2015-01-01

    Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5. The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy. Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique. We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods. Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD. PMID:26733869

  19. The Cardiomyopathy Lamin A/C D192G Mutation Disrupts Whole-Cell Biomechanics in Cardiomyocytes as Measured by Atomic Force Microscopy Loading-Unloading Curve Analysis

    PubMed Central

    Lanzicher, Thomas; Martinelli, Valentina; Puzzi, Luca; Del Favero, Giorgia; Codan, Barbara; Long, Carlin S.; Mestroni, Luisa; Taylor, Matthew R. G.; Sbaizero, Orfeo

    2015-01-01

    Atomic force microscopy (AFM) cell loading/unloading curves were used to provide comprehensive insights into biomechanical behavior of cardiomyocytes carrying the lamin A/C (LMNA) D192G mutation known to cause defective nuclear wall, myopathy and severe cardiomyopathy. Our results suggested that the LMNA D192G mutation increased maximum nuclear deformation load, nuclear stiffness and fragility as compared to controls. Furthermore, there seems to be a connection between this lamin nuclear mutation and cell adhesion behavior since LMNA D192G cardiomyocytes displayed loss of AFM probe-to-cell membrane adhesion. We believe that this loss of adhesion involves the cytoskeletal architecture since our microscopic analyses highlighted that mutant LMNA may also lead to a morphological alteration in the cytoskeleton. Furthermore, chemical disruption of the actin cytoskeleton by cytochalasin D in control cardiomyocytes mirrored the alterations in the mechanical properties seen in mutant cells, suggesting a defect in the connection between the nucleoskeleton, cytoskeleton and cell adhesion molecules in cells expressing the mutant protein. These data add to our understanding of potential mechanisms responsible for this fatal cardiomyopathy, and show that the biomechanical effects of mutant lamin extend beyond nuclear mechanics to include interference of whole-cell biomechanical properties. PMID:26323789

  20. A Hypertrophic Cardiomyopathy-associated MYBPC3 Mutation Common in Populations of South Asian Descent Causes Contractile Dysfunction*

    PubMed Central

    Kuster, Diederik W. D.; Govindan, Suresh; Springer, Tzvia I.; Martin, Jody L.; Finley, Natosha L.; Sadayappan, Sakthivel

    2015-01-01

    Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-base pair deletion in MYBPC3 is inherited in millions worldwide. Although this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-CC10mut), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-CC10mut in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca2+ transients, compared with wild-type cMyBP-C expression (cMyBP-CWT) and controls. Forty-eight hours after infection, 44% of cMyBP-CWT and 36% of cMyBP-CC10mut protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little or no localization of cMyBP-CC10mut to the C-zone, whereas cMyBP-CWT mostly showed C-zone staining, suggesting that cMyBP-CC10mut could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-CC10mut resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-CC10mut displayed significantly reduced fractional shortening, sarcomere shortening, and relaxation velocities, apparently caused by defects in sarcomere function, because Ca2+ transients were unaffected. Co-sedimentation and protein cross-linking assays confirmed that C10mut causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-CC10mut, providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-CC10mut protein is sufficient to cause contractile dysfunction in vitro. PMID:25583989

  1. Echocardiography and cardiac MRI in mutation-negative hypertrophic cardiomyopathy in an older patient: a case defining the need for ICD.

    PubMed

    Rodriguez, Fatima; Degnan, Kathleen O; Seidman, Christine E; Mangion, Judy R

    2014-08-01

    We report the case of a 67-year-old man with hypertrophic cardiomyopathy who presented for a second opinion about implantable cardio-defibrillator (ICD) placement after a witnessed syncopal episode. Despite his older age, being mutation-negative, and having a maximal septal thickness of 2.2 cm on echocardiography, he demonstrated rapid progression of myocardial fibrosis on cardiac MRI, correlating to ventricular tachyarrhythmias and syncope. We review the role of echocardiography and cardiac MRI in optimizing medical care for such patients who may not otherwise meet criteria for an ICD placement or further interventions. PMID:24816179

  2. Ca2+-regulatory function of the inhibitory peptide region of cardiac troponin I is aided by the C-terminus of cardiac troponin T: Effects of familial hypertrophic cardiomyopathy mutations cTnI R145G and cTnT R278C, alone and in combination, on filament sliding

    PubMed Central

    Brunet, Nicolas M.; Chase, P. Bryant; Mihajlović, Goran; Schoffstall, Brenda

    2014-01-01

    Investigations of cardiomyopathy mutations in Ca2+ regulatory proteins troponin and tropomyosin provide crucial information about cardiac disease mechanisms, and also provide insights into functional domains in the affected polypeptides. Hypertrophic cardiomyopathy-associated mutations TnI R145G, located within the inhibitory peptide (Ip) of human cardiac troponin I (hcTnI), and TnT R278C, located immediately C-terminal to the IT arm in human cardiac troponin T (hcTnT), share some remarkable features: structurally, biochemically, and pathologically. Using bioinformatics, we find compelling evidence that TnI and TnT, and more specifically the affected regions of hcTnI and hcTnT, may be related not just structurally but also evolutionarily. To test for functional interactions of these mutations on Ca2+-regulation, we generated and characterized Tn complexes containing either mutation alone, or both mutations simultaneously. The most important results from in vitro motility assays (varying [Ca2+], temperature or HMM density) show that the TnT mutant “rescued” some deleterious effects of the TnI mutant at high Ca2+, but exacerbated the loss of function, i.e., switching off the actomyosin interaction, at low Ca2+. Taken together, our experimental results suggest that the C-terminus of cTnT aids Ca2+-regulatory function of cTnI Ip within the troponin complex. PMID:24418317

  3. Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

    SciTech Connect

    Muchir, Antoine; Wu, Wei; Sera, Fusako; Homma, Shunichi; Worman, Howard J.

    2014-10-03

    Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna{sup H222P/H222P} mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna{sup H222P/H222P} mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male Lmna{sup H222P/H222P} mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of Lmna{sup H222P/H222P} mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left

  4. Targets for therapy in sarcomeric cardiomyopathies

    PubMed Central

    Tardiff, Jil C.; Carrier, Lucie; Bers, Donald M.; Poggesi, Corrado; Ferrantini, Cecilia; Coppini, Raffaele; Maier, Lars S.; Ashrafian, Houman; Huke, Sabine; van der Velden, Jolanda

    2015-01-01

    To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics. PMID:25634554

  5. Large-scale mapping of mutations affecting zebrafish development

    PubMed Central

    Geisler, Robert; Rauch, Gerd-Jörg; Geiger-Rudolph, Silke; Albrecht, Andrea; van Bebber, Frauke; Berger, Andrea; Busch-Nentwich, Elisabeth; Dahm, Ralf; Dekens, Marcus PS; Dooley, Christopher; Elli, Alexandra F; Gehring, Ines; Geiger, Horst; Geisler, Maria; Glaser, Stefanie; Holley, Scott; Huber, Matthias; Kerr, Andy; Kirn, Anette; Knirsch, Martina; Konantz, Martina; Küchler, Axel M; Maderspacher, Florian; Neuhauss, Stephan C; Nicolson, Teresa; Ober, Elke A; Praeg, Elke; Ray, Russell; Rentzsch, Brit; Rick, Jens M; Rief, Eva; Schauerte, Heike E; Schepp, Carsten P; Schönberger, Ulrike; Schonthaler, Helia B; Seiler, Christoph; Sidi, Samuel; Söllner, Christian; Wehner, Anja; Weiler, Christian; Nüsslein-Volhard, Christiane

    2007-01-01

    Background Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. Results We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. Conclusion By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations. PMID:17212827

  6. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy.

    PubMed

    Kirk, Edwin P; Sunde, Margaret; Costa, Mauro W; Rankin, Scott A; Wolstein, Orit; Castro, M Leticia; Butler, Tanya L; Hyun, Changbaig; Guo, Guanglan; Otway, Robyn; Mackay, Joel P; Waddell, Leigh B; Cole, Andrew D; Hayward, Christopher; Keogh, Anne; Macdonald, Peter; Griffiths, Lyn; Fatkin, Diane; Sholler, Gary F; Zorn, Aaron M; Feneley, Michael P; Winlaw, David S; Harvey, Richard P

    2007-08-01

    The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up. PMID:17668378

  7. Pediatric Cardiomyopathies

    MedlinePlus

    ... Pressure High Blood Pressure Tools & Resources Stroke More Pediatric Cardiomyopathies Updated:Oct 22,2015 Patient education material ... oxygen or high blood pressure. According to the Pediatric Cardiomyopathy Registry, one in every 100,000 children ...

  8. Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.

    PubMed

    Seiferling, Dominic; Szczepanowska, Karolina; Becker, Christina; Senft, Katharina; Hermans, Steffen; Maiti, Priyanka; König, Tim; Kukat, Alexandra; Trifunovic, Aleksandra

    2016-07-01

    The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans Far less is known about mammalian UPR(mt) signaling, although similar roles were assumed for central players, including CLPP To better understand the mammalian UPR(mt) signaling, we deleted CLPP in hearts of DARS2-deficient animals that show robust induction of UPR(mt) due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR(mt) in mammals. Surprisingly, we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPR(mt) signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases. PMID:27154400

  9. The coexistence of dynamin 2 mutation and multiple mitochondrial DNA (mtDNA) deletions in the background of severe cardiomyopathy and centronuclear myopathy.

    PubMed

    Gal, Aniko; Inczedy-Farkas, Gabriella; Pal, Endre; Remenyi, Viktoria; Bereznai, Benjamin; Geller, Laszlo; Szelid, Zsolt; Merkely, Bela; Molnar, Maria Judit

    2015-01-01

    Dynamin2 (DNM2) gene mutations may result in Charcot-Marie-Tooth disease and centronuclear myopathy. Here, we present a patient suffering from cardiomyopathy and centronuclear myopathy with repetitive discharges and mild axonal neuropathy due to DNM2 mutation. Detailed cardiological and neurological examinations, electrophysiological tests, muscle biopsy, and molecular genetic analysis were performed. The patient developed left bundle branch block at age 40 and was fitted with a pacemaker at the age of 43. The patient has severe heart failure, ptosis, strabism, facial and proximal muscle weakness. Electrophysiological investigations found myopathy, complex repetitive discharges, and axonal neuropathy. Skeletal muscle biopsy detected centronuclear myopathy and cytochrome C oxidase (COX) negative fibers. Genetic analysis detected a pathogenic c.1105C>T (p.R369W) DNM2 gene mutation and heteroplasmic multiple mitochondrial DNA (mtDNA) deletion. Our data broadens the phenotypic spectrum of DNM2 mutations. The presence of the multiple mtDNA deletions may provide new aspects to understanding the pathogenesis of multisystemic symptoms in patients with DNM2 mutations. PMID:25492887

  10. Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca(2+)-sensitivity and suppress the modulation of Ca(2+)-sensitivity by troponin I phosphorylation.

    PubMed

    Messer, Andrew E; Bayliss, Christopher R; El-Mezgueldi, Mohammed; Redwood, Charles S; Ward, Douglas G; Leung, Man-Ching; Papadaki, Maria; Dos Remedios, Cristobal; Marston, Steven B

    2016-07-01

    We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thin filaments reconstituted with actin and human cardiac tropomyosin. We used the quantitative in vitro motility assay to study Ca(2+)-regulation of unloaded movement and its modulation by troponin I phosphorylation. Troponin from a patient with the K280N TnT mutation showed no difference in Ca(2+)-sensitivity when compared with donor heart troponin and the Ca(2+)-sensitivity was also independent of the troponin I phosphorylation level (uncoupled). The recombinant K280N TnT mutation increased Ca(2+)-sensitivity 1.7-fold and was also uncoupled. The R92Q TnT mutation in troponin from transgenic mouse increased Ca(2+)-sensitivity and was also completely uncoupled. Five TnT mutations (Δ14, Δ28 + 7, ΔE160, S179F and K273E) studied in recombinant troponin increased Ca(2+)-sensitivity and were all fully uncoupled. Thus, for HCM-causing mutations in TnT, Ca(2+)-sensitisation together with uncoupling in vitro is the usual response and both factors may contribute to the HCM phenotype. We also found that Epigallocatechin-3-gallate (EGCG) can restore coupling to all uncoupled HCM-causing TnT mutations. In fact the combination of Ca(2+)-desensitisation and re-coupling due to EGCG completely reverses both the abnormalities found in troponin with a TnT HCM mutation suggesting it may have therapeutic potential. PMID:27036851

  11. Calcium Ions in Inherited Cardiomyopathies.

    PubMed

    Deftereos, Spyridon; Papoutsidakis, Nikolaos; Giannopoulos, Georgios; Angelidis, Christos; Raisakis, Konstantinos; Bouras, Georgios; Davlouros, Periklis; Panagopoulou, Vasiliki; Goudevenos, John; Cleman, Michael W; Lekakis, John

    2016-01-01

    Inherited cardiomyopathies are a known cause of heart failure, although the pathways and mechanisms leading from mutation to the heart failure phenotype have not been elucidated. There is strong evidence that this transition is mediated, at least in part, by abnormal intracellular Ca(2+) handling, a key ion in ventricular excitation, contraction and relaxation. Studies in human myocytes, animal models and in vitro reconstituted contractile protein complexes have shown consistent correlations between Ca(2+) sensitivity and cardiomyopathy phenotype, irrespective of the causal mutation. In this review we present the available data about the connection between mutations linked to familial hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathy, right ventricular arrhythmogenic cardiomyopathy/dysplasia (ARVC/D) as well as left ventricular non-compaction and the increase or decrease in Ca(2+) sensitivity, together with the results of attempts to reverse the manifestation of heart failure by manipulating Ca(2+) homeostasis. PMID:26411603

  12. Hepatitis C virus mutation affects proteasomal epitope processing

    PubMed Central

    Seifert, Ulrike; Liermann, Heike; Racanelli, Vito; Halenius, Anne; Wiese, Manfred; Wedemeyer, Heiner; Ruppert, Thomas; Rispeter, Kay; Henklein, Peter; Sijts, Alice; Hengel, Hartmut; Kloetzel, Peter-M.; Rehermann, Barbara

    2004-01-01

    The high incidence of hepatitis C virus (HCV) persistence raises the question of how HCV interferes with host immune responses. Studying a single-source HCV outbreak, we identified an HCV mutation that impaired correct carboxyterminal cleavage of an immunodominant HLA-A2–restricted CD8 cell epitope that is frequently recognized by recovered patients. The mutation, a conservative HCV nonstructural protein 3 (NS3) tyrosine to phenylalanine substitution, was absent in 54 clones of the infectious source, but present in 15/21 (71%) HLA-A2–positive and in 11/24 (46%) HLA-A2–negative patients with chronic hepatitis C. In order to analyze whether the mutation affected the processing of the HLA-A2–restricted CD8 cell epitope, mutant and wild-type NS3 polypeptides were digested in vitro with 20S constitutive proteasomes and with immunoproteasomes. The presence of the mutation resulted in impaired carboxyterminal cleavage of the epitope. In order to analyze whether impaired epitope processing affected T cell priming in vivo, HLA-A2–transgenic mice were infected with vaccinia viruses encoding either wild-type or mutant HCV NS3. The mutant induced fewer epitope-specific, IFN-γ;–producing and fewer tetramer+ cells than the wild type. These data demonstrate how a conservative mutation in the flanking region of an HCV epitope impairs the induction of epitope-specific CD8+ T cells and reveal a mechanism that may contribute to viral sequence evolution in infected patients. PMID:15254592

  13. Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation

    PubMed Central

    Witjas-Paalberends, E Rosalie; Ferrara, Claudia; Scellini, Beatrice; Piroddi, Nicoletta; Montag, Judith; Tesi, Chiara; Stienen, Ger J M; Michels, Michelle; Ho, Carolyn Y; Kraft, Theresia; Poggesi, Corrado; van der Velden, Jolanda

    2014-01-01

    The first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain (β-MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross-bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross-bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation-negative HCM patients (HCMsmn). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCMsmn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s−1, respectively). Moreover, compared to HCMsmn, tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l–1 s−1 kN−1 m−2, respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross-bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn. Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation. PMID:24928957

  14. Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy

    PubMed Central

    Moreau, Adrien; Gosselin-Badaroudine, Pascal; Delemotte, Lucie; Klein, Michael L.

