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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 Central

    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

    2015-01-01

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

  2. Genetic mutations and mechanisms in dilated cardiomyopathy.

    PubMed

    McNally, Elizabeth M; Golbus, Jessica R; Puckelwartz, Megan J

    2013-01-01

    Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are "private" or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.

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

    PubMed Central

    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.

    2016-01-01

    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

  4. 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.

  5. [Hereditary cardiomyopathies: a review. Mutation of structural proteins a common cause of hereditary cardiomyopathy].

    PubMed

    Sjöberg, Gunnar; Kostareva, Anna; Sejersen, Thomas

    Cardiomyopathy is a disorder of the cardiac muscle and can be either primary or secondary. The primary disorders have been classified by WHO into 4 groups based on structure and function; hypertrophic, dilated and restricted cardiomyopathies and arrythmogenic right ventricle dysplasia. During the last decade the familial nature of many of these cardiomyopathies has been elucidated and different genes have been found to be mutated and causative of disease. Certain patterns can be distinguished in the mutated genes, e.g. in general the genes causing hypertrophic cardiomyopathies code for proteins involved in the contractile apparatus, the sarcomere, and the genes causing dilated cardiomyopathy code for proteins that anchor the sarcomere to the cell membrane and extracellular matrix. This article reviews these recent genetic findings and discusses their potential clinical applicability.

  6. A Case of Novel Lamin A/C Mutation Manifesting as Atypical Progeroid Syndrome and Cardiomyopathy.

    PubMed

    Guo, Xiaoxiao; Ling, Chao; Liu, Yongtai; Zhang, Xue; Zhang, Shuyang

    2016-09-01

    Mutations in the gene LMNA cause a wide spectrum of diseases that selectively affect different tissues and organ systems. The clinical features of these disorders can overlap but be generally categorized into 2 groups: cardiomyopathy and neuromuscular disorders; premature aging and lipodystrophy disorders. It is significant for a single patient who harbours the 2 sets of diseases simultaneously. We present a female patient with a unique phenotype including rare atypical progeroid syndrome and dilated cardiomyopathy. Genetic mutation detection in the gene LMNA revealed a novel heterozygous de novo mutation p.Leu59Val located in the first exon of gene LMNA c.175C>CG.

  7. Cardiomyopathy

    MedlinePlus

    ... Valve Prolapse Myocardial Bridge Myocarditis Obstructive Sleep Apnea ... cardiomyopathy (HCM), ischemic cardiomyopathy, restrictive cardiomyopathy Cardiomyopathy means "disease of the heart muscle." ...

  8. Mutation in δ-Sg Gene in Familial Dilated Cardiomyopathy

    PubMed Central

    Asadi, Marzieh; Foo, Roger; Salehi, Ahmad Reza; Salehi, Rasoul; Samienasab, Mohammad Reza

    2017-01-01

    Background: Mutations in different genes including dystrophin-associated glycoprotein complex caused familial dilated cardiomyopathy which is a genetically heterogeneous disease. The δ-SG gene contains nine exons spanning a 433-kb region of genomic DNA. It encodes a 35-kDa, singlepass, and type II transmembrane glycoprotein. Materials and Methods: In this study for the first time in Iran we screened 6 patients of a large family that they had positive family history of MI or sudden death by next generation sequencing method. Results: By employing NGS method we found missense mutation (p.R97Q) of δ-SG gene in 2 of 6 patients. Conclusions: The missense mutation (p.R97Q) in familial DCM patients is reported for the first time in Iranian patients with cardiac disease. Although this mutation is already known in other populations in Iran, it is not reported before.

  9. 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

  10. Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy.

    PubMed

    Caleshu, Colleen; Sakhuja, Rahul; Nussbaum, Robert L; Schiller, Nelson B; Ursell, Philip C; Eng, Celeste; De Marco, Teresa; McGlothlin, Dana; Burchard, Esteban González; Rame, J Eduardo

    2011-09-01

    Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

  11. 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

  12. LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies

    PubMed Central

    2013-01-01

    Background LMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease. The goal of this study was to identify LMNA mutations, estimate their frequency among Polish dilated cardiomyopathy patients and characterize their effect both in vivo and in vitro. Methods Between January, 2008 and June, 2012 two patient populations were screened for the presence of LMNA mutations by direct sequencing: 66 dilated cardiomyopathy patients including 27 heart transplant recipients and 39 dilated cardiomyopathy patients with heart failure referred for heart transplantation evaluation, and 44 consecutive dilated cardiomyopathy patients, referred for a family evaluation and mutation screening. Results We detected nine non-synonymous mutations including three novel mutations: p.Ser431*, p.Val256Gly and p.Gly400Argfs*11 deletion. There were 25 carriers altogether in nine families. The carriers were mostly characterized by dilated cardiomyopathy and heart failure with conduction system disease and/or complex ventricular arrhythmia, although five were asymptomatic. Among the LMNA mutation carriers, six underwent heart transplantation, fourteen ICD implantation and eight had pacemaker. In addition, we obtained ultrastructural images of cardiomyocytes from the patient carrying p.Thr510Tyrfs*42. Furthermore, because the novel p.Val256Gly mutation was found in a sporadic case, we verified its pathogenicity by expressing the mutation in a cellular model. Conclusions In conclusion, in the two referral centre populations, the screening revealed five mutations among 66 heart transplant recipients or patients referred for heart transplantation (7.6%) and four mutations among 44 consecutive dilated cardiomyopathy patients referred for familial evaluation (9.1%). Dilated cardiomyopathy patients with LMNA mutations have poor prognosis, however considerable clinical variability is present among family members. PMID:23702046

  13. 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.

  14. 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 ...

  15. Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia.

    PubMed

    Reinstein, Eyal; Orvin, Katia; Tayeb-Fligelman, Einav; Stiebel-Kalish, Hadas; Tzur, Shay; Pimienta, Allen L; Bazak, Lily; Bengal, Tuvia; Cohen, Lior; Gaton, Dan D; Bormans, Concetta; Landau, Meytal; Kornowski, Ran; Shohat, Mordechai; Behar, Doron M

    2015-04-01

    We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β-catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.

  16. 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.

  17. Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy

    PubMed Central

    Kawana, Masataka; Sarkar, Saswata S.; Sutton, Shirley; Ruppel, Kathleen M.; Spudich, James A.

    2017-01-01

    Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hypercontractility, and therapies are aimed toward controlling the hyperactive physiology. Mutations in the β-cardiac myosin comprise ~40% of genetic mutations associated with HCM, and the converter domain of myosin is a hotspot for HCM-causing mutations; however, the underlying primary effects of these mutations on myosin’s biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human β-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations: R719W, R723G, and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15% faster for R719W and R723G myosins, whereas there is no change in velocity for G741R. Adenosine triphosphatase activities and the load-dependent velocity change profiles of all three mutant proteins are very similar to those of wild type. These results indicate that the net biomechanical properties of human β-cardiac myosin carrying these converter domain mutations are very similar to those of wild type or are even slightly hypocontractile, leading us to consider an alternative mechanism for the clinically observed hypercontractility. Future work includes how these mutations affect protein interactions within the sarcomere that increase the availability of myosin heads participating in force production. PMID:28246639

  18. Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy.