    2015-01-01

    The gating pore current, also called omega current, consists of a cation leak through the typically nonconductive voltage-sensor domain (VSD) of voltage-gated ion channels. Although the study of gating pore currents has refined our knowledge of the structure and the function of voltage-gated ion channels, their implication in cardiac disorders has not been established. Two Nav1.5 mutations (R222Q and R225W) located in the VSD are associated with atypical clinical phenotypes involving complex arrhythmias and dilated cardiomyopathy. Using the patch-clamp technique, in silico mutagenesis, and molecular dynamic simulations, we tested the hypothesis that these two mutations may generate gating pore currents, potentially accounting for their clinical phenotypes. Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the underlying pathological mechanism that links Nav1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers. PMID:25624448

  15. Leigh Syndrome Caused by the MT-ND5 m.13513G>A Mutation: A Case Presenting with WPW-Like Conduction Defect, Cardiomyopathy, Hypertension and Hyponatraemia.

    PubMed

    Brecht, Marcus; Richardson, Malcolm; Taranath, Ajay; Grist, Scott; Thorburn, David; Bratkovic, Drago

    2015-01-01

    Mitochondrial disease can present with a wide range of clinical phenotypes, and knowledge of the clinical spectrum of mitochondrial DNA mutation is constantly expanding. Leigh syndrome (LS) has been reported to be caused by the m.13513G>A mutation in the ND5 subunit of complex I (MT-ND5 m.13513G>A). We present a case of a 12-month-old infant initially diagnosed with tachyarrhythmia requiring defibrillation, subsequent presentation with hypertension and hyponatraemia secondary to renal salt loss and presumed inappropriate ADH secretion. Complex I activity in the muscle tissue was 54%, and mutation load in the muscle and lymphocytes was 50%. This case of Leigh syndrome caused by the m.13513G>A mutation in the ND5 gene illustrates that hyponatraemia due to renal sodium loss and inappropriate ADH secretion and hypertension can be features of this entity in addition to the previously reported cardiomyopathy and WPW-like conduction pattern and that they present additional challenges in diagnosis and management. PMID:25681084

  16. Structural and Kinetic Effects of Hypertrophic Cardiomyopathy Related Mutations R146G/Q and R163W on the Regulatory Switching Activity of Rat Cardiac Troponin I

    PubMed Central

    Zhou, Zhiqun; Rieck, Daniel; Li, King-Lun; Ouyang, Yexin; Dong, Wen-Ji

    2012-01-01

    Mutations in cardiac troponin I (cTnI) that cause hypertrophic cardiomyopathy (HCM) have been reported to change the contractility of cardiac myofilaments, but the underlying molecular mechanism remains elusive. In this study, Förster resonance energy transfer (FRET) was used to investigate the specific structural and kinetic effects that HCM related rat cTnI mutations R146G/Q and R163W exert on Ca2+ and myosin S1 dependent conformational transitions in rat cTn structure. Ca2+-induced changes in interactions between cTnC and cTnI were individually monitored in reconstituted thin filaments using steady state and time resolved FRET, and kinetics were determined using stopped flow. R146G/Q and R163W all changed the FRET distances between cTnC and cTnI in unique and various ways. However, kinetic rates of conformational transitions induced by Ca2+-dissociation were universally slowed when R146G/Q and R163W were present. Interestingly, the kinetic rates of changes in the inhibitory region of cTnI were always slower than that of the regulatory region, suggesting that the fly casting mechanism that normally underlies deactivation is preserved in spite of mutation. In situ rat myocardial fiber studies also revealed that FRET distance changes indicating mutation specific disruption of the cTnIIR–actin interaction were consistent with increased passive tension. PMID:23246786

  17. Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations

    PubMed Central

    Lax, Nichola Z.; Alston, Charlotte L.; Schon, Katherine; Park, Soo-Mi; Krishnakumar, Deepa; He, Langping; Falkous, Gavin; Ogilvy-Stuart, Amanda; Lees, Christoph; King, Rosalind H.; Hargreaves, Iain P.; Brown, Garry K.; McFarland, Robert; Dean, Andrew F.; Taylor, Robert W.

    2015-01-01

    Abstract Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6–8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues. PMID:26083569

  18. The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

    SciTech Connect

    Al-Saaidi, Rasha; Rasmussen, Torsten B.; Palmfeldt, Johan; Nissen, Peter H.; Beqqali, Abdelaziz; Hansen, Jakob; Pinto, Yigal M.; Boesen, Thomas; Mogensen, Jens; Bross, Peter

    2013-11-15

    Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by cardiac chamber enlargement and reduced systolic function of the left ventricle. Mutations in the LMNA gene represent the most frequent known genetic cause of DCM associated with disease of the conduction systems. The LMNA gene generates two major transcripts encoding the nuclear lamina major components lamin A and lamin C by alternative splicing. Both haploinsuffiency and dominant negative effects have been proposed as disease mechanism for premature termination codon (PTC) mutations in LMNA. These mechanisms however are still not clearly established. In this study, we used a representative LMNA nonsense mutation, p.Arg321Ter, to shed light on the molecular disease mechanisms. Cultured fibroblasts from three DCM patients carrying this mutation were analyzed. Quantitative reverse transcriptase PCR and sequencing of these PCR products indicated that transcripts from the mutant allele were degraded by the nonsense-mediated mRNA decay (NMD) mechanism. The fact that no truncated mutant protein was detectable in western blot (WB) analysis strengthens the notion that the mutant transcript is efficiently degraded. Furthermore, WB analysis showed that the expression of lamin C protein was reduced by the expected approximately 50%. Clearly decreased lamin A and lamin C levels were also observed by immunofluorescence microscopy analysis. However, results from both WB and nano-liquid chromatography/mass spectrometry demonstrated that the levels of lamin A protein were more reduced suggesting an effect on expression of lamin A from the wild type allele. PCR analysis of the ratio of lamin A to lamin C transcripts showed unchanged relative amounts of lamin A transcript suggesting that the effect on the wild type allele was operative at the protein level. Immunofluorescence microscopy analysis showed no abnormal nuclear morphology of patient fibroblast cells. Based on these data, we propose that

  19. The classical pink-eyed dilution mutation affects angiogenic responsiveness.

    PubMed

    Rogers, Michael S; Boyartchuk, Victor; Rohan, Richard M; Birsner, Amy E; Dietrich, William F; D'Amato, Robert J

    2012-01-01

    Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis. PMID:22615734

  20. Peripartum cardiomyopathy

    PubMed Central

    Blauwet, Lori A; Sliwa, Karen

    2011-01-01

    Peripartum cardiomyopathy (PPCM) is a potentially devastating disease that affects women during the last months of pregnancy or the first months after delivery. The aetiology and pathogenesis of this disease remain unclear, but oxidative stress and the generation of a cardiotoxic fragment of prolactin may play key roles. Diagnosing PPCM remains a challenge, as symptoms may mimic those women experience during normal pregnancy and the peripartum period. A high index of suspicion is thus necessary to make the diagnosis. Patients with PPCM have a varied clinical course, as some patients achieve full recovery while others progress to end-stage heart failure and even death. Standard heart failure treatment is indicated, although special provisions are necessary in pregnant and lactating women. Additional research into the pathophysiology of this disease, including possible genetic contributions, may lead to novel treatment strategies that can improve outcomes.

  1. Identification of the Syrian hamster cardiomyopathy gene.

    PubMed

    Nigro, V; Okazaki, Y; Belsito, A; Piluso, G; Matsuda, Y; Politano, L; Nigro, G; Ventura, C; Abbondanza, C; Molinari, A M; Acampora, D; Nishimura, M; Hayashizaki, Y; Puca, G A

    1997-04-01

    The BIO14.6 hamster is a widely used model for autosomal recessive cardiomyopathy. These animals die prematurely from progressive myocardial necrosis and heart failure. The primary genetic defect leading to the cardiomyopathy is still unknown. Recently, a genetic linkage map localized the cardiomyopathy locus on hamster chromosome 9qa2.1-b1, excluding several candidate genes. We now demonstrate that the cardiomyopathy results from a mutation in the delta-sarcoglycan gene that maps to the disease locus. This mutation was completely coincident with the disease in backcross and F2 pedigrees. This constitutes the first animal model identified for human sarcoglycan disorders. PMID:9097966

  2. Molecular etiology of idiopathic cardiomyopathy

    PubMed Central

    Arimura, T; Hayashi, T; Kimura, A

    2007-01-01

    Summary Idiopathic cardiomyopathy (ICM) is a primary cardiac disorder associated with abnormalities of ventricular wall thickness, size of ventricular cavity, contraction, relaxation, conduction and rhythm. Over the past two decades, molecular genetic analyses have revealed that mutations in the various genes cause ICM and such information concerning the genetic basis of ICM enables us to speculate the pathogenesis of this heterogeous cardiac disease. This review focuses on the molecular pathogenesis, i.e., genetic abnormalities and functional alterations due to the mutations especially in sarcomere/cytoskeletal components, in three characteristic features of ICM, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). Understanding the functional abnormalities of the sarcomere/cytoskeletal components, in ICM, has unraveled the function of these components not only as a contractile unit but also as a pivot for transduction of biochemical signals. PMID:18646564

  3. Early Progressive Dilated Cardiomyopathy in a Family with Becker Muscular Dystrophy Related to a Novel Frameshift Mutation in the Dystrophin Gene Exon 27

    PubMed Central

    Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O.; Marks, Harold; Flanigan, Kevin M.; Moore, Steven A.

    2014-01-01

    We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device (LVAD) implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAins GG), in which 7 base pairs are deleted and two are inserted. While this predicts an amino acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both siblings developed progressive heart failure secondary to early onset DCM. In addition, their 7 year old nephew with delayed gross motor development, mild proximal muscle weakness, and markedly elevated serum creatine kinase (CK) level (> 13,000 IU/L) at 16 months was recently demonstrated to have the familial DMD mutation. Here we report a novel genotype of BMD with early onset DCM and progressive lethal heart failure during early adolescence. PMID:25537791

  4. Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics.

    PubMed

    Farman, Gerrie P; Muthu, Priya; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta; Moore, Jeffrey R

    2014-12-15

    Familial hypertrophic cardiomyopathy (HCM) is associated with mutations in sarcomeric proteins, including the myosin regulatory light chain (RLC). Here we studied the impact of three HCM mutations located in the NH2 terminus of the RLC on the molecular mechanism of β-myosin heavy chain (MHC) cross-bridge mechanics using the in vitro motility assay. To generate mutant β-myosin, native RLC was depleted from porcine cardiac MHC and reconstituted with mutant (A13T, F18L, and E22K) or wild-type (WT) human cardiac RLC. We characterized the mutant myosin force and motion generation capability in the presence of a frictional load. Compared with WT, all three mutants exhibited reductions in maximal actin filament velocity when tested under low or no frictional load. The actin-activated ATPase showed no significant difference between WT and HCM-mutant-reconstituted myosins. The decrease in velocity has been attributed to a significantly increased duty cycle, as was measured by the dependence of actin sliding velocity on myosin surface density, for all three mutant myosins. These results demonstrate a mutation-induced alteration in acto-myosin interactions that may contribute to the pathogenesis of HCM. PMID:25324513

  5. Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor

    PubMed Central

    Glocker, Erik-Oliver; Kotlarz, Daniel; Boztug, Kaan; Gertz, E. Michael; Schäffer, Alejandro A.; Noyan, Fatih; Perro, Mario; Diestelhorst, Jana; Allroth, Anna; Murugan, Dhaarini; Hätscher, Nadine; Pfeifer, Dietmar; Sykora, Karl-Walter; Sauer, Martin; Kreipe, Hans; Lacher, Martin; Nustede, Rainer; Woellner, Cristina; Baumann, Ulrich; Salzer, Ulrich; Koletzko, Sibylle; Shah, Neil; Segal, Anthony W.; Sauerbrey, Axel; Buderus, Stephan; Snapper, Scott B.; Grimbacher, Bodo; Klein, Christoph

    2009-01-01

    BACKGROUND The molecular cause of inflammatory bowel disease is largely unknown. METHODS We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients’ peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient. RESULTS In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10–induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor α and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10–dependent “negative feedback” regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful. CONCLUSIONS Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient. PMID:19890111

  6. A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort.

    PubMed

    Rubattu, Speranza; Bozzao, Cristina; Pennacchini, Ermelinda; Pagannone, Erika; Musumeci, Beatrice Maria; Piane, Maria; Germani, Aldo; Savio, Camilla; Francia, Pietro; Volpe, Massimo; Autore, Camillo; Chessa, Luciana

    2016-01-01

    Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective. PMID:27483260

  7. A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort

    PubMed Central

    Rubattu, Speranza; Bozzao, Cristina; Pennacchini, Ermelinda; Pagannone, Erika; Musumeci, Beatrice Maria; Piane, Maria; Germani, Aldo; Savio, Camilla; Francia, Pietro; Volpe, Massimo; Autore, Camillo; Chessa, Luciana

    2016-01-01

    Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective. PMID:27483260

  8. Takotsubo Cardiomyopathy Associated with Severe Hypothyroidism in an Elderly Female.

    PubMed

    Brenes-Salazar, Jorge A

    2016-01-01

    Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a syndrome that affects predominantly postmenopausal women. Despite multiple described mechanisms, intense, neuroadrenergic myocardial stimulation appears to be the main trigger. Hyperthyroidism, but rarely hypothyroidism, has been described in association with Takotsubo cardiomyopathy. Herein, we present a case of stress cardiomyopathy in the setting of symptomatic hypothyroidism. PMID:27512537

  9. [Hypertrophic cardiomyopathy. Arrhythmia in hypertrophic cardiomyopathy].

    PubMed

    Colín Lizalde, Luis de Jesús

    2003-01-01

    Hypertrophic cardiomyopathy is a relatively common genetic disorder with heterogeneity in mutations, forms of presentation, prognosis and treatment strategies. Hypertrophic cardiomyopathy is recognized as the most common cause of sudden cardiac death that occurs in young people, including athletes. The clinical diagnosis is complemented with the ecocardiographic study, in which an abnormal myocardial hypertrophy of the septum can be observed in the absence of a cardiac or systemic disease (arterial systemic hypertension, aortic stenosis). The annual sudden mortality rate is 1% and, in selected populations, it ranges between 3 and 6%. The therapeutic strategies depend on the different subsets of patients according to the morbidity and mortality, sudden cardiac death, obstructive symptoms, heart failure or atrial fibrillation and stroke. High risk patients for sudden death may effectively be treated with the automatic implantable cardioverter-defibrillator. PMID:12966640

  10. Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein.

    PubMed

    Gaffin, Robert D; Peña, James R; Alves, Marco S L; Dias, Fernando A L; Chowdhury, Shamim A K; Heinrich, Lynley S; Goldspink, Paul H; Kranias, Evangelia G; Wieczorek, David F; Wolska, Beata M

    2011-11-01

    We have recently shown that a temporary increase in sarcoplasmic reticulum (SR) cycling via adenovirus-mediated overexpression of sarcoplasmic reticulum ATPase (SERCA2) transiently improves relaxation and delays hypertrophic remodeling in a familial hypertrophic cardiomyopathy (FHC) caused by a mutation in the thin filament protein, tropomyosin (i.e., α-TmE180G or Tm180). In this study, we sought to permanently alter calcium fluxes via phospholamban (PLN) gene deletion in Tm180 mice in order to sustain long-term improvements in cardiac function and adverse cardiac remodeling/hypertrophy. While similar work has been done in FHCs resulting from mutations in thick myofilament proteins, no one has studied these effects in an FHC resulting from a thin filament protein mutation. Tm180 transgenic (TG) mice were crossbred with PLN knockout (KO) mice and four groups were studied in parallel: 1) non-TG (NTG), 2) Tm180, 3) PLNKO/NTG and 4) PLNKO/Tm180. Tm180 mice exhibit increased heart weight/body weight and hypertrophic gene markers compared to NTG mice, but levels in PLNKO/Tm180 mice were similar to NTG. Tm180 mice also displayed altered function as assessed via in situ pressure-volume analysis and echocardiography at 3-6 months and one year; however, altered function in Tm180 mice was rescued back to NTG levels in PLNKO/Tm180 mice. Collagen deposition, as assessed by Picrosirius Red staining, was increased in Tm180 mice but was similar in NTG and in PLNKO/Tm180 mice. Extracellular signal-regulated kinase (ERK1/2) phosphorylation increased in Tm180 mice while levels in PLNKO/Tm180 mice were similar to NTGs. The present study shows that by modulating SR calcium cycling, we were able to rescue many of the deleterious aspects of FHC caused by a mutation in the thin filament protein, Tm. PMID:21840315

  11. Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

    PubMed Central

    Nag, Suman; Sommese, Ruth F.; Ujfalusi, Zoltan; Combs, Ariana; Langer, Stephen; Sutton, Shirley; Leinwand, Leslie A.; Geeves, Michael A.; Ruppel, Kathleen M.; Spudich, James A.

    2015-01-01

    Hypertrophic cardiomyopathy (HCM) is the most frequently occurring inherited cardiovascular disease. It is caused by mutations in genes encoding the force-generating machinery of the cardiac sarcomere, including human β-cardiac myosin. We present a detailed characterization of the most debated HCM-causing mutation in human β-cardiac myosin, R403Q. Despite numerous studies, most performed with nonhuman or noncardiac myosin, there is no consensus about the mechanism of action of this mutation on the function of the enzyme. We use recombinant human β-cardiac myosin and new methodologies to characterize in vitro contractility parameters of the R403Q myosin compared to wild type. We extend our studies beyond pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin. We find that, with pure actin, the intrinsic force generated by R403Q is ~15% lower than that generated by wild type. The unloaded velocity is, however, ~10% higher for R403Q myosin, resulting in a load-dependent velocity curve that has the characteristics of lower contractility at higher external loads compared to wild type. With regulated actin filaments, there is no increase in the unloaded velocity and the contractility of the R403Q myosin is lower than that of wild type at all loads. Unlike that with pure actin, the actin-activated adenosine triphosphatase activity for R403Q myosin with Ca2+-regulated actin filaments is ~30% lower than that for wild type, predicting a lower unloaded duty ratio of the motor. Overall, the contractility parameters studied fit with a loss of human β-cardiac myosin contractility as a result of the R403Q mutation. PMID:26601291

  12. [Peripartum cardiomyopathy].

    PubMed

    Fennira, S; Demiraj, A; Khouaja, A; Boujnah, M R

    2006-10-01

    Peripartum cardiomyopathy is a rare and under recognized form of dilated cardiomyopathy, defined as a heart failure in the last month of pregnancy or in the first five months post-partum with absence of determinable cause for cardiac failure and absence of demonstrable heart disease. The incidence of peripartum cardiomyopathy ranges from 1 in 1300 to 1 in 15,000 pregnancy. Advanced maternal age, multiparity, twin births, preeclampsia and black race are known risk factors. The etiology of peripartum cardiomyopathy remains unknown but viral, autoimmune or idiopathic myocarditis are highly suggested. The clinical presentation on patients with peripartum cardiomyopathy is similar to that of patients with systolic heart failure. The treatment is based on drugs for sympyomatic control. Studies in graeter populations are need to determine the role of immunosupressive treatment. About half patients of peripartum cardiomyopathy recover. The left ventricular ejection fraction and the left ventricular end-diastolic diameter are statistically significant prognostic factors. The risk of developing peripartum cardiomyopathy in subsequent pregnancies remains high. The place of dobutamine stress test in counseling the patients who desire pregnancy must be more studied. PMID:17078264

  13. Cardiomyopathy in becker muscular dystrophy: Overview.

    PubMed

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-06-26

    Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

  14. Cardiomyopathy in becker muscular dystrophy: Overview

    PubMed Central

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-01-01

    Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

  15. Importance of genetic evaluation and testing in pediatric cardiomyopathy.

    PubMed

    Tariq, Muhammad; Ware, Stephanie M

    2014-11-26

    Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotype-phenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children. PMID:25429328

  16. Dilated cardiomyopathy

    MedlinePlus

    Hare JM. The dilated, restrictive, and infiltrative cardiomyopathies. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 9th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 68.

  17. What's Cardiomyopathy

    MedlinePlus

    ... or more chambers of the heart. Usually, the enlargement begins in one of the two lower pumping ... idiopathic hypertrophic subaortic stenosis (IHSS) and asymmetrical septal hypertrophy (ASH), non-obstructive hypertrophic cardiomyopathy (HCM) The second ...

  18. Molecular genetics and pathogenesis of cardiomyopathy.

    PubMed

    Kimura, Akinori

    2016-01-01

    Cardiomyopathy is defined as a disease of functional impairment in the cardiac muscle and its etiology includes both extrinsic and intrinsic factors. Cardiomyopathy caused by the intrinsic factors is called as primary cardiomyopathy of which two major clinical phenotypes are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Genetic approaches have revealed the disease genes for hereditary primary cardiomyopathy and functional studies have demonstrated that characteristic functional alterations induced by the disease-associated mutations are closely related to the clinical types, such that increased and decreased Ca(2+) sensitivities of muscle contraction are associated with HCM and DCM, respectively. In addition, recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere, respectively. Moreover, functional analysis of mutations in the other components of cardiac muscle have suggested that the altered response to metabolic stresses is associated with cardiomyopathy, further indicating the heterogeneity in the etiology and pathogenesis of cardiomyopathy. PMID:26178429

  19. Mutations affecting the chemosensory neurons of Caenorhabditis elegans.

    PubMed

    Starich, T A; Herman, R K; Kari, C K; Yeh, W H; Schackwitz, W S; Schuyler, M W; Collet, J; Thomas, J H; Riddle, D L

    1995-01-01

    We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filing defective mutants are important for the differentiation of amphid and phasmid chemosensilla. PMID:7705621

  20. Mutations affecting the chemosensory neurons of Caenorhabditis elegans

    SciTech Connect

    Starich, T.A.; Herman, R.K.; Kari, C.K.

    1995-01-01

    We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filling defective mutants are important for the differentiation of amphid and phasmid chemosensilla. 58 refs., 3 figs., 6 tabs.

  1. An explicitly solvated full atomistic model of the cardiac thin filament and application on the calcium binding affinity effects from familial hypertrophic cardiomyopathy linked mutations

    NASA Astrophysics Data System (ADS)

    Williams, Michael; Schwartz, Steven

    2015-03-01

    The previous version of our cardiac thin filament (CTF) model consisted of the troponin complex (cTn), two coiled-coil dimers of tropomyosin (Tm), and 29 actin units. We now present the newest revision of the model to include explicit solvation. The model was developed to continue our study of genetic mutations in the CTF proteins which are linked to familial hypertrophic cardiomyopathies. Binding of calcium to the cTnC subunit causes subtle conformational changes to propagate through the cTnC to the cTnI subunit which then detaches from actin. Conformational changes propagate through to the cTnT subunit, which allows Tm to move into the open position along actin, leading to muscle contraction. Calcium disassociation allows for the reverse to occur, which results in muscle relaxation. The inclusion of explicit TIP3 water solvation allows for the model to get better individual local solvent to protein interactions; which are important when observing the N-lobe calcium binding pocket of the cTnC. We are able to compare in silica and in vitro experimental results to better understand the physiological effects from mutants, such as the R92L/W and F110V/I of the cTnT, on the calcium binding affinity compared to the wild type.

  2. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds...

  3. [Peripartum cardiomyopathy].

    PubMed

    Mouquet, Frédéric; Bouabdallaoui, Nadia

    2015-01-01

    The peripartum cardiomyopathy is a rare form of dilated cardiomyopathy resulting from alteration of angiogenesis toward the end of pregnancy. The diagnosis is based on the association of clinical heart failure and systolic dysfunction assessed by echocardiography or magnetic resonance imaging. Diagnoses to rule out are myocardial infarction, amniotic liquid embolism, myocarditis, inherited cardiomyopathy, and history of treatment by anthracycline. Risk factors are advance maternal age (>30), multiparity, twin pregnancy, African origin, obesity, preeclampsia, gestational hypertension, and prolonged tocolytic therapy. Treatment of acute phase is identical to usual treatment of acute systolic heart failure. After delivery, VKA treatment should be discussed in case of systolic function <25% because of higher risk of thrombus. A specific treatment by bromocriptine can be initiated on a case-by-case basis. Complete recovery of systolic function is observed in 50% of cases. The mortality risk is low. Subsequent pregnancy should be discouraged, especially if systolic function did not recover. PMID:26160284

  4. Diabetic cardiomyopathy

    PubMed Central

    Asghar, Omar; Al-Sunni, Ahmed; Khavandi, Kaivan; Khavandi, Ali; Withers, Sarah; Greenstein, Adam; Heagerty, Anthony M.; Malik, Rayaz A.

    2009-01-01

    Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazoledinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy. PMID:19364331

  5. Evolving molecular diagnostics for familial cardiomyopathies: at the heart of it all

    PubMed Central

    Callis, Thomas E; Jensen, Brian C; Weck, Karen E; Willis, Monte S

    2016-01-01

    Cardiomyopathies are an important and heterogeneous group of common cardiac diseases. An increasing number of cardiomyopathies are now recognized to have familial forms, which result from single-gene mutations that render a Mendelian inheritance pattern, including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Recently, clinical genetic tests for familial cardiomyopathies have become available for clinicians evaluating and treating patients with these diseases, making it necessary to understand the current progress and challenges in cardiomyopathy genetics and diagnostics. In this review, we summarize the genetic basis of selected cardiomyopathies, describe the clinical utility of genetic testing for cardiomyopathies and outline the current challenges and emerging developments. PMID:20370590

  6. Danon disease with typical early-onset cardiomyopathy in a male: focus on a novel LAMP-2 mutation.

    PubMed

    Bui, Yen K; Renella, Pierangelo; Martinez-Agosto, Julian A; Verity, Anthony; Madikians, Andranik; Alejos, Juan C

    2008-03-01

    We report a case of a 16-yr-old male with Danon disease caused by a novel mutation in the LAMP-2 gene. Mutations in the LAMP-2 gene result in the absence of LAMP-2 on immunohistochemical staining of muscle tissue, thus defining Danon disease, a rare X-linked myopathy. It is characterized clinically by HCM or left ventricular hypertrophy, a WPW pattern on ECG, variable degrees of muscular weakness (skeletal myopathy), mental retardation, and retinal changes. The patient presented with severe skeletal muscular weakness and respiratory failure. He also had a history of two OHTs, the first one for severe HCM and the second for allograft rejection. The patient's myopathy was initially presumed to be exclusively related to steroid-induced "critical care myopathy." However, further evaluation with a thigh muscle biopsy revealed autophagic vacuoles with sarcolemnal features suggestive of a lysosomal storage disorder. DNA analysis ultimately identified a previously unreported hemizygous IVS6+3_+6delGAGT splice site deletion mutation in the LAMP-2 gene located within the 5' splice site of intron 6, consistent with Danon disease. PMID:18282207

  7. Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death

    PubMed Central

    Zaragoza, Michael V.; Fung, Lianna; Jensen, Ember; Oh, Frances; Cung, Katherine; McCarthy, Linda A.; Tran, Christine K.; Hoang, Van; Hakim, Simin A.; Grosberg, Anna

    2016-01-01

    The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85%) located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51%) variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies <1% for family studies. The results identified LMNA c.357-2A>G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency. PMID:27182706

  8. Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death.

    PubMed

    Zaragoza, Michael V; Fung, Lianna; Jensen, Ember; Oh, Frances; Cung, Katherine; McCarthy, Linda A; Tran, Christine K; Hoang, Van; Hakim, Simin A; Grosberg, Anna

    2016-01-01

    The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85%) located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51%) variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies <1% for family studies. The results identified LMNA c.357-2A>G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency. PMID:27182706

  9. Mutations affecting GABAergic signaling in seizures and epilepsy

    PubMed Central

    Galanopoulou, Aristea S.

    2010-01-01

    The causes of epilepsies and epileptic seizures are multifactorial. Genetic predisposition may contribute in certain types of epilepsies and seizures, whether idiopathic or symptomatic of genetic origin. Although these are not very common, they have offered a unique opportunity to investigate the molecular mechanisms underlying epileptogenesis and ictogenesis. Among the implicated gene mutations, a number of GABAA receptor subunit mutations have been recently identified that contribute to several idiopathic epilepsies, febrile seizures, and rarely to certain types of symptomatic epilepsies, like the severe myoclonic epilepsy of infancy. Deletion of GABAA receptor genes has also been linked to Angelman syndrome. Furthermore, mutations of proteins controlling chloride homeostasis, which indirectly defines the functional consequences of GABAA signaling, have been identified. These include the chloride channel 2 (CLCN2) and the potassium chloride cotransporter KCC3. The pathogenic role of CLCN2 mutations has not been clearly demonstrated and may represent either susceptibility genes or, in certain cases, innocuous polymorphisms. KCC3 mutations have been associated with hereditary motor and sensory polyneuropathy with corpus callosum agenesis (Andermann syndrome) that often manifests with epileptic seizures. This review summarizes the recent progress in the genetic linkages of epilepsies and seizures to the above genes and discusses potential pathogenic mechanisms that contribute to the age, sex, and conditional expression of these seizures in carriers of these mutations. PMID:20352446

  10. Cirrhotic cardiomyopathy

    PubMed Central

    Ruiz-del-Árbol, Luis; Serradilla, Regina

    2015-01-01

    During the course of cirrhosis, there is a progressive deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to a failure in heart function with decreased cardiac output. This is due to a deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy in the absence of other known cardiac disease. Other findings of this specific cardiomyopathy include impaired contractile responsiveness to stress stimuli and electrophysiological abnormalities with prolonged QT interval. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of the b-adrenergic receptor signalling, abnormal cardiomyocyte membrane lipid composition and biophysical properties, ion channel defects and overactivity of humoral cardiodepressant factors. Cirrhotic cardiomyopathy may be difficult to determine due to the lack of a specific diagnosis test. However, an echocardiogram allows the detection of the diastolic dysfunction and the E/e′ ratio may be used in the follow-up progression of the illness. Cirrhotic cardiomyopathy plays an important role in the pathogenesis of the impairment of effective arterial blood volume and correlates with the degree of liver failure. A clinical consequence of cardiac dysfunction is an inadequate cardiac response in the setting of vascular stress that may result in renal hypoperfusion leading to renal failure. The prognosis is difficult to establish but the severity of diastolic dysfunction may be a marker of mortality risk. Treatment is non-specific and liver transplantation may normalize the cardiac function. PMID:26556983

  11. Cirrhotic cardiomyopathy.

    PubMed

    Milani, A; Zaccaria, R; Bombardieri, G; Gasbarrini, A; Pola, P

    2007-06-01

    Decompensated liver cirrhosis is characterized by a peripheral vasodilation with a low-resistance hyperdynamic circulation. The sustained increase of cardiac work load associated with such a condition may result in an inconstant and often subclinical series of heart abnormalities, constituting a new clinical entity known as "cirrhotic cardiomyopathy". Cirrhotic cardiomyopathy is variably associated with baseline increase in cardiac output, defective myocardial contractility and lowered systo-diastolic response to inotropic and chronotropic stimuli, down-regulated beta-adrenergic function, slight histo-morphological changes, and impaired electric "recovery" ability of ventricular myocardium. Cirrhotic cardiomyopathy is usually clinically latent or mild, likely because the peripheral vasodilation significantly reduces the left ventricle after-load, thus actually "auto-treating" the patient and masking any severe manifestation of heart failure. In cirrhotic patients, the presence of cirrhotic cardiomyopathy may become unmasked and clinically evident by certain treatment interventions that increase the effective blood volume and cardiac pre-load, including surgical or transjugular intrahepatic porto-systemic shunts, peritoneo-venous shunts (LeVeen) and orthotopic liver transplantation. Under these circumstances, an often transient overt congestive heart failure may develop, with increased cardiac output as well as right atrial, pulmonary artery and capillary wedge pressures. PMID:17383244

  12. Cardiomyopathy, familial dilated

    PubMed Central

    Taylor, Matthew RG; Carniel, Elisa; Mestroni, Luisa

    2006-01-01

    Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20–48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection

  13. Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes

    PubMed Central

    Akdis, Deniz; Brunckhorst, Corinna; Duru, Firat

    2016-01-01

    This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes. At later stages, heart failure may occur. Diagnosis is established with the 2010 Task Force Criteria (TFC). Modern imaging tools are crucial for ACM diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting functional and structural alternations. Of note, structural findings often become visible after electrical alterations, such as premature ventricular beats, ventricular fibrillation (VF) and ventricular tachycardia (VT). 12-lead ECG is important to assess for depolarisation and repolarisation abnormalities, including T-wave inversions as the most common ECG abnormality. Family history and the detection of causative mutations, mostly affecting the desmosome, have been incorporated in the TFC, and stress the importance of cascade family screening. Differential diagnoses include idiopathic right ventricular outflow tract (RVOT) VT, sarcoidosis, congenital heart disease, myocarditis, dilated cardiomyopathy, athlete’s heart, Brugada syndrome and RV infarction. Therapeutic strategies include restriction from endurance and competitive sports, β-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverter-defibrillators and endocardial/epicardial catheter ablation. PMID:27617087

  14. Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes.