    PubMed

    Kawana, Masataka; Sarkar, Saswata S; Sutton, Shirley; Ruppel, Kathleen M; Spudich, James A

    2017-02-01

    Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hypercontractility, and therapies are aimed toward controlling the hyperactive physiology. Mutations in the β-cardiac myosin comprise ~40% of genetic mutations associated with HCM, and the converter domain of myosin is a hotspot for HCM-causing mutations; however, the underlying primary effects of these mutations on myosin's biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human β-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations: R719W, R723G, and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15% faster for R719W and R723G myosins, whereas there is no change in velocity for G741R. Adenosine triphosphatase activities and the load-dependent velocity change profiles of all three mutant proteins are very similar to those of wild type. These results indicate that the net biomechanical properties of human β-cardiac myosin carrying these converter domain mutations are very similar to those of wild type or are even slightly hypocontractile, leading us to consider an alternative mechanism for the clinically observed hypercontractility. Future work includes how these mutations affect protein interactions within the sarcomere that increase the availability of myosin heads participating in force production.

  19. Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy.

    PubMed

    Biagini, Elena; Olivotto, Iacopo; Iascone, Maria; Parodi, Maria I; Girolami, Francesca; Frisso, Giulia; Autore, Camillo; Limongelli, Giuseppe; Cecconi, Massimiliano; Maron, Barry J; Maron, Martin S; Rosmini, Stefania; Formisano, Francesco; Musumeci, Beatrice; Cecchi, Franco; Iacovoni, Attilio; Haas, Tammy S; Bacchi Reggiani, Maria L; Ferrazzi, Paolo; Salvatore, Francesco; Spirito, Paolo; Rapezzi, Claudio

    2014-09-01

    End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ≥60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ≤0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes.

  20. Ile90Met, a novel mutation in the cardiac troponin T gene for familial hypertrophic cardiomyopathy in a Chinese pedigree.

    PubMed

    Xu, Chao; Wei, Meng; Su, Bin; Hua, Xue-Wei; Zhang, Guo-Wei; Xue, Xiao-Pei; Pan, Cun-Ming; Liu, Rong; Sheng, Yan; Lu, Zhi-Gang; Jin, Li-Ren; Song, Huai-Dong

    2008-10-01

    To identify the disease-causing gene for a large multi-generational Chinese family affected by familial hypertrophic cardiomyopathy (FHCM), genome-wide screening was carried out in a Chinese family with FHCM using micro-satellite markers, and linkage analysis was performed using the MLINK program. The disease locus was mapped to 1q32 in this family. Screening for a mutation in the cardiac troponin T (cTnT) gene was performed by a PCR and sequencing was done with an ABI Prism 3700 sequencer. A novel C-->G transition located in the ninth exon of the cTnT gene, leading to a predicted amino acid residue change from Ile to Met at codon 90, was identified in all individuals with hypertrophic cardiomyopathy (HCM). The results presented here strongly suggest that Ile90Met, a novel mutation in the cTnT gene, is causative agent of HCM in this family.

  1. 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

  2. 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

    2016-02-26

    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.

  3. Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction

    PubMed Central

    Hastings, Robert; de Villiers, Carin P.; Hooper, Charlotte; Ormondroyd, Liz; Pagnamenta, Alistair; Lise, Stefano; Salatino, Silvia; Knight, Samantha J.L.; Taylor, Jenny C.; Thomson, Kate L.; Arnold, Linda; Chatziefthimiou, Spyros D.; Konarev, Petr V.; Wilmanns, Matthias; Ehler, Elisabeth; Ghisleni, Andrea; Gautel, Mathias; Blair, Edward; Watkins, Hugh

    2016-01-01

    Background— High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Methods and Results— Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterized in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small-angle x ray scattering, and circular dichroism spectroscopy suggest partial unfolding and domain destabilization in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin. Conclusions— Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left ventricular noncompaction. This expands the spectrum of titin’s roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. PMID:27625337

  4. Whole exome sequencing identifies a troponin T mutation hot spot in familial dilated cardiomyopathy.

    PubMed

    Campbell, Nzali; Sinagra, Gianfranco; Jones, Kenneth L; Slavov, Dobromir; Gowan, Katherine; Merlo, Marco; Carniel, Elisa; Fain, Pamela R; Aragona, Pierluigi; Di Lenarda, Andrea; Mestroni, Luisa; Taylor, Matthew R G

    2013-01-01

    Dilated cardiomyopathy (DCM) commonly causes heart failure and shows extensive genetic heterogeneity that may be amenable to newly developed next-generation DNA sequencing of the exome. In this study we report the successful use of exome sequencing to identify a pathogenic variant in the TNNT2 gene using segregation analysis in a large DCM family. Exome sequencing was performed on three distant relatives from a large family with a clear DCM phenotype. Missense, nonsense, and splice variants were analyzed for segregation among the three affected family members and confirmed in other relatives by direct sequencing. A c.517T C>T, Arg173Trp TNNT2 variant segregated with all affected family members and was also detected in one additional DCM family in our registry. The inclusion of segregation analysis using distant family members markedly improved the bioinformatics filtering process by removing from consideration variants that were not shared by all affected subjects. Haplotype analysis confirmed that the variant found in both DCM families was located on two distinct haplotypes, supporting the notion of independent mutational events in each family. In conclusion, an exome sequencing strategy that includes segregation analysis using distant affected relatives within a family represents a viable diagnostic strategy in a genetically heterogeneous disease like DCM.

  5. Whole Exome Sequencing Identifies a Troponin T Mutation Hot Spot in Familial Dilated Cardiomyopathy

    PubMed Central

    Campbell, Nzali; Sinagra, Gianfranco; Jones, Kenneth L.; Slavov, Dobromir; Gowan, Katherine; Merlo, Marco; Carniel, Elisa; Fain, Pamela R.; Aragona, Pierluigi; Di Lenarda, Andrea; Mestroni, Luisa; Taylor, Matthew R. G.

    2013-01-01

    Dilated cardiomyopathy (DCM) commonly causes heart failure and shows extensive genetic heterogeneity that may be amenable to newly developed next-generation DNA sequencing of the exome. In this study we report the successful use of exome sequencing to identify a pathogenic variant in the TNNT2 gene using segregation analysis in a large DCM family. Exome sequencing was performed on three distant relatives from a large family with a clear DCM phenotype. Missense, nonsense, and splice variants were analyzed for segregation among the three affected family members and confirmed in other relatives by direct sequencing. A c.517T C>T, Arg173Trp TNNT2 variant segregated with all affected family members and was also detected in one additional DCM family in our registry. The inclusion of segregation analysis using distant family members markedly improved the bioinformatics filtering process by removing from consideration variants that were not shared by all affected subjects. Haplotype analysis confirmed that the variant found in both DCM families was located on two distinct haplotypes, supporting the notion of independent mutational events in each family. In conclusion, an exome sequencing strategy that includes segregation analysis using distant affected relatives within a family represents a viable diagnostic strategy in a genetically heterogeneous disease like DCM. PMID:24205113

  6. Restrictive Cardiomyopathy Caused by Troponin Mutations: Application of Disease Animal Models in Translational Studies

    PubMed Central

    Liu, Xiaoyan; Zhang, Lei; Pacciulli, Daniel; Zhao, Jianquan; Nan, Changlong; Shen, Wen; Quan, Junjun; Tian, Jie; Huang, Xupei