    PubMed

    Akdis, Deniz; Brunckhorst, Corinna; Duru, Firat; Saguner, Ardan M

    2016-08-01

    This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes. At later stages, heart failure may occur. Diagnosis is established with the 2010 Task Force Criteria (TFC). Modern imaging tools are crucial for ACM diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting functional and structural alternations. Of note, structural findings often become visible after electrical alterations, such as premature ventricular beats, ventricular fibrillation (VF) and ventricular tachycardia (VT). 12-lead ECG is important to assess for depolarisation and repolarisation abnormalities, including T-wave inversions as the most common ECG abnormality. Family history and the detection of causative mutations, mostly affecting the desmosome, have been incorporated in the TFC, and stress the importance of cascade family screening. Differential diagnoses include idiopathic right ventricular outflow tract (RVOT) VT, sarcoidosis, congenital heart disease, myocarditis, dilated cardiomyopathy, athlete's heart, Brugada syndrome and RV infarction. Therapeutic strategies include restriction from endurance and competitive sports, β-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverter-defibrillators and endocardial/epicardial catheter ablation. PMID:27617087

  15. Calmodulin Point Mutations Affect Drosophila Development and Behavior

    PubMed Central

    Nelson, H. B.; Heiman, R. G.; Bolduc, C.; Kovalick, G. E.; Whitley, P.; Stern, M.; Beckingham, K.

    1997-01-01

    Calmodulin (CAM) is recognized as a major intermediary in intracellular calcium signaling, but as yet little is known of its role in developmental and behavioral processes. We have generated and studied mutations to the endogenous Cam gene of Drosophila melanogaster that change single amino acids within the protein coding region. One of these mutations produces a striking pupal lethal phenotype involving failure of head eversion. Various mutant combinations produce specific patterns of ectopic wing vein formation or melanotic scabs on the cuticle. Anaphase chromosome bridging is also seen as a maternal effect during the early embryonic nuclear divisions. In addition, specific behavioral defects such as poor climbing and flightlessness are detected among these mutants. Comparisons with other Drosophila mutant phenotypes suggests potential CAM targets that may mediate these developmental and behavioral effects, and analysis of the CAM crystal structure suggests the structural consequences of the individual mutations. PMID:9409836

  16. Alcoholic cardiomyopathy

    PubMed Central

    Guzzo-Merello, Gonzalo; Cobo-Marcos, Marta; Gallego-Delgado, Maria; Garcia-Pavia, Pablo

    2014-01-01

    Alcohol is the most frequently consumed toxic substance in the world. Low to moderate daily intake of alcohol has been shown to have beneficial effects on the cardiovascular system. In contrast, exposure to high levels of alcohol for a long period could lead to progressive cardiac dysfunction and heart failure. Cardiac dysfunction associated with chronic and excessive alcohol intake is a specific cardiac disease known as alcoholic cardiomyopathy (ACM). In spite of its clinical importance, data on ACM and how alcohol damages the heart are limited. In this review, we evaluate available evidence linking excessive alcohol consumption with heart failure and dilated cardiomyopathy. Additionally, we discuss the clinical presentation, prognosis and treatment of ACM. PMID:25228956

  17. Infiltrative Cardiomyopathies

    PubMed Central

    Bejar, David; Colombo, Paolo C; Latif, Farhana; Yuzefpolskaya, Melana

    2015-01-01

    Infiltrative cardiomyopathies can result from a wide spectrum of both inherited and acquired conditions with varying systemic manifestations. They portend an adverse prognosis, with only a few exceptions (ie, glycogen storage disease), where early diagnosis can result in potentially curative treatment. The extent of cardiac abnormalities varies based on the degree of infiltration and results in increased ventricular wall thickness, chamber dilatation, and disruption of the conduction system. These changes often lead to the development of heart failure, atrioventricular (AV) block, and ventricular arrhythmia. Because these diseases are relatively rare, a high degree of clinical suspicion is important for diagnosis. Electrocardiography and echocardiography are helpful, but advanced techniques including cardiac magnetic resonance (CMR) and nuclear imaging are increasingly preferred. Treatment is dependent on the etiology and extent of the disease and involves medications, device therapy, and, in some cases, organ transplantation. Cardiac amyloid is the archetype of the infiltrative cardiomyopathies and is discussed in great detail in this review. PMID:26244036

  18. Reversible Cardiomyopathies

    PubMed Central

    Patel, Harsh; Madanieh, Raef; Kosmas, Constantine E; Vatti, Satya K; Vittorio, Timothy J

    2015-01-01

    Cardiomyopathies (CMs) have many etiological factors that can result in severe structural and functional dysregulation. Fortunately, there are several potentially reversible CMs that are known to improve when the root etiological factor is addressed. In this article, we discuss several of these reversible CMs, including tachycardia-induced, peripartum, inflammatory, hyperthyroidism, Takotsubo, and chronic illness–induced CMs. Our discussion also includes a review on their respective pathophysiology, as well as possible management solutions. PMID:26052233

  19. Nonsense mutations in the human. beta. -globin gene affect mRNA metabolism

    SciTech Connect

    Baserga, S.J.; Benz, E.J. Jr. )

    1988-04-01

    A number of premature translation termination mutations (nonsense mutations) have been described in the human {alpha}- and {beta}-globin genes. Studies on mRNA isolated from patients with {beta}{sup 0}-thalassemia have shown that for both the {beta}-17 and the {beta}-39 mutations less than normal levels of {beta}-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human {beta}-globin mRNA). In vitro studies using the cloned {beta}-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. The authors have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, they have studied the effect of five nonsense mutations and two missense mutations on the expression of human {beta}-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation.

  20. Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families.

    PubMed

    Vorster, A A; Beighton, P; Ramesar, R S

    2015-05-01

    Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL), type 1 is an autosomal recessive disorder which has been identified in more than 30 affected children in the Afrikaans-speaking community of South Africa. Sequencing of B3GALT6 revealed a specific mutation, c.235A > G, in homozygous form in four families, while three others were compound heterozygotes for this mutation in combination with the c.200C > T mutation. In addition, a proband from one family carried the c.16C > T mutation combined with c.200C > T. In a series of five Iranian persons, mutations in B3GALT6 have been implicated in a syndrome characterised by skeletal abnormalities with intellectual disability, bone and connective tissue fragility. Other mutations in B3GALT6 resulted in the classical SEMD-JL phenotype in seven Japanese families and in a syndrome which has been likened to a progeroid form of Ehlers-Danlos syndrome (EDS). It is evident that there is considerable intragenic heterogeneity in B3GALT6. One of the mutations, c.200C > T, in the affected South Africans was also present in one of the Japanese persons and the respective phenotypes were identical. The multiplicity of allelic mutations and the phenotypic differences in the affected persons supports the concept that a spectrum of connective tissue disorders is programmed by mutations in B3GALT6. PMID:24766538

  1. Mutation of the Zinc-Binding Metalloprotease Motif Affects Bacteroides fragilis Toxin Activity but Does Not Affect Propeptide Processing

    PubMed Central

    Franco, Augusto A.; Buckwold, Simy L.; Shin, Jai W.; Ascon, Miguel; Sears, Cynthia L.

    2005-01-01

    To evaluate the role of the zinc-binding metalloprotease in Bacteroides fragilis toxin (BFT) processing and activity, the zinc-binding consensus sequences (H348, E349, H352, G355, H358, and M366) were mutated by site-directed-mutagenesis. Our results indicated that single point mutations in the zinc-binding metalloprotease motif do not affect BFT processing but do reduce or eliminate BFT biologic activity in vitro. PMID:16041055

  2. Arrhythmogenic right ventricular cardiomyopathy in a weimaraner

    PubMed Central

    Eason, Bryan D.; Leach, Stacey B.; Kuroki, Keiichi

    2015-01-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed postmortem in a weimaraner dog. Syncope, ventricular arrhythmias, and sudden death in this patient combined with the histopathological fatty tissue infiltration affecting the right ventricular myocardium are consistent with previous reports of ARVC in non-boxer dogs. Arrhythmogenic right ventricular cardiomyopathy has not been previously reported in weimaraners. PMID:26483577

  3. Arrhythmogenic ventricular cardiomyopathy: A paradigm shift from right to biventricular disease

    PubMed Central

    Saguner, Ardan M; Brunckhorst, Corinna; Duru, Firat

    2014-01-01

    Arrhythmogenic ventricular cardiomyopathy (AVC) is generally referred to as arrhythmogenic right ventricular (RV) cardiomyopathy/dysplasia and constitutes an inherited cardiomyopathy. Affected patients may succumb to sudden cardiac death (SCD), ventricular tachyarrhythmias (VTA) and heart failure. Genetic studies have identified causative mutations in genes encoding proteins of the intercalated disk that lead to reduced myocardial electro-mechanical stability. The term arrhythmogenic RV cardiomyopathy is somewhat misleading as biventricular involvement or isolated left ventricular (LV) involvement may be present and thus a broader term such as AVC should be preferred. The diagnosis is established on a point score basis according to the revised 2010 task force criteria utilizing imaging modalities, demonstrating fibrous replacement through biopsy, electrocardiographic abnormalities, ventricular arrhythmias and a positive family history including identification of genetic mutations. Although several risk factors for SCD such as previous cardiac arrest, syncope, documented VTA, severe RV/LV dysfunction and young age at manifestation have been identified, risk stratification still needs improvement, especially in asymptomatic family members. Particularly, the role of genetic testing and environmental factors has to be further elucidated. Therapeutic interventions include restriction from physical exercise, beta-blockers, sotalol, amiodarone, implantable cardioverter-defibrillators and catheter ablation. Life-long follow-up is warranted in symptomatic patients, but also asymptomatic carriers of pathogenic mutations. PMID:24772256

  4. Troponins, intrinsic disorder, and cardiomyopathy.

    PubMed

    Na, Insung; Kong, Min J; Straight, Shelby; Pinto, Jose R; Uversky, Vladimir N

    2016-08-01

    Cardiac troponin is a dynamic complex of troponin C, troponin I, and troponin T (TnC, TnI, and TnT, respectively) found in the myocyte thin filament where it plays an essential role in cardiac muscle contraction. Mutations in troponin subunits are found in inherited cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The highly dynamic nature of human cardiac troponin and presence of numerous flexible linkers in its subunits suggest that understanding of structural and functional properties of this important complex can benefit from the consideration of the protein intrinsic disorder phenomenon. We show here that mutations causing decrease in the disorder score in TnI and TnT are significantly more abundant in HCM and DCM than mutations leading to the increase in the disorder score. Identification and annotation of intrinsically disordered regions in each of the troponin subunits conducted in this study can help in better understanding of the roles of intrinsic disorder in regulation of interactomes and posttranslational modifications of these proteins. These observations suggest that disease-causing mutations leading to a decrease in the local flexibility of troponins can trigger a whole plethora of functional changes in the heart. PMID:27074551

  5. [Clinical and instrumental characteristics of idiopathic hypertrophic cardiomyopathy and dynamics of echocardiographic indices as affected by beta-adrenergic blockaders].

    PubMed

    Barats, S S; Kheĭnonen, I M; Klets, F Kh; Serebrennikov, V A; Lipchenko, A A

    1983-10-01

    Clinical investigation of 31 patients with idiopathic hypertrophic subaortal stenosis (IHSS) and idiopathic hypertrophic nonobstructive cardiomyopathy (IHNCMP) comprised electro- and phonocardiography, roentgenologic examination and echocardiography. The disease was latent in 3 patients, and ischemic heart disease or rheumatic heart lesion had been diagnosed prior to echocardiography in 26. Asymmetrical hypertrophy and hypokinesia of the upper third of the ventricular septum, narrowed left-ventricular cavity and septum-wise systolic movement of the anterior mitral cusp were findings common to all IHSS patients. The ventricular septum/left-ventricular posterior wall thickness ratio was elevated (1.42 +/- 0.06). In IHNCMP patients, this ratio was within normal range. The results of an acute pharmacologic test with 10 mg intravenous obsidan given to 10 IHSS patients suggested that the obstruction of left-ventricular outflow pathway was somewhat reduced. Prolonged (2 months to 3 years) obsidan treatment was given to 25 patients and was associated with positive effect in terms of improved subjective manifestations of the disease. However, echocardiographic patterns only showed moderate improvement in 9 of the 13 patients who had completed 1-3 years' treatment course. PMID:6139501

  6. Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C.

    PubMed

    Zot, Henry G; Hasbun, Javier E; Michell, Clara A; Landim-Vieira, Maicon; Pinto, Jose R

    2016-07-01

    Higher affinity for TnI explains how troponin C (TnC) carrying a causative hypertrophic cardiomyopathy mutation, TnC(A8V), sensitizes muscle cells to Ca(2+). Muscle fibers reconstituted with TnC(A8V) require ∼2.3-fold less [Ca(2+)] to achieve 50% maximum-tension compared to fibers reconstituted with wild-type TnC (TnC(WT)). Binding measurements rule out a significant change in N-terminus Ca(2+)-affinity of isolated TnC(A8V), and TnC(A8V) binds the switch-peptide of troponin-I (TnI(sp)) ∼1.6-fold more strongly than TnC(WT); thus we model the TnC-TnI(sp) interaction as competing with the TnI-actin interaction. Tension data are well-fit by a model constrained to conditions in which the affinity of TnC(A8V) for TnI(sp) is 1.5-1.7-fold higher than that of TnC(WT) at all [Ca(2+)]. Mean ATPase rates of reconstituted cardiac myofibrils is greater for TnC(A8V) than TnC(WT) at all [Ca(2+)], with statistically significant differences in the means at higher [Ca(2+)]. To probe TnC-TnI interaction in low Ca(2+), displacement of bis-ANS from TnI was monitored as a function of TnC. Whereas Ca(2+)-TnC(WT) displaces significantly more bis-ANS than Mg(2+)-TnC(WT), Ca(2+)-TnC(A8V) displaces probe equivalently to Mg(2+)-TnC(A8V) and Ca(2+)-TnC(WT), consistent with stronger Ca(2+)-independent TnC(A8V)-TnI(sp). A Matlab program for computing theoretical activation is reported. Our work suggests that contractility is constantly above normal in hearts made hypertrophic by TnC(A8V). PMID:26976709

  7. Mutations in Ran system affected telomere silencing in Saccharomyces cerevisiae

    SciTech Connect

    Hayashi, Naoyuki Kobayashi, Masahiko; Shimizu, Hiroko; Yamamoto, Ken-ichi; Murakami, Seishi; Nishimoto, Takeharu

    2007-11-23

    The Ran GTPase system regulates the direction and timing of several cellular events, such as nuclear-cytosolic transport, centrosome formation, and nuclear envelope assembly in telophase. To gain insight into the Ran system's involvement in chromatin formation, we investigated gene silencing at the telomere in several mutants of the budding yeast Saccharomyces cerevisiae, which had defects in genes involved in the Ran system. A mutation of the RanGAP gene, rna1-1, caused reduced silencing at the telomere, and partial disruption of the nuclear Ran binding factor, yrb2-{delta}2, increased this silencing. The reduced telomere silencing in rna1-1 cells was suppressed by a high dosage of the SIR3 gene or the SIT4 gene. Furthermore, hyperphosphorylated Sir3 protein accumulated in the rna1-1 mutant. These results suggest that RanGAP is required for the heterochromatin structure at the telomere in budding yeast.

  8. Parental Age Affects Somatic Mutation Rates in the Progeny of Flowering Plants1

    PubMed Central

    Singh, Amit Kumar; Bashir, Tufail; Sailer, Christian; Gurumoorthy, Viswanathan; Ramakrishnan, Anantha Maharasi; Dhanapal, Shanmuhapreya; Grossniklaus, Ueli; Baskar, Ramamurthy

    2015-01-01

    In humans, it is well known that the parental reproductive age has a strong influence on mutations transmitted to their progeny. Meiotic nondisjunction is known to increase in older mothers, and base substitutions tend to go up with paternal reproductive age. Hence, it is clear that the germinal mutation rates are a function of both maternal and paternal ages in humans. In contrast, it is unknown whether the parental reproductive age has an effect on somatic mutation rates in the progeny, because these are rare and difficult to detect. To address this question, we took advantage of the plant model system Arabidopsis (Arabidopsis thaliana), where mutation detector lines allow for an easy quantitation of somatic mutations, to test the effect of parental age on somatic mutation rates in the progeny. Although we found no significant effect of parental age on base substitutions, we found that frameshift mutations and transposition events increased in the progeny of older parents, an effect that is stronger through the maternal line. In contrast, intrachromosomal recombination events in the progeny decrease with the age of the parents in a parent-of-origin-dependent manner. Our results clearly show that parental reproductive age affects somatic mutation rates in the progeny and, thus, that some form of age-dependent information, which affects the frequency of double-strand breaks and possibly other processes involved in maintaining genome integrity, is transmitted through the gametes. PMID:25810093

  9. Parental age affects somatic mutation rates in the progeny of flowering plants.

    PubMed

    Singh, Amit Kumar; Bashir, Tufail; Sailer, Christian; Gurumoorthy, Viswanathan; Ramakrishnan, Anantha Maharasi; Dhanapal, Shanmuhapreya; Grossniklaus, Ueli; Baskar, Ramamurthy

    2015-05-01

    In humans, it is well known that the parental reproductive age has a strong influence on mutations transmitted to their progeny. Meiotic nondisjunction is known to increase in older mothers, and base substitutions tend to go up with paternal reproductive age. Hence, it is clear that the germinal mutation rates are a function of both maternal and paternal ages in humans. In contrast, it is unknown whether the parental reproductive age has an effect on somatic mutation rates in the progeny, because these are rare and difficult to detect. To address this question, we took advantage of the plant model system Arabidopsis (Arabidopsis thaliana), where mutation detector lines allow for an easy quantitation of somatic mutations, to test the effect of parental age on somatic mutation rates in the progeny. Although we found no significant effect of parental age on base substitutions, we found that frameshift mutations and transposition events increased in the progeny of older parents, an effect that is stronger through the maternal line. In contrast, intrachromosomal recombination events in the progeny decrease with the age of the parents in a parent-of-origin-dependent manner. Our results clearly show that parental reproductive age affects somatic mutation rates in the progeny and, thus, that some form of age-dependent information, which affects the frequency of double-strand breaks and possibly other processes involved in maintaining genome integrity, is transmitted through the gametes. PMID:25810093

  10. Peripartum cardiomyopathy.

    PubMed

    Okeke, Tc; Ezenyeaku, Cct; Ikeako, Lc

    2013-07-01

    Peripartum cardiomyopathy (PPCM) is a rare form of unexplained cardiac failure of unknown origin, unique to the pregnant woman with highly variable outcome associated with high morbidity and mortality. PPCM is fraught with controversies in its definition, epidemiology, pathophysiology, diagnosis and management. PPCM is frequently under diagnosed, inadequately treated and without a laid down follow-up regimen, thus, the aim of this review. Publications on PPCM were accessed using Medline, Google scholar and Pubmed databases. Relevant materials on PPCM, selected references from internet services, journals, textbooks, and lecture notes on PPCM were also accessed and critically reviewed. PPCM is multifactorial in origin. It is a diagnosis of exclusion and should be based on classic echocardiographic criteria. The outcome of PPCM is also highly variable with high morbidity and mortality rates. Future pregnancies are not recommended in women with persistent ventricular dysfunction because the heart cannot tolerate increased cardiovascular workload associated with the pregnancy. Although, multiparity is associated with PPCM, there is an increased risk of fetal prematurity and fetal loss. PPCM is a rare form of dilated cardiomyopathy of unknown origin, unique to pregnant women. The pathophysiology is poorly understood. Echocardiography is central to diagnosis of PPCM and effective treatment monitoring in patients of PPCM. The outcome is highly variable and related to reversal of ventricular dysfunction. PMID:24116305

  11. Characterization of mitochondrial DNA in primary cardiomyopathies.

    PubMed

    Bobba, A; Giannattasio, S; Pucci, A; Lippolis, R; Camaschella, C; Marra, E

    1995-12-29

    With the aim of studying the involvement of the mitochondrial genome in the impairment of heart function, mitochondrial DNA was analyzed by modified primer shift-polymerase chain reaction in a panel of young patients affected by primary cardiomyopathies. Mitochondrial DNA molecules harboring the 7436 bp deletion were specifically found in cardiomyopathic patients as compared with a panel of control subjects. The 4977 bp deletion was commonly detected among the subjects analyzed whereas none of the specific tRNA gene point mutations generally associated with the cardiomyopathic trait were detected. The presence of the 7436 bp deletion as a consequence of a premature aging of the heart muscle, secondary to heart dysfunction, is discussed. PMID:8747493

  12. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.

    PubMed

    Cordeddu, Viviana; Yin, Jiani C; Gunnarsson, Cecilia; Virtanen, Carl; Drunat, Séverine; Lepri, Francesca; De Luca, Alessandro; Rossi, Cesare; Ciolfi, Andrea; Pugh, Trevor J; Bruselles, Alessandro; Priest, James R; Pennacchio, Len A; Lu, Zhibin; Danesh, Arnavaz; Quevedo, Rene; Hamid, Alaa; Martinelli, Simone; Pantaleoni, Francesca; Gnazzo, Maria; Daniele, Paola; Lissewski, Christina; Bocchinfuso, Gianfranco; Stella, Lorenzo; Odent, Sylvie; Philip, Nicole; Faivre, Laurence; Vlckova, Marketa; Seemanova, Eva; Digilio, Cristina; Zenker, Martin; Zampino, Giuseppe; Verloes, Alain; Dallapiccola, Bruno; Roberts, Amy E; Cavé, Hélène; Gelb, Bruce D; Neel, Benjamin G; Tartaglia, Marco

    2015-11-01

    The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain. PMID:26173643

  13. In vitro evaluation of mitochondrial dysfunction and treatment with adeno-associated virus vector in fibroblasts from Doberman Pinschers with dilated cardiomyopathy and a pyruvate dehydrogenase kinase 4 mutation.

    PubMed

    Sosa, Ivan; Estrada, Amara H; Winter, Brandy D; Erger, Kirsten E; Conlon, Thomas J

    2016-02-01

    OBJECTIVE To compare mitochondrial oxygen consumption rate (OCR) of fibroblasts from Doberman Pinschers with and without dilated cardiomyopathy (DCM) and mutation of the gene for pyruvate dehydrogenase kinase isozyme 4 (PDK4) and to evaluate in vitro whether treatment with adeno-associated virus (AAV) vector (ie, gene therapy) would alter metabolic efficiency. ANIMALS 10 Doberman Pinschers screened for DCM and PDK4 mutation. PROCEDURES Fibroblasts were harvested from skin biopsy specimens obtained from Doberman Pinschers, and dogs were classified as without DCM or PDK4 mutation (n = 3) or with occult DCM and heterozygous (4) or homozygous (3) for PDK4 mutation. Fibroblasts were or were not treated with tyrosine mutant AAV type 2 vector containing PDK4 at multiplicities of infection of 1,000. Mitochondrial OCR was measured to evaluate mitochondrial metabolism. The OCR was compared among dog groups and between untreated and treated fibroblasts within groups. RESULTS Mean ± SD basal OCR of fibroblasts from heterozygous (74 ± 8 pmol of O2/min) and homozygous (58 ± 12 pmol of O2/min) dogs was significantly lower than that for dogs without PDK4 mutation (115 ± 9 pmol of O2/min). After AAV transduction, OCR did not increase significantly in any group (mutation-free group, 121 ± 26 pmol of O2/min; heterozygous group, 88 ± 6 pmol of O2/min; homozygous group, 59 ± 3 pmol of O2/min). CONCLUSIONS AND CLINICAL RELEVANCE Mitochondrial function was altered in skin fibroblasts of Doberman Pinschers with DCM and PDK4 mutation. Change in mitochondrial function after in vitro gene therapy at the multiplicities of infection used in this study was not significant. (Am J Vet Res 2016;77:156-161). PMID:27027709

  14. NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis.

    PubMed

    Otto, Edgar A; Trapp, Melissa L; Schultheiss, Ulla T; Helou, Juliana; Quarmby, Lynne M; Hildebrandt, Friedhelm

    2008-03-01

    Nephronophthisis, an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first 3 decades of life. Causative mutations in 8 genes (NPHP1-8) have been identified, and homologous mouse models for NPHP2/INVS and NPHP3 have been described. The jck mouse is another model of recessive cystic kidney disease, and this mouse harbors a missense mutation, G448V, in the highly conserved RCC1 domain of Nek8. We hypothesized that mutations in NEK8 might cause nephronophthisis in humans, so we performed mutational analysis in a worldwide cohort of 588 patients. We identified 3 different amino acid changes that were conserved through evolution (L330F, H425Y, and A497P) and that were absent from at least 80 ethnically matched controls. All 3 mutations were within RCC1 domains, and the mutation H425Y was positioned within the same RCC1 repeat as the mouse jck mutation. To test the functional significance of these mutations, we introduced them into full-length mouse Nek8 GFP-tagged cDNA constructs. We transiently overexpressed the constructs in inner medullary collecting duct cells (IMCD-3 cell line) and compared the subcellular localization of mutant Nek8 to wild-type Nek8. All mutant forms of Nek8 showed defects in ciliary localization to varying degrees; the H431Y mutant (human H425Y) was completely absent from cilia and the amount localized to centrosomes was decreased. Overexpression of these mutants did not affect overall ciliogenesis, mitosis, or centriole number. Our genetic and functional data support the assumption that mutations in NEK8 cause nephronophthisis (NPHP9), adding another link between proteins mutated in cystic kidney disease and their localization to cilia and centrosomes. PMID:18199800

  15. Children's Cardiomyopathy Foundation

    MedlinePlus

    Search The Children's Cardiomyopathy Foundation (CCF) is a national, non-profit organization focused on pediatric cardiomyopathy, a chronic disease of the heart muscle. CCF is dedicated to accelerating the search for ...

  16. Types of Cardiomyopathy

    MedlinePlus

    ... ventricles, making it harder for the heart to pump blood. Hypertrophic cardiomyopathy also can cause stiffness of the ... Over time, the heart loses the ability to pump blood effectively. Dilated cardiomyopathy can lead to heart failure , ...

  17. First missense mutation outside of SERAC1 lipase domain affecting intracellular cholesterol trafficking.

    PubMed

    Rodríguez-García, María Elena; Martín-Hernández, Elena; de Aragón, Ana Martínez; García-Silva, María Teresa; Quijada-Fraile, Pilar; Arenas, Joaquín; Martín, Miguel A; Martínez-Azorín, Francisco

    2016-01-01

    We report the clinical and genetic findings in a Spanish boy who presented MEGDEL syndrome, a very rare inborn error of metabolism. Whole-exome sequencing uncovered a new homozygous mutation in the serine active site containing 1 (SERAC1) gene, which is essential for both mitochondrial function and intracellular cholesterol trafficking. Functional studies in patient fibroblasts showed that p.D224G mutation affects the intracellular cholesterol trafficking. Only three missense mutations in this gene have been described before, being p.D224G the first missense mutation outside of the SERAC1 serine-lipase domain. Therefore, we conclude that the defect in cholesterol trafficking is not limited to alterations in this specific part of the protein. PMID:26445863

  18. A molecular description of mutations affecting the pollen component of the Nicotiana alata S locus.

    PubMed Central

    Golz, J F; Su, V; Clarke, A E; Newbigin, E

    1999-01-01

    Mutations affecting the self-incompatibility response of Nicotiana alata were generated by irradiation. Mutants in the M1 generation were selected on the basis of pollen tube growth through an otherwise incompatible pistil. Twelve of the 18 M1 plants obtained from the mutagenesis screen were self-compatible. Eleven self-compatible plants had mutations affecting only the pollen function of the S locus (pollen-part mutants). The remaining self-compatible plant had a mutation affecting only the style function of the S locus (style-part mutant). Cytological examination of the pollen-part mutant plants revealed that 8 had an extra chromosome (2n + 1) and 3 did not. The pollen-part mutation in 7 M1 plants was followed in a series of crosses. DNA blot analysis using probes for S-RNase genes (encoding the style function of the S locus) indicated that the pollen-part mutation was associated with an extra S allele in 4 M1 plants. In 3 of these plants, the extra S allele was located on the additional chromosome. There was no evidence of an extra S allele in the 3 remaining M1 plants. The breakdown of self-incompatibility in plants with an extra S allele is discussed with reference to current models of the molecular basis of self-incompatibility. PMID:10388830

  19. Suppressors of Mutations in the rII Gene of Bacteriophage T4 Affect Promoter Utilization

    PubMed Central

    Hall, Dwight H.; Snyder, Ronald D.

    1981-01-01

    Homyk, Rodriguez and Weil (1976) have described T4 mutants, called sip, that partially suppress the inability of T4rII mutants to grow in λ lysogens. We have found that mutants sip1 and sip2 are resistant to folate analogs and overproduce FH2 reductase. The results of recombination and complementation studies indicate that sip mutations are in the mot gene. Like other mot mutations (Mattson, Richardson and Goodin 1974; Chace and Hall 1975; Sauerbier, Hercules and Hall 1976), the sip2 mutation affects the expression of many genes and appears to affect promoter utilization. The mot gene function is not required for T4 growth on most hosts, but we have found that it is required for good growth on E. coli CTr5X. Homyk, Rodriguez and Weil (1976) also described L mutations that reverse the effects of sip mutations. L2 decreases the folate analog resistance and the inability of sip2 to grow on CTr5X. L2 itself is partially resistant to a folate analog, and appears to reverse the effects of sip2 on gene expression. These results suggest that L2 affects another regulatory gene related to the mot gene. PMID:7262547

  20. The genetic landscape of cardiomyopathy and its role in heart failure

    PubMed Central

    McNally, Elizabeth M; Barefield, David Y; Puckelwartz, Megan J

    2015-01-01

    Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output. Dilated cardiomyopathy is often triggered by mutations that disrupt the giant protein titin. The energetic consequences of these mutations offer molecular targets and opportunities for new drug development and gene correction therapies. PMID:25651172

  1. The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy.

    PubMed

    Hiippala, Anita; Vasilescu, Catalina; Tallila, Jonna; Alastalo, Tero-Pekka; Paetau, Anders; Tyni, Tiina; Suomalainen, Anu; Euro, Liliya; Ojala, Tiina

    2016-06-01

    We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. © 2016 Wiley Periodicals, Inc. PMID:26888048

  2. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism.

    PubMed

    Sartorato, Paola; Lapeyraque, Anne-Laure; Armanini, Decio; Kuhnle, Ursula; Khaldi, Yasmina; Salomon, Rémi; Abadie, Véronique; Di Battista, Eliana; Naselli, Arturo; Racine, Alain; Bosio, Maurizio; Caprio, Massimiliano; Poulet-Young, Véronique; Chabrolle, Jean-Pierre; Niaudet, Patrick; De Gennes, Christiane; Lecornec, Marie-Hélène; Poisson, Elodie; Fusco, Anna Maria; Loli, Paola; Lombès, Marc; Zennaro, Maria-Christina

    2003-06-01

    We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease. PMID:12788847

  3. A novel mutation in TFL1 homolog affecting determinacy in cowpea (Vigna unguiculata).

    PubMed

    Dhanasekar, P; Reddy, K S

    2015-02-01

    Mutations in the widely conserved Arabidopsis Terminal Flower 1 (TFL1) gene and its homologs have been demonstrated to result in determinacy across genera, the knowledge of which is lacking in cowpea. Understanding the molecular events leading to determinacy of apical meristems could hasten development of cowpea varieties with suitable ideotypes. Isolation and characterization of a novel mutation in cowpea TFL1 homolog (VuTFL1) affecting determinacy is reported here for the first time. Cowpea TFL1 homolog was amplified using primers designed based on conserved sequences in related genera and sequence variation was analysed in three gamma ray-induced determinate mutants, their indeterminate parent "EC394763" and two indeterminate varieties. The analyses of sequence variation exposed a novel SNP distinguishing the determinate mutants from the indeterminate types. The non-synonymous point mutation in exon 4 at position 1,176 resulted from transversion of cytosine (C) to adenine (A) leading to an amino acid change (Pro-136 to His) in determinate mutants. The effect of the mutation on protein function and stability was predicted to be detrimental using different bioinformatics/computational tools. The functionally significant novel substitution mutation is hypothesized to affect determinacy in the cowpea mutants. Development of suitable regeneration protocols in this hitherto recalcitrant crop and subsequent complementation assay in mutants or over-expressing assay in parents could decisively conclude the role of the SNP in regulating determinacy in these cowpea mutants. PMID:25146839

  4. Mutations in the su(s) gene affect RNA processing in Drosophila melanogaster.

    PubMed Central

    Geyer, P K; Chien, A J; Corces, V G; Green, M M

    1991-01-01

    We have studied the effect of mutations in the suppressor of sable [su(s)] gene on P element-induced yellow alleles. Two independent mutations tested, y76d28 and y1#7, contain a 1.1-kilobase (kb) P element inserted in the 5' transcribed untranslated portion of the yellow gene. Sequences responsible for the y1#7 mutation are inserted in the same transcriptional orientation as yellow and cannot be processed by splicing, and this mutation is not suppressed by su(s) mutations. P element sequences are located in a transcriptional orientation opposite to that of the yellow gene in y76d28; these sequences can be spliced from a composite P element-yellow mRNA, resulting in low accumulation of a functional 1.9-kb yellow transcript. The levels of both the putative precursor P element-yellow RNA and the 1.9-kb yellow transcript increase in y76d28 su(s) flies, suggesting that mutations in su(s) do not affect the efficiency of splicing of the P element sequences. Analysis of y76d28 cDNAs isolated from flies carrying a wild-type or mutant su(s) gene demonstrates that the choice of splice junctions to process P element sequences is unchanged in these different backgrounds, suggesting that mutations in su(s) do not affect the selection of donor and acceptor splice sites. We propose that the su(s) protein functions to control the stability of unprocessed RNA during the splicing reaction. Images PMID:1714588

  5. Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria.