    2016-01-01

    Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. Studies have shown that the deficiency of cTnI or mutations in cTnI (particularly in the C-terminus of cTnI) results in diastolic dysfunction (impaired relaxation) due to an increased myofibril sensitivity to calcium. The first clinical study revealing the association between restrictive cardiomyopathy (RCM) with cardiac troponin mutations was reported in 2003. In order to illustrate the mechanisms underlying the cTnI mutation caused cardiomyopathy, we have generated a cTnI gene knockout mouse model and transgenic mouse lines with the reported point mutations in cTnI C-terminus. In this paper, we summarize our studies using these animal models from our laboratory and the other in vitro studies using reconstituted filament and cultured cells. The potential mechanisms underlying diastolic dysfunction and heart failure caused by these cTnI C-terminal mutations are discussed as well. Furthermore, calcium desensitizing in correction of impaired relaxation in myocardial cells due to cTnI mutations is discussed. Finally, we describe a model of translational study, i.e., from bedside to bench and from bench to bedside. These studies may enrich our understanding of the mechanism underlying inherited cardiomyopathies and provide the clues to search for target-oriented medication aiming at the treatment of diastolic dysfunction and heart failure. PMID:28066262

  7. MicroRNA transcriptome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations.

    PubMed

    Kuster, Diederik W D; Mulders, Joyce; Ten Cate, Folkert J; Michels, Michelle; Dos Remedios, Cristobal G; da Costa Martins, Paula A; van der Velden, Jolanda; Oudejans, Cees B M

    2013-12-01

    Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in genes encoding sarcomeric proteins. One of the most frequent affected genes is MYBPC3, which encodes the thick filament protein cardiac myosin binding protein C. Despite the prevalence of HCM, disease pathology and clinical outcome of sarcomeric mutations are largely unknown. We hypothesized that microRNAs (miRNAs) could play a role in the disease process. To determine which miRNAs were changed in expression, miRNA arrays were performed on heart tissue from HCM patients with a MYBPC3 mutation (n=6) and compared with hearts of non-failing donors (n=6). 532 out of 664 analyzed miRNAs were expressed in at least one heart sample. 13 miRNAs were differentially expressed in HCM compared with donors (at p<0.01, fold change ≥ 2). The genomic context of these differentially expressed miRNAs revealed that miR-204 (fold change 2.4 in HCM vs. donor) was located in an intron of the TRPM3 gene, encoding an aspecific cation channel involved in calcium entry. RT-PCR analysis revealed a trend towards TRPM3 upregulation in HCM compared with donor myocardium (fold change 2.3, p=0.078). In silico identification of mRNA targets of differentially expressed miRNAs showed a large proportion of genes involved in cardiac hypertrophy and cardiac beta-adrenergic receptor signaling and we showed reduced phosphorylation of cardiac troponin I in the HCM myocardium when compared with donor. HCM patients with MYBPC3 mutations have a specific miRNA expression profile. Downstream mRNA targets reveal possible involvement in cardiac signaling pathways.

  8. TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy.

    PubMed

    Theis, Jeanne L; Zimmermann, Michael T; Larsen, Brandon T; Rybakova, Inna N; Long, Pamela A; Evans, Jared M; Middha, Sumit; de Andrade, Mariza; Moss, Richard L; Wieben, Eric D; Michels, Virginia V; Olson, Timothy M

    2014-11-01

    Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes, yet the molecular basis for these disorders remains idiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.

  9. 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.

  10. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity

    PubMed Central

    Ruggiero, Alessandra; Chen, Suet Nee; Lombardi, Raffaella; Rodriguez, Gabriela; Marian, Ali J.

    2013-01-01

    Aims The role of calcineurin protein phosphatase 2B (PP2B) in the pathogenesis of human hypertrophic cardiomyopathy (HCM) remains unsettled. We determined potential involvement of calcineurin in the pathogenesis of HCM caused by mutations in myozenin 2 (MYOZ2), an inhibitor of calcineurin. Methods and results We generated multiple lines of transgenic mice expressing either Flag-tagged wild-type (WT) (MYOZ2WT) or mutant MYOZ2S48P and MYOZ2I246M, identified in families with HCM, in the heart. To mimic the human genotype, we generated bigenic mice expressing WT and mutant MYOZ2 in the background of hemizygous endogenous MYOZ2 (Myoz2+/−). Transgene proteins constituted 15–48% of the total MYOZ2 protein in the heart. Mutant MYOZ2 mice showed molecular, cellular, and gross cardiac hypertrophy, preserved systolic function, and interstitial fibrosis. Immunofluorescence staining showed co-localization of WT and mutant MYOZ2 proteins with α-actinin at the Z disks. Electron microscopy showed disrupted and mal-aligned Z disks in the mutant mice. Cardiac calcineurin activity, determined by quantifying Rcan1.4 mRNA and protein levels, luciferase activity in triple transgenic Myoz2+/−:NFATc-Luc:MYOZ2I246M and Myoz2+/−:NFATc-Luc:MYOZ2WT mice, and NFATc transcriptional activity assay, was unchanged in the mutant transgenic mice. However, levels of phospho-ERK1/2 and JNK54/46 were altered in the transgenic mice. Likewise, lentiviral-mediated expression of the MYOZ2I246M did not affect RCAN1.4 and calcineurin (PPP3CB) protein levels. Conclusions Thus, the cardiac phenotype in HCM caused by MYOZ2 mutations might be independent of calcineurin activity in the heart. Z disk abnormalities might provide the stimulus for the induction of cardiac hypertrophy caused by MYOZ2 mutations. PMID:22987565

  11. Comprehensive analysis of desmosomal gene mutations in Han Chinese patients with arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    Zhou, Xiujuan; Chen, Minglong; Song, Hualian; Wang, Benqi; Chen, Hongwu; Wang, Jing; Wang, Wei; Feng, Shangpeng; Zhang, Fengxiang; Ju, Weizhu; Li, Mingfang; Gu, Kai; Cao, Kejiang; Wang, Dao W; Yang, Bing

    2015-04-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiomyopathy that primarily involves the right ventricle. Mutations in desmosomal genes have been associated with ARVC. But its prevalence and spectrum are much less defined in the Chinese population, especially Han Chinese, a majority ethnic group in China; also the genotype-phenotype correlation regarding left ventricular involvement is still poorly understood. The aim of this study was to elucidate the genotype in Han Chinese patients with ARVC and the phenotype regarding cardiac left ventricle involvement in mutation carriers of ARVC. 48 Han Chinese patients were recruited into the present study based on the Original International Task Force Criteria of ARVC. Clinical data were reassessed according to the modified criteria published in 2010. A total of 36 subjects were diagnosed with ARVC; 12 patients were diagnosed with suspected ARVC. Five desmosomal genes (PKP2, DSG2, DSP, DSC2 and JUP) were sequenced directly from genomic DNA. Among the 36 patients, 21 mutations, 12 of which novel, were discovered in 19 individuals (19 of 36, 53%). The distribution of the mutations was 25% in PKP2, 14% in DSP, 11% in DSG2, 6% in JUP, and 3% in DSC2. Multiple mutations were identified in 2 subjects (2 of 36, 6%); both had digenic heterozygosity. Eight mutations, of which six were novel, were located in highly conserved regions. Seven mutations introduced a stop codon prematurely, which would result in premature termination of the protein synthesis. Two-dimensional echocardiography showed that LDVd and LDVs parameters were significantly larger in nonsense mutation carriers than in carriers of other mutations. In this comprehensive desmosome genetic analysis, 21 mutations were identified in five desmosomal genes in a group of 48 local Han Chinese subjects with ARVC, 12 of which were novel. PKP2 mutations were the most common variants. Left ventricular involvement could be a sign that the patient is a carrier of a

  12. Sports in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy and desmosomal mutations.

    PubMed

    Sawant, A C; Calkins, H

    2015-05-01

    Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare cardiomyopathy associated with life-threatening arrhythmias and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, environmental factors such as exercise and sport have been implicated in the pathogenesis of the disease. Recent studies have shown that exercise may be associated with adverse outcomes in patients with ARVD/C. On the basis of current evidence, patients with ARVD/C are recommended to limit exercise irrespective of their mutation status. Some studies have suggested the presence of an entirely acquired form of the disease caused by exercise, which has been dubbed "exercise-induced ARVD/C."

  13. 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

  14. Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin.

    PubMed

    Adhikari, Arjun S; Kooiker, Kristina B; Sarkar, Saswata S; Liu, Chao; Bernstein, Daniel; Spudich, James A; Ruppel, Kathleen M

    2016-12-13

    Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the molecular biomechanics of human β-cardiac myosin. We observed significant increases (20%-90%) in actin gliding velocity, intrinsic force, and ATPase activity in comparison to wild-type myosin. Moreover, for H251N, we found significantly lower binding affinity between the S1 and S2 domains of myosin, suggesting that this mutation may further increase hyper-contractility by releasing active motors. Unlike previous HCM mutations studied at the molecular level using human β-cardiac myosin, early-onset HCM mutations lead to significantly larger changes in the fundamental biomechanical parameters and show clear hyper-contractility.

  15. Targeting Mitogen-Activated Protein Kinase Signaling in Mouse Models of Cardiomyopathy Caused by Lamin A/C Gene Mutations

    PubMed Central

    Muchir, Antoine; Worman, Howard J.

    2016-01-01

    The most frequently occurring mutations in the gene encoding nuclear lamin A and nuclear lamin C cause striated muscle diseases virtually always involving the heart. In this review, we describe the approaches and methods used to discover that cardiomyopathy-causing lamin A/C gene mutations increase MAP kinase signaling in the heart and that this plays a role in disease pathogenesis. We review different mouse models of cardiomyopathy caused by lamin A/C gene mutations and how transcriptomic analysis of one model identified increased cardiac activity of the ERK1/2, JNK, and p38α MAP kinases. We describe methods used to measure the activity of these MAP kinases in mouse hearts and then discuss preclinical treatment protocols using pharmacological inhibitors to demonstrate their role in pathogenesis. Several of these kinase inhibitors are in clinical development and could potentially be used to treat human subjects with cardiomyopathy caused by lamin A/C gene mutations. PMID:26795484

  16. 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

  17. Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation

    PubMed Central

    Hwang, Ji-won; Jang, Mi-Ae; Jang, Shin Yi; Seo, Soo Hyun; Seong, Moon-Woo; Park, Sung Sup; Ki, Chang-Seok

    2017-01-01

    Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies. PMID:28382084

  18. Co segregation of the m.1555A>G mutation in the MT-RNR1 gene and mutations in MT-ATP6 gene in a family with dilated mitochondrial cardiomyopathy and hearing loss: A whole mitochondrial genome screening.

    PubMed

    Alila-Fersi, Olfa; Chamkha, Imen; Majdoub, Imen; Gargouri, Lamia; Mkaouar-Rebai, Emna; Tabebi, Mouna; Tlili, Abdelaziz; Keskes, Leila; Mahfoudh, Abdelmajid; Fakhfakh, Faiza

    2017-02-26

    Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to dysfunction of the mitochondrial respiratory chain, which is responsible for the generation of most cellular energy. Because cardiac muscles are one of the high energy demanding tissues, mitochondrial cardiomyopathies is one of the most frequent mitochondria disorders. Mitochondrial cardiomyopathy has been associated with several point mutations of mtDNA in both genes encoded mitochondrial proteins and mitochondrial tRNA and rRNA. We reported here the first description of mutations in MT-ATP6 gene in two patients with clinical features of dilated mitochondrial cardiomyopathy. The mutational analysis of the whole mitochondrial DNA revealed the presence of m.1555A>G mutation in MT-RNR1 gene associated to the m.8527A>G (p.M>V) and the m.8392C>T (p.136P>S) variations in the mitochondrial MT-ATP6 gene in patient1 and his family members with variable phenotype including hearing impairment. The second patient with isolated mitochondrial cardiomyopathy presented the m.8605C>T (p.27P>S) mutation in the MT-ATP6 gene. The three mutations p.M1V, p.P27S and p.P136S detected in MT-ATP6 affected well conserved residues of the mitochondrial protein ATPase 6. In addition, the substitution of proline residue at position 27 and 136 effect hydrophobicity and structure flexibility conformation of the protein.

  19. 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.

  20. Evaluation of the flanking nucleotide sequences of sarcomeric hypertrophic cardiomyopathy substitution mutations.

    PubMed

    Meurs, Kathryn M; Mealey, Katrina L

    2008-07-03

    Hypertrophic cardiomyopathy (HCM) is a familial myocardial disease with a prevalence of 1 in 500. More than 400 causative mutations have been identified in 13 sarcomeric and myofilament related genes, 350 of these are substitution mutations within eight sarcomeric genes. Within a population, examples of recurring identical disease causing mutations that appear to have arisen independently have been noted as well as those that appear to have been inherited from a common ancestor. The large number of novel HCM mutations could suggest a mechanism of increased mutability within the sarcomeric genes. The objective of this study was to evaluate the most commonly reported HCM genes, beta myosin heavy chain (MYH7), myosin binding protein C, troponin I, troponin T, cardiac regulatory myosin light chain, cardiac essential myosin light chain, alpha tropomyosin and cardiac alpha-actin for sequence patterns surrounding the substitution mutations that may suggest a mechanism of increased mutability. The mutations as well as the 10 flanking nucleotides were evaluated for frequency of di-, tri- and tetranucleotides containing the mutation as well as for the presence of certain tri- and tetranculeotide motifs. The most common substitutions were guanine (G) to adenine (A) and cytosine (C) to thymidine (T). The CG dinucleotide had a significantly higher relative mutability than any other dinucleotide (p<0.05). The relative mutability of each possible trinucleotide and tetranucleotide sequence containing the mutation was calculated; none were at a statistically higher frequency than the others. The large number of G to A and C to T mutations as well as the relative mutability of CG may suggest that deamination of methylated CpG is an important mechanism for mutation development in at least some of these cardiac genes.

  1. Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin.

    PubMed

    Spudich, James A; Aksel, Tural; Bartholomew, Sadie R; Nag, Suman; Kawana, Masataka; Yu, Elizabeth Choe; Sarkar, Saswata S; Sung, Jongmin; Sommese, Ruth F; Sutton, Shirley; Cho, Carol; Adhikari, Arjun S; Taylor, Rebecca; Liu, Chao; Trivedi, Darshan; Ruppel, Kathleen M

    2016-01-01

    Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.

  2. Autosomal Recessive Dilated Cardiomyopathy due to DOLK Mutations Results from Abnormal Dystroglycan O-Mannosylation

    PubMed Central

    Morava, Eva; Riemersma, Moniek; Schuurs-Hoeijmakers, Janneke H. M.; Absmanner, Birgit; Verrijp, Kiek; van den Akker, Willem M. R.; Huijben, Karin; Steenbergen, Gerry; van Reeuwijk, Jeroen; Jozwiak, Adam; Zucker, Nili; Lorber, Avraham; Lammens, Martin; Knopf, Carlos; van Bokhoven, Hans; Grünewald, Stephanie; Lehle, Ludwig; Kapusta, Livia; Mandel, Hanna; Wevers, Ron A.