    PubMed

    Dhayat, Nasser; Simonin, Alexandre; Anderegg, Manuel; Pathare, Ganesh; Lüscher, Benjamin P; Deisl, Christine; Albano, Giuseppe; Mordasini, David; Hediger, Matthias A; Surbek, Daniel V; Vogt, Bruno; Sass, Jörn Oliver; Kloeckener-Gruissem, Barbara; Fuster, Daniel G

    2016-05-01

    A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome. PMID:26376857

  6. Water Collective Dynamics in Whole Photosynthetic Green Algae as Affected by Protein Single Mutation.

    PubMed

    Russo, Daniela; Rea, Giuseppina; Lambreva, Maya D; Haertlein, Michael; Moulin, Martine; De Francesco, Alessio; Campi, Gaetano

    2016-07-01

    In the context of the importance of water molecules for protein function/dynamics relationship, the role of water collective dynamics in Chlamydomonas green algae carrying both native and mutated photosynthetic proteins has been investigated by neutron Brillouin scattering spectroscopy. Results show that single point genetic mutation may notably affect collective density fluctuations in hydrating water providing important insight on the transmission of information possibly correlated to biological functionality. In particular, we highlight that the damping factor of the excitations is larger in the native compared to the mutant algae as a signature of a different plasticity and structure of the hydrogen bond network. PMID:27300078

  7. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy

    PubMed Central

    Nakamura, Akinori

    2015-01-01

    X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD) gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD) and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment. PMID:26066469

  8. Mitochondrial ND5 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy in a Chinese pedigree.

    PubMed

    Liu, Zhong; Song, Yanrui; Gu, Shulian; He, Xiangyu; Zhu, Xiaoyu; Shen, Yaoyao; Wu, Bifeng; Wang, Wei; Li, Shishi; Jiang, Pingping; Lu, Jianhua; Huang, Wendong; Yan, Qingfeng

    2012-09-15

    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 79 years 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. PMID:22759514

  9. A novel SMARCAL1 missense mutation that affects splicing in a severely affected Schimke immunoosseous dysplasia patient.

    PubMed

    Barraza-García, Jimena; Rivera-Pedroza, Carlos I; Belinchón, Alberta; Fernández-Camblor, Carlota; Valenciano-Fuente, Blanca; Lapunzina, Pablo; Heath, Karen E

    2016-08-01

    Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disease characterized by skeletal dysplasia, focal segmental glomerulosclerosis, renal failure and immunodeficiency. In this work, we report the molecular studies undertaken in a severely affected SIOD patient that died at six years old due to nephropathy. The patient was screened for mutations using a targeted skeletal dysplasias panel. A homozygous novel missense mutation was identified, c.1615C > G (p.[Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 cells. Thus, the splicing alteration, c.1615C > G; r.1615c > g, 1615_1644del; (p.[Leu539_Ile548del]), results in the loss of 10 amino acids of the HARP-ATPase catalytic domain and the RPA-binding domain. Several studies have demonstrated a weak genotype-phenotype correlation among such patients. Thus, the molecular characterization has helped us to understand why a predicted weakly pathogenic missense mutation results in severe SIOD and should be considered in similar scenarios. PMID:27282802

  10. Progranulin Mutations Affects Brain Oscillatory Activity in Fronto-Temporal Dementia

    PubMed Central

    Moretti, Davide V.; Benussi, Luisa; Fostinelli, Silvia; Ciani, Miriam; Binetti, Giuliano; Ghidoni, Roberta

    2016-01-01

    Background: Mild cognitive impairment (MCI) is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto-temporal dementia (FTD). Progranulin (PGRN) has been recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD) due to GRN null mutations. Electroencephalography (EEG) is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD) as well as differences between GRN mutation carriers versus non-carriers in patients with overt FTD. Materials and Methods: EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE). Results: MCI-FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers. Conclusion: EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations. PMID:26973510

  11. Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency

    PubMed Central

    Toderici, Mara; de la Morena-Barrio, María Eugenia; Padilla, José; Miñano, Antonia; Antón, Ana Isabel; Iniesta, Juan Antonio; Herranz, María Teresa; Fernández, Nuria; Vicente, Vicente; Corral, Javier

    2016-01-01

    Antithrombin is a crucial anticoagulant serpin whose even moderate deficiency significantly increases the risk of thrombosis. Most cases with antithrombin deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with antithrombin deficiency but without known genetic defects. Three cases with moderate antithrombin deficiency (63–78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in antithrombin deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments. PMID:27003919

  12. Mutations in the putative calcium-binding domain of polyomavirus VP1 affect capsid assembly

    NASA Technical Reports Server (NTRS)

    Haynes, J. I. 2nd; Chang, D.; Consigli, R. A.; Spooner, B. S. (Principal Investigator)

    1993-01-01

    Calcium ions appear to play a major role in maintaining the structural integrity of the polyomavirus and are likely involved in the processes of viral uncoating and assembly. Previous studies demonstrated that a VP1 fragment extending from Pro-232 to Asp-364 has calcium-binding capabilities. This fragment contains an amino acid stretch from Asp-266 to Glu-277 which is quite similar in sequence to the amino acids that make up the calcium-binding EF hand structures found in many proteins. To assess the contribution of this domain to polyomavirus structural integrity, the effects of mutations in this region were examined by transfecting mutated viral DNA into susceptible cells. Immunofluorescence studies indicated that although viral protein synthesis occurred normally, infective viral progeny were not produced in cells transfected with polyomavirus genomes encoding either a VP1 molecule lacking amino acids Thr-262 through Gly-276 or a VP1 molecule containing a mutation of Asp-266 to Ala. VP1 molecules containing the deletion mutation were unable to bind 45Ca in an in vitro assay. Upon expression in Escherichia coli and purification by immunoaffinity chromatography, wild-type VP1 was isolated as pentameric, capsomere-like structures which could be induced to form capsid-like structures upon addition of CaCl2, consistent with previous studies. However, although VP1 containing the point mutation was isolated as pentamers which were indistinguishable from wild-type VP1 pentamers, addition of CaCl2 did not result in their assembly into capsid-like structures. Immunogold labeling and electron microscopy studies of transfected mammalian cells provided in vivo evidence that a mutation in this region affects the process of viral assembly.

  13. Thoracic Aortic Aneurysm (TAAD)-causing Mutation in Actin Affects Formin Regulation of Polymerization*

    PubMed Central

    Malloy, Lindsey E.; Wen, Kuo-Kuang; Pierick, Alyson R.; Wedemeyer, Elesa W.; Bergeron, Sarah E.; Vanderpool, Nicole D.; McKane, Melissa; Rubenstein, Peter A.; Bartlett, Heather L.

    2012-01-01

    More than 30 mutations in ACTA2, which encodes α-smooth muscle actin, have been identified to cause autosomal dominant thoracic aortic aneurysm and dissection. The mutation R256H is of particular interest because it also causes patent ductus arteriosus and moyamoya disease. R256H is one of the more prevalent mutations and, based on its molecular location near the strand-strand interface in the actin filament, may affect F-actin stability. To understand the molecular ramifications of the R256H mutation, we generated Saccharomyces cerevisiae yeast cells expressing only R256H yeast actin as a model system. These cells displayed abnormal cytoskeletal morphology and increased sensitivity to latrunculin A. After cable disassembly induced by transient exposure to latrunculin A, mutant cells were delayed in reestablishing the actin cytoskeleton. In vitro, mutant actin exhibited a higher than normal critical concentration and a delayed nucleation. Consequently, we investigated regulation of mutant actin by formin, a potent facilitator of nucleation and a protein needed for normal vascular smooth muscle cell development. Mutant actin polymerization was inhibited by the FH1-FH2 fragment of the yeast formin, Bni1. This fragment strongly capped the filament rather than facilitating polymerization. Interestingly, phalloidin or the presence of wild type actin reversed the strong capping behavior of Bni1. Together, the data suggest that the R256H actin mutation alters filament conformation resulting in filament instability and misregulation by formin. These biochemical effects may contribute to abnormal histology identified in diseased arterial samples from affected patients. PMID:22753406

  14. Thoracic aortic aneurysm (TAAD)-causing mutation in actin affects formin regulation of polymerization.

    PubMed

    Malloy, Lindsey E; Wen, Kuo-Kuang; Pierick, Alyson R; Wedemeyer, Elesa W; Bergeron, Sarah E; Vanderpool, Nicole D; McKane, Melissa; Rubenstein, Peter A; Bartlett, Heather L

    2012-08-17

    More than 30 mutations in ACTA2, which encodes α-smooth muscle actin, have been identified to cause autosomal dominant thoracic aortic aneurysm and dissection. The mutation R256H is of particular interest because it also causes patent ductus arteriosus and moyamoya disease. R256H is one of the more prevalent mutations and, based on its molecular location near the strand-strand interface in the actin filament, may affect F-actin stability. To understand the molecular ramifications of the R256H mutation, we generated Saccharomyces cerevisiae yeast cells expressing only R256H yeast actin as a model system. These cells displayed abnormal cytoskeletal morphology and increased sensitivity to latrunculin A. After cable disassembly induced by transient exposure to latrunculin A, mutant cells were delayed in reestablishing the actin cytoskeleton. In vitro, mutant actin exhibited a higher than normal critical concentration and a delayed nucleation. Consequently, we investigated regulation of mutant actin by formin, a potent facilitator of nucleation and a protein needed for normal vascular smooth muscle cell development. Mutant actin polymerization was inhibited by the FH1-FH2 fragment of the yeast formin, Bni1. This fragment strongly capped the filament rather than facilitating polymerization. Interestingly, phalloidin or the presence of wild type actin reversed the strong capping behavior of Bni1. Together, the data suggest that the R256H actin mutation alters filament conformation resulting in filament instability and misregulation by formin. These biochemical effects may contribute to abnormal histology identified in diseased arterial samples from affected patients. PMID:22753406

  15. DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling.

    PubMed

    Richter-Dennerlein, Ricarda; Korwitz, Anne; Haag, Mathias; Tatsuta, Takashi; Dargazanli, Sascha; Baker, Michael; Decker, Thorsten; Lamkemeyer, Tobias; Rugarli, Elena I; Langer, Thomas

    2014-07-01

    Prohibitins form large protein and lipid scaffolds in the inner membrane of mitochondria that are required for mitochondrial morphogenesis, neuronal survival, and normal lifespan. Here, we have defined the interactome of PHB2 in mitochondria and identified DNAJC19, mutated in dilated cardiomyopathy with ataxia, as binding partner of PHB complexes. We observed impaired cell growth, defective cristae morphogenesis, and similar transcriptional responses in the absence of either DNAJC19 or PHB2. The loss of PHB/DNAJC19 complexes affects cardiolipin acylation and leads to the accumulation of cardiolipin species with altered acyl chains. Similar defects occur in cells lacking the transacylase tafazzin, which is mutated in Barth syndrome. Our experiments suggest that PHB/DNAJC19 membrane domains regulate cardiolipin remodeling by tafazzin and explain similar clinical symptoms in two inherited cardiomyopathies by an impaired cardiolipin metabolism in mitochondrial membranes. PMID:24856930

  16. Mendelian and non-mendelian mutations affecting surface antigen expression in Paramecium tetraurelia

    SciTech Connect

    Epstein, L.M.; Forney, J.D.

    1984-08-01

    A screening procedure was devised for the isolation of X-ray-induced mutations affecting the expression of the A immobilization antigen (i-antigen) in Paramecium tetraurelia. Two of the mutations isolated by this procedure proved to be in modifier genes. The two genes are unlinked to each other and unlinked to the structural A i-antigen gene. These are the first modifier genes identified in a Paramecium sp. that affect surface antigen expression. Another mutation was found to be a deletion of sequences just downstream from the A i-antigen gene. In cells carrying this mutation, the A i-antigen gene lies in close proximity to the end of a macronuclear chromosome. The expression of the A i-antigen is not affected in these cells, demonstrating that downstream sequences are not important for the regulation and expression of the A i-antigen gene. A stable cell line was also recovered which shows non-Mendelian inheritance of a macronuclear deletion of the A i-antigen gene. This mutant does not contain the gene in its macronucleus, but contains a complete copy of the gene in its micronucleus. In the cytoplasm of wild-type animals, the micronuclear gene is included in the developing macronucleus; in the cytoplasm of the mutant, the incorporation of the A i-antigen gene into the macronucleus is inhibited. This is the first evidence that a mechanism is available in ciliates to control the expression of a gene by regulating its incorporation into developing macronuclei.

  17. Restrictive Cardiomyopathy

    MedlinePlus

    ... in a buildup of iron in the body. Sarcoidosis is the name of an inflammatory disease that ... and form larger lumps that attack other organs. Sarcoidosis often affects your skin, eyes, or liver, but ...

  18. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

    PubMed

    Ware, James S; Li, Jian; Mazaika, Erica; Yasso, Christopher M; DeSouza, Tiffany; Cappola, Thomas P; Tsai, Emily J; Hilfiker-Kleiner, Denise; Kamiya, Chizuko A; Mazzarotto, Francesco; Cook, Stuart A; Halder, Indrani; Prasad, Sanjay K; Pisarcik, Jessica; Hanley-Yanez, Karen; Alharethi, Rami; Damp, Julie; Hsich, Eileen; Elkayam, Uri; Sheppard, Richard; Kealey, Angela; Alexis, Jeffrey; Ramani, Gautam; Safirstein, Jordan; Boehmer, John; Pauly, Daniel F; Wittstein, Ilan S; Thohan, Vinay; Zucker, Mark J; Liu, Peter; Gorcsan, John; McNamara, Dennis M; Seidman, Christine E; Seidman, Jonathan G; Arany, Zoltan

    2016-01-21

    Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder. PMID:26735901

  19. Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing

    SciTech Connect

    Wong, A.; Boutis, P.; Hekimi, S.

    1995-03-01

    We have identified three allelic, maternal-effect mutations that affect developmental and behavioral timing in Caenorhabditis elegans. They result in a mean lengthening of embryonic and postembryonic development, the cell cycle period and life span, as well as the periods of the defecation, swimming and pumping cycles. These mutants also display a number of additional phenotypes related to timing. For example, the variability in the length of embryonic development is several times larger in the mutants than in the wild type, resulting in the occasional production of mutant embryos developing more rapidly than the most rapidly developing wild-type embryos. In addition, the duration of embryonic development of the mutants, but not of the wild type, depends on the temperature at which their parents were raised. Finally, individual variations in the severity of distinct mutant phenotypes are correlated in a counterintuitive way. For example, the animals with the shortest embryonic development have the longest defecation cycle and those with the longest embryonic development have the shortest defecation cycle. Most of the features affected by these mutations are believed to be controlled by biological clocks, and we therefore call the gene defined by these mutations clk-1, for {open_quotes}abnormal function of biological clocks.{close_quotes} 52 refs., 5 figs., 4 tabs.