    2011-01-01

    Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5–13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations. PMID:22242004

  3. 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

  4. A Scandinavian case of skin fragility, alopecia and cardiomyopathy caused by DSP mutations.

    PubMed

    Vahlquist, A; Virtanen, M; Hellström-Pigg, M; Dragomir, A; Ryberg, K; Wilson, N J; Östman--Smith, I; Lu, L; McGrath, J A; Smith, F J D

    2014-01-01

    Congenital skin fragility is a heterogeneous disorder with epidermolysis bullosa and various skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause skin fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy.

  5. 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

  6. Function of a novel plakophilin-2 mutation in the abnormal expression of connexin43 in a patient with arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    Wang, Pei-Ning; Wu, Shu-Lin; Zhang, Bin; Lin, Qiu-Xiong; Shan, Zhi-Xin

    2015-03-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a desmosomal disease. Desmosomes and gap junctions are important structural components of cardiac intercalated discs. The proteins plakophilin-2 (PKP-2) and connexin43 (Cx43) are components of desmosomes and gap junctions, respectively. This study was conducted to determine whether Cx43 expression is affected by the mutation of the PKP-2 gene in patients with ARVC. A novel mutation was detected in a typical patient with ARVC. The mutated gene was transfected into rat mesenchymal stem cells expressing Cx43 through a pReversied-M-29 plasmid. Cx43 expression was detected using quantitative polymerase chain reaction analysis. Cx43 expression was significantly decreased in the mutant PKP-2 group compared with that in the wild-type PKP-2 group. In conclusion, PKP-2 affected Cx43 expression at the gene transcription level in the patient with ARVC.

  7. Perturbed Length–Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

    PubMed Central

    Sequeira, Vasco; Wijnker, Paul J.M.; Nijenkamp, Louise L.A.M.; Kuster, Diederik W.D.; Najafi, Aref; Witjas-Paalberends, E. Rosalie; Regan, Jessica A.; Boontje, Nicky; ten Cate, Folkert J.; Germans, Tjeerd; Carrier, Lucie; Sadayappan, Sakthivel; van Slegtenhorst, Marjon A.; Zaremba, Ruud; Foster, D. Brian; Murphy, Anne M.; Poggesi, Corrado; dos Remedios, Cris; Stienen, Ger J.M.; Ho, Carolyn Y.; Michels, Michelle; van der Velden, Jolanda

    2013-01-01

    Rationale High-myofilament Ca2+-sensitivity has been proposed as trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) based on in vitro and transgenic mice studies. However, myofilament Ca2+-sensitivity depends on protein phosphorylation and muscle length, and at present, data in human are scarce. Objective To investigate whether high-myofilament Ca2+-sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick- and thin-filament proteins. Methods and Results Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca2+-sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA)-targets compared with donors. After exogenous PKA treatment, myofilament Ca2+-sensitivity was either similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. Conclusions High-myofilament Ca2+-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein–protein interactions, and represents a

  8. Effects of troponin T cardiomyopathy mutations on the calcium sensitivity of the regulated thin filament and the actomyosin cross-bridge kinetics of human β-cardiac myosin.

    PubMed

    Sommese, Ruth F; Nag, Suman; Sutton, Shirley; Miller, Susan M; Spudich, James A; Ruppel, Kathleen M

    2013-01-01

    Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) lead to significant cardiovascular morbidity and mortality worldwide. Mutations in the genes encoding the sarcomere, the force-generating unit in the cardiomyocyte, cause familial forms of both HCM and DCM. This study examines two HCM-causing (I79N, E163K) and two DCM-causing (R141W, R173W) mutations in the troponin T subunit of the troponin complex using human β-cardiac myosin. Unlike earlier reports using various myosin constructs, we found that none of these mutations affect the maximal sliding velocities or maximal Ca(2+)-activated ADP release rates involving the thin filament human β-cardiac myosin complex. Changes in Ca(2+) sensitivity using the human myosin isoform do, however, mimic changes seen previously with non-human myosin isoforms. Transient kinetic measurements show that these mutations alter the kinetics of Ca(2+) induced conformational changes in the regulatory thin filament proteins. These changes in calcium sensitivity are independent of active, cycling human β-cardiac myosin.

  9. Effects of Troponin T Cardiomyopathy Mutations on the Calcium Sensitivity of the Regulated Thin Filament and the Actomyosin Cross-Bridge Kinetics of Human β-Cardiac Myosin

    PubMed Central

    Sutton, Shirley; Miller, Susan M.; Spudich, James A.; Ruppel, Kathleen M.

    2013-01-01

    Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) lead to significant cardiovascular morbidity and mortality worldwide. Mutations in the genes encoding the sarcomere, the force-generating unit in the cardiomyocyte, cause familial forms of both HCM and DCM. This study examines two HCM-causing (I79N, E163K) and two DCM-causing (R141W, R173W) mutations in the troponin T subunit of the troponin complex using human β-cardiac myosin. Unlike earlier reports using various myosin constructs, we found that none of these mutations affect the maximal sliding velocities or maximal Ca2+-activated ADP release rates involving the thin filament human β-cardiac myosin complex. Changes in Ca2+ sensitivity using the human myosin isoform do, however, mimic changes seen previously with non-human myosin isoforms. Transient kinetic measurements show that these mutations alter the kinetics of Ca2+ induced conformational changes in the regulatory thin filament proteins. These changes in calcium sensitivity are independent of active, cycling human β-cardiac myosin. PMID:24367593

  10. Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy

    PubMed Central

    Mouton, Jomien M; Kinnear, Craig J; Moolman-Smook, Johanna C; Herbst, Philip G; Pellizzon, Adriano S; Goosen, Althea; Brink, Paul A

    2015-01-01

    Summary Introduction The minimum criterion for the diagnosis of hypertrophic cardiomyopathy (HCM) is thickening of the left ventricular wall, typically in an asymmetrical or focal fashion, and it requires no functional deficit. Using this criterion, we identified a family with four affected individuals and a single unrelated individual essentially with restrictive cardiomyopathy (RCM). Mutations in genes coding for the thin filaments of cardiac muscle have been described in RCM and HCM with ‘restrictive features’. One such gene encodes for cardiac troponin I (TNNI3), a sub-unit of the troponin complex involved in the regulation of striated muscle contraction. We hypothesised that mutations in TNNI3 could underlie this particular phenotype, and we therefore screened TNNI3 for mutations in 115 HCM probands. Methods Clinical investigation involved examination, echocardiography, chest X-ray and an electrocardiogram of both the index cases and close relatives. The study cohort consisted of 113 South African HCM probands, with and without known founder HCM mutations, and 100 ethnically matched control individuals. Mutation screening of TNNI3 for disease-causing mutations were performed using high-resolution melt (HRM) analysis. Results HRM analyses identified three previously described HCM-causing mutations (p.Pro82Ser, p.Arg162Gln, p.Arg170Gln) and a novel exonic variant (p.Leu144His). A previous study involving the same amino acid identified a p.Leu144Gln mutation in a patient presenting with RCM, with clinical features of HCM. We observed the novel p.Leu144His mutation in three siblings with clinical RCM and varying degrees of ventricular hypertrophy. The isolated index case with the de novo p.Arg170Gln mutation presented with a similar phenotype. Both mutations were absent in a healthy control group. Conclusion We have identified a novel disease-causing p.Leu144His mutation and a de novo p.Arg170Gln mutation associated with RCM and focal ventricular hypertrophy

  11. Atrial natriuretic peptide affects cardiac remodeling, function, heart failure, and survival in a mouse model of dilated cardiomyopathy.

    PubMed

    Wang, Dong; Gladysheva, Inna P; Fan, Tai-Hwang M; Sullivan, Ryan; Houng, Aiilyan K; Reed, Guy L

    2014-03-01

    Dilated cardiomyopathy is a frequent cause of heart failure and death. Atrial natriuretic peptide (ANP) is a biomarker of dilated cardiomyopathy, but there is controversy whether ANP modulates the development of heart failure. Therefore, we examined whether ANP affects heart failure, cardiac remodeling, function, and survival in a well-characterized, transgenic model of dilated cardiomyopathy. Mice with dilated cardiomyopathy with normal ANP levels survived longer than mice with partial ANP (P<0.01) or full ANP deficiency (P<0.001). In dilated cardiomyopathy mice, ANP protected against the development of heart failure as indicated by reduced lung water, alveolar congestion, pleural effusions, etc. ANP improved systolic function and reduced cardiomegaly. Pathological cardiac remodeling was diminished in mice with normal ANP as indicated by decreased ventricular interstitial and perivascular fibrosis. Mice with dilated cardiomyopathy and normal ANP levels had better systolic function (P<0.001) than mice with dilated cardiomyopathy and ANP deficiency. Dilated cardiomyopathy was associated with diminished cardiac transcripts for NP receptors A and B in mice with normal ANP and ANP deficiency, but transcripts for NP receptor C and C-type natriuretic peptide were selectively altered in mice with dilated cardiomyopathy and ANP deficiency. Taken together, these data indicate that ANP has potent effects in experimental dilated cardiomyopathy that reduce the development of heart failure, prevent pathological remodeling, preserve systolic function, and reduce mortality. Despite the apparent overlap in physiological function between the NPs, these data suggest that the role of ANP in dilated cardiomyopathy and heart failure is not compensated physiologically by other NPs.

  12. Sporadic myopathy, myoclonus, leukoencephalopathy, neurosensory deafness, hypertrophic cardiomyopathy and insulin resistance associated with the mitochondrial 8306 T>C MTTK mutation.

    PubMed

    Cardaioli, Elena; Malfatti, Edoardo; Battisti, Carla; Da Pozzo, Paola; Rubegni, Anna; Gallus, Gian Nicola; Malandrini, Alessandro; Federico, Antonio

    2012-10-15

    We report a new T8306C transition in the D-stem of the MTTK gene of a 67-year-old man who manifested severe adult onset myopathy, myoclonus, leukoencephalopathy, neurosensory hypoacusis, hypertrophic cardiomyopathy and insulin resistance. No other family member was affected, suggesting that our patient was a sporadic case. The T8306C mutation was heteroplasmic in several tissues of the proband, while it was absent from his asymptomatic siblings. Single fibre analysis confirmed the segregation of higher mutational load in cytochrome c oxidase-deficient fibres. The mutation T8306C is predicted to disrupt a highly conserved base pair and was not found in more than 120 controls. This finding broadens the phenotypic and molecular spectrum of mitochondrial tRNA(Lys) associated disorders.

  13. 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.

  14. Clinical features, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy in South Africans

    PubMed Central

    Ntusi, Ntobeko AB; Shaboodien, Gasnat; Badri, Motasim; Mayosi, Bongani M; Badri, Motasim; Gumedze, Freedom

    2016-01-01

    Summary Background Little is known about the clinical characteristics, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy (HCM) in Africans. The objective of this study was to delineate the clinical and genetic features and outcome of HCM in African patients. Methods Information on clinical presentation, electrocardiographic and echocardiographic findings, and outcome of cases with HCM was collected from the Cardiac Clinic at Groote Schuur Hospital over a mean duration of follow up of 9.1 ± 3.4 years. Genomic DNA was screened for mutations in 15 genes that cause HCM, i.e. cardiac myosinbinding protein C (MYBPC3), cardiac β-myosin heavy chain (MYH7), cardiac troponin T2 (TNNT2), cardiac troponin I (TNNI3), regulatory light chain of myosin (MYL2), essential light chain of myosin (MYL3), tropomyosin 1 (TPM1), phospholamban (PLN), α-actin (ACTC1), cysteine and glycine-rich protein 3 (CSRP3), AMP-activated protein kinase (PRKAG2), α-galactosidase (GLA), four-and-a-half LIM domains 1 (FHL1), lamin A/C (LMNA) and lysosomeassociated membrane protein 2 (LAMP2). Survival and its predictors were analysed using the Kaplan–Meier and Cox proportional hazards regression methods, respectively. Results Forty-three consecutive patients [mean age 38.5 ± 14.3 years; 25 (58.1%) male; and 13 (30.2%) black African] were prospectively enrolled in the study from January 1996 to December 2012. Clinical presentation was similar to that reported in other studies. The South African founder mutations that cause HCM were not found in the 42 probands. Ten of 35 index cases (28.6%) tested for mutations in 15 genes had disease-causing mutations in MYH7 (six cases or 60%) and MYBPC3 (four cases or 40%). No disease-causing mutation was found in the other 13 genes screened. The annual mortality rate was 2.9% per annum and overall survival was 74% at 10 years, which was similar to the general South African population. Cox’s proportional hazards regression showed

  15. 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.

  16. 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

  17. Cell-Intrinsic Functional Effects of the α-Cardiac Myosin Arg-403-Gln Mutation in Familial Hypertrophic Cardiomyopathy

    PubMed Central

    Chuan, Peiying; Sivaramakrishnan, Sivaraj; Ashley, Euan A.; Spudich, James A.

    2012-01-01

    Human familial hypertrophic cardiomyopathy is the most common Mendelian cardiovascular disease worldwide. Among the most severe presentations of the disease are those in families heterozygous for the mutation R403Q in β-cardiac myosin. Mice heterozygous for this mutation in the α-cardiac myosin isoform display typical familial hypertrophic cardiomyopathy pathology. Here, we study cardiomyocytes from heterozygous 403/+ mice. The effects of the R403Q mutation on force-generating capabilities and dynamics of cardiomyocytes were investigated using a dual carbon nanofiber technique to measure single-cell parameters. We demonstrate the Frank-Starling effect at the single cardiomyocyte level by showing that cell stretch causes an increase in amplitude of contraction. Mutant 403/+ cardiomyocytes exhibit higher end-diastolic and end-systolic stiffness than +/+ cardiomyocytes, whereas active force generation capabilities remain unchanged. Additionally, 403/+ cardiomyocytes show slowed relaxation dynamics. These phenotypes are consistent with increased end-diastolic and end-systolic chamber elastance, as well as diastolic dysfunction seen at the level of the whole heart. Our results show that these functional effects of the R403Q mutation are cell-intrinsic, a property that may be a general phenomenon in familial hypertrophic cardiomyopathy. PMID:22735528

  18. 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.

  19. Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance.