  20. Pathogenesis of Arrhythmogenic Cardiomyopathy.

    PubMed

    Asimaki, Angeliki; Kleber, Andre G; Saffitz, Jeffrey E

    2015-11-01

    Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease. It is characterized by frequent ventricular arrhythmias and increased risk of sudden cardiac death typically arising as an early manifestation before the onset of significant myocardial remodelling. Myocardial degeneration, often confined to the right ventricular free wall, with replacement by fibrofatty scar tissue, develops in many patients. ACM is a familial disease but genetic penetrance can be low and disease expression is highly variable. Inflammation might promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbour mutations in genes that encode desmosomal proteins, which has raised the possibility that defective cell-cell adhesion might play a role in disease pathogenesis. Recent advances have implicated changes in the canonical wingless-type mouse mammary tumour virus integration site (Wnt)/β-catenin and Hippo signalling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. In this review we summarize the current understanding of the pathogenesis of ACM and highlight future research directions. PMID:26199027

  1. AAV9-mediated gene transfer of desmin ameliorates cardiomyopathy in desmin-deficient mice.

    PubMed

    Heckmann, M B; Bauer, R; Jungmann, A; Winter, L; Rapti, K; Strucksberg, K-H; Clemen, C S; Li, Z; Schröder, R; Katus, H A; Müller, O J

    2016-08-01

    Mutations of the human desmin (DES) gene cause autosomal dominant and recessive myopathies affecting skeletal and cardiac muscle tissue. Desmin knockout mice (DES-KO), which develop progressive myopathy and cardiomyopathy, mirror rare human recessive desminopathies in which mutations on both DES alleles lead to a complete ablation of desmin protein expression. Here, we investigated whether an adeno-associated virus-mediated gene transfer of wild-type desmin cDNA (AAV-DES) attenuates cardiomyopathy in these mice. Our approach leads to a partial reconstitution of desmin protein expression and the de novo formation of the extrasarcomeric desmin-syncoilin network in cardiomyocytes of treated animals. This finding was accompanied by reduced fibrosis and heart weights and improved systolic left-ventricular function when compared with control vector-treated DES-KO mice. Since the re-expression of desmin protein in cardiomyocytes of DES-KO mice restores the extrasarcomeric desmin-syncoilin cytoskeleton, attenuates the degree of cardiac hypertrophy and fibrosis, and improves contractile function, AAV-mediated desmin gene transfer may be a novel and promising therapeutic approach for patients with cardiomyopathy due to the complete lack of desmin protein expression. PMID:27101257

  2. Primary Carnitine Deficiency and Cardiomyopathy

    PubMed Central

    Fu, Lijun; Huang, Meirong

    2013-01-01

    Carnitine is essential for the transfer of long-chain fatty acids from the cytosol into mitochondria for subsequent β-oxidation. A lack of carnitine results in impaired energy production from long-chain fatty acids, especially during periods of fasting or stress. Primary carnitine deficiency (PCD) is an autosomal recessive disorder of mitochondrial β-oxidation resulting from defective carnitine transport and is one of the rare treatable etiologies of metabolic cardiomyopathies. Patients affected with the disease may present with acute metabolic decompensation during infancy or with severe cardiomyopathy in childhood. Early recognition of the disease and treatment with L-carnitine may be life-saving. In this review article, the pathophysiology, clinical presentation, diagnosis, treatment and prognosis of PCD are discussed, with a focus on cardiac involvements. PMID:24385988

  3. Genetic mapping of hph2, a mutation affecting amino acid transport in the mouse.

    PubMed

    Symula, D J; Shedlovsky, A; Dove, W F

    1997-02-01

    We describe the genetic mapping of hyperphenylal-aninemia 2 (hph2), a recessive mutation in the mouse that causes deficient amino acid transport similar to Hartnup disorder, a human genetic amino acid transport disorder. The hph2 locus was mapped in three separate crosses to identify candidate genes for hph2 and a region of homology in the human genome where we propose the Hartnup Disorder gene might lie. The mutation maps to mouse Chromosome (Chr) 7 distal of the simple sequence length polymorphism (SSLP) marker D7Mit140 and does not recombine with D7Nds4, an SSLP marker in the fibroblast growth factor 3 (Fgf3) gene. Unexpectedly, the mutant chromosome affects recombination frequency in the D7Mit12 to D7Nds4 interval. PMID:9060407

  4. A Point Mutation within the Replicase Gene Differentially Affects Coronavirus Genome versus Minigenome Replication

    PubMed Central

    Galán, Carmen; Enjuanes, Luis; Almazán, Fernando

    2005-01-01

    During the construction of the transmissible gastroenteritis virus (TGEV) full-length cDNA clone, a point mutation at position 637 that was present in the defective minigenome DI-C was maintained as a genetic marker. Sequence analysis of the recovered viruses showed a reversion at this position to the original virus sequence. The effect of point mutations at nucleotide 637 was analyzed by reverse genetics using a TGEV full-length cDNA clone and cDNAs from TGEV-derived minigenomes. The replacement of nucleotide 637 of TGEV genome by a T, as in the DI-C sequence, or an A severely affected virus recovery from the cDNA, yielding mutant viruses with low titers and small plaques compared to those of the wild type. In contrast, T or A at position 637 was required for minigenome rescue in trans by the helper virus. No relationship between these observations and RNA secondary-structure predictions was found, indicating that mutations at nucleotide 637 most likely had an effect at the protein level. Nucleotide 637 occupies the second codon position at amino acid 108 of the pp1a polyprotein. This position is predicted to map in the N-terminal polyprotein papain-like proteinase (PLP-1) cleavage site at the p9/p87 junction. Replacement of G-637 by A, which causes a drastic amino acid change (Gly to Asp) at position 108, affected PLP-1-mediated cleavage in vitro. A correlation was found between predicted cleaving and noncleaving mutations and efficient virus rescue from cDNA and minigenome amplification, respectively. PMID:16306572

  5. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.

    PubMed

    Mills, Philippa B; Camuzeaux, Stephane S M; Footitt, Emma J; Mills, Kevin A; Gissen, Paul; Fisher, Laura; Das, Krishna B; Varadkar, Sophia M; Zuberi, Sameer; McWilliam, Robert; Stödberg, Tommy; Plecko, Barbara; Baumgartner, Matthias R; Maier, Oliver; Calvert, Sophie; Riney, Kate; Wolf, Nicole I; Livingston, John H; Bala, Pronab; Morel, Chantal F; Feillet, François; Raimondi, Francesco; Del Giudice, Ennio; Chong, W Kling; Pitt, Matthew; Clayton, Peter T

    2014-05-01

    The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or

  6. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome

    PubMed Central

    Mills, Philippa B.; Camuzeaux, Stephane S.M.; Footitt, Emma J.; Mills, Kevin A.; Gissen, Paul; Fisher, Laura; Das, Krishna B.; Varadkar, Sophia M.; Zuberi, Sameer; McWilliam, Robert; Stödberg, Tommy; Plecko, Barbara; Baumgartner, Matthias R.; Maier, Oliver; Calvert, Sophie; Riney, Kate; Wolf, Nicole I.; Livingston, John H.; Bala, Pronab; Morel, Chantal F.; Feillet, François; Raimondi, Francesco; Del Giudice, Ennio; Chong, W. Kling; Pitt, Matthew

    2014-01-01

    The first described patients with pyridox(am)ine 5’-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5’-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5’-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5’-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5’-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5’-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5’-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin

  7. Drastic Ca{sup 2+} sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy

    SciTech Connect

    Yumoto, Fumiaki; Lu, Q.-W.; Morimoto, Sachio . E-mail: morimoto@med.kyushu-u.ac.jp; Tanaka, Hiroyuki; Kono, Naoko; Nagata, Koji; Ojima, Takao; Takahashi-Yanaga, Fumi; Miwa, Yoshikazu; Sasaguri, Toshiyuki; Nishita, Kiyoyoshi; Tanokura, Masaru; Ohtsuki, Iwao

    2005-12-23

    Six missense mutations in human cardiac troponin I (cTnI) were recently found to cause restrictive cardiomyopathy (RCM). We have bacterially expressed and purified these human cTnI mutants and examined their functional and structural consequences. Inserting the human cTnI into skinned cardiac muscle fibers showed that these mutations had much greater Ca{sup 2+}-sensitizing effects on force generation than the cTnI mutations in hypertrophic cardiomyopathy (HCM). The mutation K178E in the second actin-tropomyosin (Tm) binding region showed a particularly potent Ca{sup 2+}-sensitizing effect among the six RCM-causing mutations. Circular dichroism and nuclear magnetic resonance spectroscopy revealed that this mutation does not extensively affect the structure of the whole cTnI molecule, but induces an unexpectedly subtle change in the structure of a region around the mutated residue. The results indicate that the K178E mutation has a localized effect on a structure that is critical to the regulatory function of the second actin-Tm binding region of cTnI. The present study also suggests that both HCM and RCM involving cTnI mutations share a common feature of increased Ca{sup 2+} sensitivity of cardiac myofilament, but more severe change in Ca{sup 2+} sensitivity is associated with the clinical phenotype of RCM.

  8. A predictive model for canine dilated cardiomyopathy-a meta-analysis of Doberman Pinscher data.

    PubMed

    Simpson, Siobhan; Edwards, Jennifer; Emes, Richard D; Cobb, Malcolm A; Mongan, Nigel P; Rutland, Catrin S

    2015-01-01

    Dilated cardiomyopathy is a prevalent and often fatal disease in humans and dogs. Indeed dilated cardiomyopathy is the third most common form of cardiac disease in humans, reported to affect approximately 36 individuals per 100,000 individuals. In dogs, dilated cardiomyopathy is the second most common cardiac disease and is most prevalent in the Irish Wolfhound, Doberman Pinscher and Newfoundland breeds. Dilated cardiomyopathy is characterised by ventricular chamber enlargement and systolic dysfunction which often leads to congestive heart failure. Although multiple human loci have been implicated in the pathogenesis of dilated cardiomyopathy, the identified variants are typically associated with rare monogenic forms of dilated cardiomyopathy. The potential for multigenic interactions contributing to human dilated cardiomyopathy remains poorly understood. Consistent with this, several known human dilated cardiomyopathy loci have been excluded as common causes of canine dilated cardiomyopathy, although canine dilated cardiomyopathy resembles the human disease functionally. This suggests additional genetic factors contribute to the dilated cardiomyopathy phenotype.This study represents a meta-analysis of available canine dilated cardiomyopathy genetic datasets with the goal of determining potential multigenic interactions relating the sex chromosome genotype (XX vs. XY) with known dilated cardiomyopathy associated loci on chromosome 5 and the PDK4 gene in the incidence and progression of dilated cardiomyopathy. The results show an interaction between known canine dilated cardiomyopathy loci and an unknown X-linked locus. Our study is the first to test a multigenic contribution to dilated cardiomyopathy and suggest a genetic basis for the known sex-disparity in dilated cardiomyopathy outcomes. PMID:25834770

  9. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23.

    PubMed Central

    Messina, D N; Speer, M C; Pericak-Vance, M A; McNally, E M

    1997-01-01

    Inherited cardiomyopathies may arise from mutations in genes that are normally expressed in both heart and skeletal muscle and therefore may be accompanied by skeletal muscle weakness. Phenotypically, patients with familial dilated cardiomyopathy (FDC) show enlargement of all four chambers of the heart and develop symptoms of congestive heart failure. Inherited cardiomyopathies may also be accompanied by cardiac conduction-system defects that affect the atrioventricular node, resulting in bradycardia. Several different chromosomal regions have been linked with the development of autosomal dominant FDC, but the gene defects in these disorders remain unknown. We now characterize an autosomal dominant disorder involving dilated cardiomyopathy, cardiac conduction-system disease, and adult-onset limb-girdle muscular dystrophy (FDC, conduction disease, and myopathy [FDC-CDM]). Genetic linkage was used to exclude regions of the genome known to be linked to dilated cardiomyopathy and muscular dystrophy phenotypes and to confirm genetic heterogeneity of these disorders. A genomewide scan identified a region on the long arm of chromosome 6 that is significantly associated with the presence of myopathy (D6S262; maximum LOD score [Z(max)] 4.99 at maximum recombination fraction [theta(max)] .00), identifying FDC-CDM as a genetically distinct disease. Haplotype analysis refined the interval containing the genetic defect, to a 3-cM interval between D6S1705 and D6S1656. This haplotype analysis excludes a number of striated muscle-expressed genes present in this region, including laminin alpha2, laminin alpha4, triadin, and phospholamban. Images Figure 2 PMID:9382102

  10. Identification of a mutation affecting an alanine-alpha-ketoisovalerate transaminase activity in Escherichia coli K-12.

    PubMed

    Falkinham, J O

    1979-10-01

    A mutation affecting alanine-alpha-ketoisovalerate transaminase activity has been shown to be cotransducible with ilv gene cluster. The transaminase deficiency results in conditional isoleucine auxotrophy in the presence of alanine. PMID:396446

  11. The effect of cardiomyopathy mutation (R97L) in mouse cardiac troponin T on the muscle length-mediated recruitment of crossbridges is modified divergently by α- and β-myosin heavy chain.

    PubMed

    Gollapudi, Sampath K; Chandra, Murali

    2016-07-01

    Hypertrophic cardiomyopathy mutations in cardiac troponin T (TnT) lead to sudden cardiac death. Augmented myofilament Ca(2+) sensitivity is a common feature in TnT mutants, but such observations fail to provide a rational explanation for severe cardiac phenotypes. To better understand the mutation-induced effect on the cardiac phenotype, it is imperative to determine the effects on dynamic contractile features such as the muscle length (ML)-mediated activation against α- and β-myosin heavy chain (MHC) isoforms. α- and β-MHC are not only differentially expressed in rodent and human hearts, but they also modify ML-mediated activation differently. Mouse analog of human TnTR94L (TnTR97L) or wild-type TnT was reconstituted into de-membranated muscle fibers from normal (α-MHC) and transgenic (β-MHC) mouse hearts. TnTR97L augmented myofilament Ca(2+) sensitivity by a similar amount in α- and β-MHC fibers. However, TnTR97L augmented the negative impact of strained crossbridges on other crossbridges (γ) by 22% in α-MHC fibers, but attenuated γ by 21% in β-MHC fibers. TnTR97L decreased the magnitude of ML-mediated recruitment of crossbridges (ER) by 37% in α-MHC fibers, but increased ER by 35% in β-MHC fibers. We provide a mechanistic basis for the TnTR97L-induced effects in α- and β-MHC fibers and discuss the relevance to human hearts. PMID:26792537

  12. SPL1-1, a Saccharomyces cerevisiae mutation affecting tRNA splicing.

    PubMed Central

    Kolman, C; Söll, D

    1993-01-01

    A genetic approach was used to isolate and characterize Saccharomyces cerevisiae genes affecting tRNA processing. Three mutants were isolated which were able to process and utilize splicing-deficient transcripts from inactivated Schizosaccharomyces pombe suppressor tRNA genes. Extragenic recovery of suppressibility was verified by the suppression of nonsense mutations in LEU2, HIS4, and ADE1. One mutant, SPL1-1, was chosen for detailed analysis on the basis of its increased synthesis of mature suppressor tRNA over wild-type cell levels as determined by Northern (RNA) analysis. This mutant exhibited strong suppression exclusively with the defective tRNA gene used in the mutant selection. Genetic analysis revealed that a single, dominant, haplo-lethal mutation was responsible for the suppression phenotype. The mutation mapped on chromosome III to an essential 1.5-kb open reading frame (L. S. Symington and T. D. Petes, Mol. Cell. Biol. 8:595-604, 1988), recently named NFS1 (S. G. Oliver et al., Nature [London] 357:38-46, 1992), located adjacent (centromere proximal) to LEU2. Images PMID:8444805

  13. Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding

    PubMed Central

    Canault, Matthias; Ghalloussi, Dorsaf; Grosdidier, Charlotte; Guinier, Marie; Perret, Claire; Chelghoum, Nadjim; Germain, Marine; Raslova, Hana; Peiretti, Franck; Morange, Pierre E.; Saut, Noemie; Pillois, Xavier; Nurden, Alan T.; Cambien, François; Pierres, Anne; van den Berg, Timo K.; Kuijpers, Taco W.; Tregouet, David-Alexandre

    2014-01-01

    The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation. Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI. The mutation impairs the platelet’s ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding. Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3. Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading. Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2. Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis. PMID:24958846

  14. Recombination affects accumulation of damaging and disease-associated mutations in human populations.

    PubMed

    Hussin, Julie G; Hodgkinson, Alan; Idaghdour, Youssef; Grenier, Jean-Christophe; Goulet, Jean-Philippe; Gbeha, Elias; Hip-Ki, Elodie; Awadalla, Philip

    2015-04-01

    Many decades of theory have demonstrated that, in non-recombining systems, slightly deleterious mutations accumulate non-reversibly, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion; however, it is not clear the extent to which damaging mutations accumulate along chromosomes with highly variable rates of crossing over. Using high-coverage sequencing data from over 1,400 individuals in the 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the distribution of putatively deleterious variants across the entire human genome. Exons in regions of low recombination are significantly enriched for deleterious and disease-associated variants, a signature varying in strength across worldwide human populations with different demographic histories. Regions with low recombination rates are enriched for highly conserved genes with essential cellular functions and show an excess of mutations with demonstrated effects on health, a phenomenon likely affecting disease susceptibility in humans. PMID:25685891

  15. Mutations Affecting the Trna-Splicing Endonuclease Activity of Saccharomyces Cerevisiae

    PubMed Central

    Winey, M.; Culbertson, M. R.