    PubMed

    Seebohm, B; Matinmehr, F; Köhler, J; Francino, A; Navarro-Lopéz, F; Perrot, A; Ozcelik, C; McKenna, W J; Brenner, B; Kraft, T

    2009-08-05

    The ability of myosin to generate motile forces is based on elastic distortion of a structural element of the actomyosin complex (cross-bridge) that allows strain to develop before filament sliding. Addressing the question, which part of the actomyosin complex experiences main elastic distortion, we suggested previously that the converter domain might be the most compliant region of the myosin head domain. Here we test this proposal by studying functional effects of naturally occurring missense mutations in the beta-myosin heavy chain, 723Arg --> Gly (R723G) and 736Ile --> Thr (I736T), in comparison to 719Arg --> Trp (R719W). All three mutations are associated with hypertrophic cardiomyopathy and are located in the converter region of the myosin head domain. We determined several mechanical parameters of single skinned slow fibers isolated from Musculus soleus biopsies of hypertrophic cardiomyopathy patients and healthy controls. Major findings of this study for mutation R723G were i), a >40% increase in fiber stiffness in rigor with a 2.9-fold increase in stiffness per myosin head (S( *)(rigor R723G) = 0.84 pN/nm S( *)(rigor WT) = 0.29 pN/nm); and ii), a significant increase in force per head (F( *)(10 degrees C), 1.99 pN vs. 1.49 pN = 1.3-fold increase; F( *)(20 degrees C), 2.56 pN vs. 1.92 pN = 1.3-fold increase) as well as stiffness per head during isometric steady-state contraction (S( *)(active10 degrees C), 0.52 pN/nm vs. 0.28 pN/nm = 1.9-fold increase). Similar changes were found for mutation R719W (2.6-fold increase in S( *)(rigor); 1.8-fold increase in F( *)(10 degrees C), 1.6-fold in F( *)(20 degrees C); twofold increase in S( *)(active10 degrees C)). Changes in active cross-bridge cycling kinetics could not account for the increase in force and active stiffness. For the above estimates the previously determined fraction of mutated myosin in the biopsies was taken into account. Data for wild-type myosin of slow soleus muscle fibers support previous

  20. Diltiazem Treatment for Preclinical Hypertrophic Cardiomyopathy Mutation Carriers: A Pilot Randomized Trial to Modify Disease Expression

    PubMed Central

    Ho, Carolyn Y.; Lakdawala, Neal K.; Cirino, Allison L.; Lipshultz, Steven E.; Sparks, Elizabeth; Abbasi, Siddique A.; Kwong, Raymond Y.; Antman, Elliott M.; Semsarian, Christopher; González, Arantxa; López, Begoña; Diez, Javier; Orav, E. John; Colan, Steven D.; Seidman, Christine E.

    2014-01-01

    Background Hypertrophic cardiomyopathy (HCM) is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate alterations in intracellular calcium handling before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. Objectives To assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk HCM mutation carriers. Methods In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean age 15.8 years) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Results Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular end diastolic diameter improved towards normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. −0.5; P<0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group, but increased in controls (−0.02 vs. +0.15; P=0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, two in each treatment group. Conclusions Preclinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. PMID:25543971

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

    PubMed Central

    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.

    2016-01-01

    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

  2. Obtaining insurance after DNA diagnostics: a survey among hypertrophic cardiomyopathy mutation carriers.

    PubMed

    Christiaans, Imke; Kok, Tjitske M; van Langen, Irene M; Birnie, Erwin; Bonsel, Gouke J; Wilde, Arthur A M; Smets, Ellen M A

    2010-02-01

    Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with increased mortality. Disclosure of DNA test results may have social implications such as low access to insurance. In The Netherlands, insurance companies are restricted in the use of genetic information of their clients by the Medical Examination Act. A cross-sectional survey was used to assess the frequency and type of problems encountered by HCM mutation carriers applying for insurance, and associations with carriers' characteristics. The response rate was 86% (228/264). A total of 66 carriers (29%) applied for insurance of whom 39 reported problems (59%) during an average follow-up of 3 years since the DNA test result. More problems were encountered by carriers with manifest disease (P<0.001) and carriers with symptoms of HCM (P=0.049). Carriers identified after predictive DNA testing less frequently experienced problems (P=0.002). Three carriers without manifest HCM reported problems (5% of applicants). Frequently reported problems were higher premium (72%), grant access to medical records (62%), and complete rejection (33%). In conclusion, HCM mutation carriers frequently encounter problems when applying for insurances, often in the case of manifest disease, but the risk assessment of insurance companies is largely justified. Still, 5% of carriers encounter potentially unjustified problems, indicating the necessity to monitor the application of the existing laws and regulations by insurance companies and to educate counselees on the implications of these laws and regulations.

  3. 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

  4. Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a TRβ Mutation

    PubMed Central

    Wakasaki, Hisao; Matsumoto, Miyuki; Tamaki, Shinya; Miyata, Kaori; Yamamoto, Shohei; Minaga, Takamasa; Hayashi, Yoshitaka; Komukai, Kenichi; Imanishi, Toshio; Yamaoka, Hiroyuki; Matsuno, Shohei; Nishi, Masahiro; Akamizu, Takashi

    2016-01-01

    Resistance to thyroid hormone (RTH) is a genetic disorder characterized by reduced tissue responsiveness to thyroid hormone. We herein describe a 60-year old man who presented with the clinical features of cardiomyopathy, diabetes mellitus and elevated thyroid hormones with unsuppressed thyroid stimulating hormone. A genetic analysis of thyroid hormone receptor (TR) revealed a missense mutation (A268D) in the TRβ gene. Clinical manifestations of RTH may be variable due to different tissue distributions of TR subtypes and different actions of mutant receptors. The current case demonstrates that patients with a TRβ mutation may have impaired his glucose metabolism and a reduced cardiac function, although patients appear clinically euthyroid. PMID:27853072

  5. [Cardiomyopathies. I: classification of cardiomyopathies--dilated cardiomyopathy].

    PubMed

    Schultheiss, H P; Noutsias, M; Kühl, U; Lassner, D; Gross, U; Poller, W; Pauschinger, M

    2005-11-01

    Cardiomyopathies are common causes of heart failure and sudden cardiac death. According to the WHO classification, "specific" cardiomyopathies are differentiated from "idiopathic" cardiomyopathies. Thus, this classification is primarily based on pathophysiological characteristics. The diagnostic spectrum in cardiomyopathies comprises the entire spectrum of non-invasive and invasive cardiological examination techniques. The exact verification of certain cardiomyopathies necessitates additionally investigations. For example, immunohistological and molecular biological investigations of endomyocardial biopsies may confirm inflammatory cardiomyopathy, which is often induced by viruses. Several studies have shown that specific immunomodulatory treatment options can halt the progressive course of the disease. Several gene mutations have been identified in genetic/familial dilated cardiomyopathy. First-degree relatives should be screened for early stages. Primary prevention of sudden cardiac death shows increasing superiority of the implantable defibrillator compared with pharmacological approaches (i.e. amiodarone).

  6. Dilated cardiomyopathy

    MedlinePlus

    ... Exposure to heavy metals such as lead, arsenic, cobalt, or mercury This condition can affect anyone at ... 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 60. Read More Anemia Arrhythmias Cardiomyopathy Fainting Headache Heart ...

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

    PubMed Central

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

    2017-01-01

    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

  8. 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

    2016-04-02

    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

  9. Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy.

    PubMed

    Emperador, Sonia; Bayona-Bafaluy, M Pilar; Fernández-Marmiesse, Ana; Pineda, Mercedes; Felgueroso, Blanca; López-Gallardo, Ester; Artuch, Rafael; Roca, Iria; Ruiz-Pesini, Eduardo; Couce, María Luz; Montoya, Julio

    2016-01-01

    Oxidative phosphorylation dysfunction has been found in many different disorders. This biochemical pathway depends on mitochondrial protein synthesis. Thus, mutations in components of the mitochondrial translation system can be responsible for some of these pathologies. We identified a new homozygous missense mutation in the mitochondrial translation elongation factor Ts gene in a patient suffering from slowly progressive childhood ataxia and hypertrophic cardiomyopathy. Using cell, biochemical and molecular-genetic protocols, we confirm it as the etiologic factor of this phenotype. Moreover, as an important functional confirmation, we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts. Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors.