    1988-01-01

    Two unlinked mutations that alter the enzyme activity of tRNA-splicing endonuclease have been identified in yeast. The sen1-1 mutation, which maps on chromosome 12, causes temperature-sensitive growth, reduced in vitro endonuclease activity, and in vivo accumulation of unspliced pre-tRNAs. The sen2-1 mutation does not confer a detectable growth defect, but causes a temperature-dependent reduction of in vitro endonuclease activity. Pre-tRNAs do not accumulate in sen2-1 strains. The in vitro enzyme activities of sen1-1 and sen2-1 complement in extracts from a heterozygous diploid, but fail to complement in mixed extracts from separate sen1-1 and sen2-1 haploid strains. These results suggest a direct role for SEN gene products in the enzymatic removal of introns from tRNA that is distinct from the role of other products known to affect tRNA splicing. PMID:3284787

  16. Mutations in the white gene of Drosophila melanogaster affecting ABC transporters that determine eye colouration.

    PubMed

    Mackenzie, S M; Brooker, M R; Gill, T R; Cox, G B; Howells, A J; Ewart, G D

    1999-07-15

    The white, brown and scarlet genes of Drosophila melanogaster encode proteins which transport guanine or tryptophan (precursors of the red and brown eye colour pigments) and belong to the ABC transporter superfamily. Current models envisage that the white and brown gene products interact to form a guanine specific transporter, while white and scarlet gene products interact to form a tryptophan transporter. In this study, we report the nucleotide sequence of the coding regions of five white alleles isolated from flies with partially pigmented eyes. In all cases, single amino acid changes were identified, highlighting residues with roles in structure and/or function of the transporters. Mutations in w(cf) (G589E) and w(sat) (F590G) occur at the extracellular end of predicted transmembrane helix 5 and correlate with a major decrease in red pigments in the eyes, while brown pigments are near wild-type levels. Therefore, those residues have a more significant role in the guanine transporter than the tryptophan transporter. Mutations identified in w(crr) (H298N) and w(101) (G243S) affect amino acids which are highly conserved among the ABC transporter superfamily within the nucleotide binding domain. Both cause substantial and similar decreases of red and brown pigments indicating that both tryptophan and guanine transport are impaired. The mutation identified in w(Et87) alters an amino acid within an intracellular loop between transmembrane helices 2 and 3 of the predicted structure. Red and brown pigments are reduced to very low levels by this mutation indicating this loop region is important for the function of both guanine and tryptophan transporters. PMID:10407069

  17. Nutrition in Pediatric Cardiomyopathy

    PubMed Central

    Miller, Tracie L.; Neri, Daniela; Extein, Jason; Somarriba, Gabriel; Strickman-Stein, Nancy

    2007-01-01

    Pediatric cardiomyopathies are heterogeneous groups of serious disorders of the heart muscle and are responsible for significant morbidity and mortality among children who have the disease. While enormous improvements have been made in the treatment and survival of children with congenital heart disease, parallel strides have not been made in the outcomes for cardiomyopathies. Thus, ancillary therapies, such as nutrition and nutritional interventions, that may not cure but may potentially improve cardiac function and quality of life, are imperative to consider in children with all types of cardiomyopathy. Growth failure is one of the most significant clinical problems of children with cardiomyopathy with nearly one-third of children with this disorder manifesting some degree of growth failure during the course of their illness. Optimal intake of macronutrients can help improve cardiac function. In addition, several specific nutrients have been shown to correct myocardial abnormalities that often occur with cardiomyopathy and heart failure. In particular, antioxidants that can protect against free radical damage that often occurs in heart failure and nutrients that augment myocardial energy production are important therapies that have been explored more in adults with cardiomyopathy than in the pediatric population. Future research directions should pay particular attention to the effect of overall nutrition and specific nutritional therapies on clinical outcomes and quality of life in children with pediatric cardiomyopathy. PMID:18159216

  18. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm.

    PubMed

    Chetaille, Philippe; Preuss, Christoph; Burkhard, Silja; Côté, Jean-Marc; Houde, Christine; Castilloux, Julie; Piché, Jessica; Gosset, Natacha; Leclerc, Séverine; Wünnemann, Florian; Thibeault, Maryse; Gagnon, Carmen; Galli, Antonella; Tuck, Elizabeth; Hickson, Gilles R; El Amine, Nour; Boufaied, Ines; Lemyre, Emmanuelle; de Santa Barbara, Pascal; Faure, Sandrine; Jonzon, Anders; Cameron, Michel; Dietz, Harry C; Gallo-McFarlane, Elena; Benson, D Woodrow; Moreau, Claudia; Labuda, Damian; Zhan, Shing H; Shen, Yaoqing; Jomphe, Michèle; Jones, Steven J M; Bakkers, Jeroen; Andelfinger, Gregor

    2014-11-01

    The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-β signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm. PMID:25282101

  19. Cardiomyopathies in children

    PubMed Central

    2013-01-01

    Cardiomyopathy (CMP) is a heterogeneous disease caused by a functional abnormality of the cardiac muscle. CMP is of 2 major types, dilated and hypertrophic, and is further classified as either primary or secondary. Secondary CMP is caused by extrinsic factors, including infection, ischemia, hypertension, and metabolic disorders. Primary CMP is diagnosed when the extrinsic factors of secondary CMP are absent. Furthermore, the World Health Organization, American Heart Association, and European Cardiology Association have different systems for clinically classifying primary CMP. Primary CMP is rare and associated with a family history of the disease, implying that genetic factors might affect its incidence. In addition, the incidence of CMP varies widely according to patient ethnicity. Genetic testing plays an important role in the care of patients with CMP and their families because it confirms diagnosis, determines the appropriate care for the patient, and possibly affects patient prognosis. The diagnosis and genetic identification of CMP in patients' families allow the possibility to identify novel genes that may lead to new treatments. This review focuses on the epidemiology, pathophysiology, diagnosis, and treatment of CMP, with the aim of providing pediatricians with insights that may be helpful in the early identification and management of idiopathic CMP in children. PMID:23482511

  20. Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ1 and miR-29 pathways

    PubMed Central

    Zhang, Yang; Wang, Jing-Hao; Zhang, Yi-Yuan; Wang, Ying-Zhe; Wang, Jin; Zhao, Yue; Jin, Xue-Xin; Xue, Gen-Long; Li, Peng-Hui; Sun, Yi-Lin; Huang, Qi-He; Song, Xiao-Tong; Zhang, Zhi-Ren; Gao, Xu; Yang, Bao-Feng; Du, Zhi-Min; Pan, Zhen-Wei

    2016-01-01

    Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFβ1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFβ1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis. PMID:26972749

  1. Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene

    PubMed Central

    Moncayo-Arlandi, Javier; Allegue, Catarina; Iglesias, Anna; Mangas, Alipio; Brugada, Ramon

    2016-01-01

    Background Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations. Methods and Results Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment. Conclusions We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures. PMID:27391596

  2. Rapidly Progressing Chagas Cardiomyopathy.

    PubMed

    Hollowed, John; McCullough, Matthew; Sanchez, Daniel; Traina, Mahmoud; Hernandez, Salvador; Murillo, Efrain

    2016-04-01

    Chagas disease, caused by the parasiteTrypanosoma cruzi, can cause a potentially life-threatening cardiomyopathy in approximately 10-40% of afflicted individuals. The decline in cardiac function characteristically progresses over the course of many years. We report a case of Chagas disease in which the patient experienced an atypical rapid deterioration to severe cardiomyopathy over the course of 16 months. This case argues the need for increased routine surveillance for patients with confirmedT. cruziinfection, who are determined to be at high-risk for worsening cardiomyopathy. PMID:26856912

  3. Rare Mutations of CACNB2 Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function

    PubMed Central

    Breitenkamp, Alexandra F. S.; Matthes, Jan; Nass, Robert Daniel; Sinzig, Judith; Lehmkuhl, Gerd; Nürnberg, Peter; Herzig, Stefan

    2014-01-01

    Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism. PMID:24752249

  4. The transcriptional activities and cellular localization of the human estrogen receptor alpha are affected by the synonymous Ala87 mutation.

    PubMed

    Fernández-Calero, Tamara; Astrada, Soledad; Alberti, Alvaro; Horjales, Sofía; Arnal, Jean Francois; Rovira, Carlos; Bollati-Fogolín, Mariela; Flouriot, Gilles; Marin, Mónica

    2014-09-01

    Until recently, synonymous mutations (which do not change amino acids) have been much neglected. Some evidence suggests that this kind of mutations could affect mRNA secondary structure or stability, translation kinetics and protein structure. To explore deeper the role of synonymous mutations, we studied their consequence on the functional activity of the estrogen receptor alpha (ERα). The ERα is a ligand-inducible transcription factor that orchestrates pleiotropic cellular effects, at both genomic and non-genomic levels in response to estrogens. In this work we analyzed in transient transfection experiments, the activity of ERα carrying the synonymous mutation Ala87, a polymorphism involving about 5-10% of the population. In comparison to the wild type receptor, our results show that ERαA87 mutation reduces the transactivation efficiency of ERα on an ERE reporter gene while its expression level remains similar. This mutation enhances 4-OHT-induced transactivation of ERα on an AP1 reporter gene. Finally, the mutation affects the subcellular localization of ERα in a cell type specific manner. It enhances the cytoplasmic location of ERα without significant changes in non-genomic effects of E2. The functional alteration of the ERαA87 determined in this work highlights the relevance of synonymous mutations for biomedical and pharmacological points of view. PMID:24607813

  5. Mutations of the Drosophila Myosin Regulatory Light Chain Affect Courtship Song and Reduce Reproductive Success

    PubMed Central

    Chakravorty, Samya; Vu, Hien; Foelber, Veronica; Vigoreaux, Jim O.

    2014-01-01

    The Drosophila indirect flight muscles (IFM) rely on an enhanced stretch-activation response to generate high power output for flight. The IFM is neurally activated during the male courtship song, but its role, if any, in generating the small amplitude wing vibrations that produce the song is not known. Here, we examined the courtship song properties and mating behavior of three mutant strains of the myosin regulatory light chain (DMLC2) that are known to affect IFM contractile properties and impair flight: (i) Dmlc2Δ2–46 (Ext), an N-terminal extension truncation; (ii) Dmlc2S66A,S67A (Phos), a disruption of two MLC kinase phosphorylation sites; and (iii) Dmlc2Δ2–46;S66A,S67A (Dual), expressing both mutations. Our results show that the Dmlc2 gene is pleiotropic and that mutations that have a profound effect on flight mechanics (Phos and Dual) have minimal effects on courtship song. None of the mutations affect interpulse interval (IPI), a determinant of species-specific song, and intrapulse frequency (IPF) compared to Control (Dmlc2+ rescued null strain). However, abnormalities in the sine song (increased frequency) and the pulse song (increased cycles per pulse and pulse length) evident in Ext males are not apparent in Dual males suggesting that Ext and Phos interact differently in song and flight mechanics, given their known additive effect on the latter. All three mutant males produce a less vigorous pulse song and exhibit impaired mating behavior compared to Control males. As a result, females are less receptive to Ext, Phos, and Dual males when a Control male is present. These results open the possibility that DMLC2, and perhaps contractile protein genes in general, are partly under sexual selection. That mutations in DMLC2 manifest differently in song and flight suggest that this protein fulfills different roles in song and flight and that stretch activation plays a smaller role in song production than in flight. PMID:24587213

  6. How Is Cardiomyopathy Treated?

    MedlinePlus

    ... arrest Stopping the disease from getting worse Heart-Healthy Lifestyle Changes Your doctor may suggest lifestyle changes to manage a condition that’s causing your cardiomyopathy including: Heart-healthy eating Aiming for a healthy weight Managing stress ...

  7. Sex differences in cardiomyopathies.

    PubMed

    Meyer, Sven; van der Meer, Peter; van Tintelen, J Peter; van den Berg, Maarten P

    2014-03-01

    Cardiomyopathies are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes. According to the contemporary European Society of Cardiology classification, they are classified into hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), restrictive (RCM), and unclassified cardiomyopathies. Each class is aetiologically further categorized into inherited (familial) and non-inherited (non-familial) forms. There is substantial evidence that biological sex is a strong modulator of the clinical manifestation of these cardiomyopathies, and sex-specific characteristics are detectable in all classes. For the clinician, it is important to know the sex-specific aspects of clinical disease expression and the potential modes of inheritance or the hereditary influences underlying the development of cardiomyopathies, since these may aid in diagnosing such diseases in both sexes. PMID:24464619

  8. Clinical and structural impact of mutations affecting the residue Phe367 of FOXP3 in patients with IPEX syndrome.

    PubMed

    Colobran, Roger; Álvarez de la Campa, Elena; Soler-Palacín, Pere; Martín-Nalda, Andrea; Pujol-Borrell, Ricardo; de la Cruz, Xavier; Martínez-Gallo, Mónica

    2016-02-01

    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic autoimmune disease characterized by early-onset life-threatening multisystemic autoimmunity. This rare hereditary disorder is caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor, which plays a key role in the differentiation and function of CD4(+)CD25(+) natural regulatory T cells (Tregs), essential for the establishment and maintenance of natural tolerance. We identified a novel mutation in the FOXP3 gene affecting the Phe367 residue of the protein (F367V) in a family with three male siblings affected by IPEX. Two other mutations affecting the FOXP3 Phe367 residue (F367L and F367C) have been described previously. This unique situation of three mutations affecting the same residue in FOXP3 led us to study the molecular impact of these mutations on the structure of FOXP3 protein. Structure analysis showed that Phe367 is involved in a rich interaction network related to both monomer and dimer structure stabilization, and is crucial for FOXP3 regulatory activity. The relevance of this location is confirmed by the results of SIFT and PolyPhen-2 pathogenicity predictions for F367V mutation. In summary, as assessment of the pathogenicity of a novel mutation is crucial to achieve a proper molecular diagnosis, we analysed the impact of mutations affecting the Phe367 residue using a combined approach that provides a mechanistic view of their pathogenic effect. PMID:26748374

  9. Insights into the hereditability of canine cardiomyopathy.

    PubMed

    Meurs, K M

    1998-11-01

    There is evidence for a genetic etiology of dilated cardiomyopathy in at least two breeds, the Doberman pinscher and the Boxer dog. Significant effort toward determining a genetic etiology in these breeds will depend on careful characterization of the disease, determination of criteria for diagnosing asymptomatic affected individuals, determination of a pattern of inheritance, and, eventually, molecular evaluation of the specific gene. PMID:10098247

  10. Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells.

    PubMed

    Söllner, Christian; Rauch, Gerd-Jörg; Siemens, Jan; Geisler, Robert; Schuster, Stephan C; Müller, Ulrich; Nicolson, Teresa

    2004-04-29

    Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (cdh23). Mutations in Cdh23 also cause deafness and vestibular defects in mice and humans, and the protein is present in hair bundles. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputnik(tc317e) larvae. Moreover, tip links are absent in larvae carrying weak alleles of cdh23 that affect mechanotransduction but not hair bundle integrity. We conclude that Cdh23 is an essential tip link component required for hair-cell mechanotransduction. PMID:15057246