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

    PubMed

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

    2015-06-19

    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.

  11. 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

  12. Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

    PubMed Central

    2010-01-01

    Background MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients. Methods Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families. Results 16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9]. Conclusions Mutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM. PMID:20433692

  13. A novel mitochondrial DNA tRNAIle (m.4322dupC) mutation associated with idiopathic dilated cardiomyopathy.

    PubMed

    Mahjoub, Sinda; Sternberg, Damien; Boussaada, Rafik; Filaut, Sandrine; Gmira, Fathi; Mechmech, Rachid; Jardel, Claude; Arab, Saïda Ben

    2007-12-01

    We identified a novel heteroplasmic mitochondrial DNA (mtDNA) (m.4322dupC) mutation in tRNA gene associated with isolated dilated cardiomyopathy (DCM) as maternal trait. Mutation screening techniques and automated DNA sequencing were performed to identify mtDNA mutations and to assess heteroplasmy in family's proband and healthy control subjects. All family members tested had heteroplasmic mtDNA m.4322dupC mutation. We also screened 350 normal controls for this mutation and found no evidence of heteroplasmy. The m.4322dupC mutation was found in the skeletal tissue from the proband that exhibited slightly reduced deficiency of mitochondrial respiratory chain enzymes (complex III). The present study reports the novel m.4322dupC mutation in tRNA gene, which is possibly associated to the disease, to isolated DCM. It was localized in a hot-spot region for mutations and is possibly pathogenic because of a cosegregation with the matrilineal transmission of DCM.

  14. 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.

  15. HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy.

    PubMed

    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

    2015-08-28

    Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] 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 TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived 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 remodeling.

  16. Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

    PubMed

    Dausse, E; Komajda, M; Fetler, L; Dubourg, O; Dufour, C; Carrier, L; Wisnewsky, C; Bercovici, J; Hengstenberg, C; al-Mahdawi, S

    1993-12-01

    Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

  17. The Hypertrophic Cardiomyopathy Myosin Mutation R453C Alters ATP Binding and Hydrolysis of Human Cardiac β-Myosin*

    PubMed Central

    Bloemink, Marieke; Deacon, John; Langer, Stephen; Vera, Carlos; Combs, Ariana; Leinwand, Leslie; Geeves, Michael A.

    2014-01-01

    The human hypertrophic cardiomyopathy mutation R453C results in one of the more severe forms of the myopathy. Arg-453 is found in a conserved surface loop of the upper 50-kDa domain of the myosin motor domain and lies between the nucleotide binding pocket and the actin binding site. It connects to the cardiomyopathy loop via a long α-helix, helix O, and to Switch-2 via the fifth strand of the central β-sheet. The mutation is, therefore, in a position to perturb a wide range of myosin molecular activities. We report here the first detailed biochemical kinetic analysis of the motor domain of the human β-cardiac myosin carrying the R453C mutation. A recent report of the same mutation (Sommese, R. F., Sung, J., Nag, S., Sutton, S., Deacon, J. C., Choe, E., Leinwand, L. A., Ruppel, K., and Spudich, J. A. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 12607–12612) found reduced ATPase and in vitro motility but increased force production using an optical trap. Surprisingly, our results show that the mutation alters few biochemical kinetic parameters significantly. The exceptions are the rate constants for ATP binding to the motor domain (reduced by 35%) and the ATP hydrolysis step/recovery stroke (slowed 3-fold), which could be the rate-limiting step for the ATPase cycle. Effects of the mutation on the recovery stroke are consistent with a perturbation of Switch-2 closure, which is required for the recovery stroke and the subsequent ATP hydrolysis. PMID:24344137

  18. High resolution systematic digital histological quantification of cardiac fibrosis and adipose tissue in phospholamban p.Arg14del mutation associated cardiomyopathy.

    PubMed

    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.

  19. 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.

  20. Pregnancy, cardiomyopathies, and genetics.

    PubMed

    Van Tintelen, J Peter; Pieper, Petronella G; Van Spaendonck-Zwarts, Karin Y; Van Den Berg, Maarten P

    2014-03-15

    Although familial forms of cardiomyopathy such as hypertrophic or dilated cardiomyopathy have been recognized for decades, it is only recently that much of the genetic basis of these inherited cardiomyopathies has been elucidated. This has provided important insights into the pathophysiological mechanisms underlying the disease phenotype. This increased knowledge and the availability of genetic testing has resulted in increasing numbers of mutation carriers who are being monitored, including many who are now of child-bearing age. Pregnancy is generally well tolerated in asymptomatic patients or mutation carriers with inherited cardiomyopathies. However, since pregnancy leads to major physiological changes in the cardiovascular system, in women with genetic cardiomyopathies or who carry a mutation pre-disposing to a genetic cardiomyopathy, pregnancy entails a risk of developing heart failure and/or arrhythmias. This deterioration of cardiac function may occur despite optimal medical treatment. Advanced left ventricular dysfunction, poor functional class (NYHA class III or IV), or prior cardiac events appear to increase the risk of maternal cardiac complications. However, there are no large series of cardiomyopathy patients who are regularly evaluated for cardiac complications during pregnancy and for certain types of inherited cardiomyopathy, only case reports on individual pregnancies are available. Pre-conception cardiologic evaluation and genetic counselling are important for every woman with a cardiomyopathy or a cardiomyopathy-related mutation who is considering having a family. In this article, we give an overview of the basic clinical aspects, genetics, and pregnancy outcome in women with different types of inherited cardiomyopathies. We also discuss the genetic aspects of pregnancy-associated cardiomyopathy, including peripartum cardiomyopathy.

  1. Age-associated cardiomyopathy in heterozygous carrier mice of a pathological mutation of carnitine transporter gene, OCTN2.

    PubMed

    Xiaofei, E; Wada, Yasuhiko; Dakeishi, Miwako; Hirasawa, Fujiko; Murata, Katsuyuki; Masuda, Hirotake; Sugiyama, Toshihiro; Nikaido, Hiroko; Koizumi, Akio

    2002-07-01

    The purpose of this study was to test whether heterozygotes of juvenile visceral steatosis mice, a model for systemic carnitine deficiency, may develop age-associated cardiomyopathy. Tissue morphological observations were carried out by light and electron microscopy to compare the heterozygous and age-matched control mice at periods of 1 and 2 years. Possible effects of the pathological mutation on lipid and glucose levels was also evaluated in humans and mice. Except mild increases in serum cholesterol levels in male heterozygous mice and humans, no changes were found in other factors, indicating that none of the confounding factors seems to be profound. Results demonstrated that heterozygous mice had larger left ventriclular myocyte diameters than the control mice. Morphological changes in cardiac muscles by electron microscopy revealed age-associated changes of lipid deposition and abnormal mitochondria in heterozygous mice. Two out of 60 heterozygous cohort and one out of nine heterozygous trim-kill mice had cardiac hypertrophy at ages older than 2 years. The present study and our previous work suggest that the carrier state of OCTN2 pathological mutations might be a risk factor for age-associated cardiomyopathy.

  2. Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children.

    PubMed

    Mayr, Johannes A; Zimmermann, Franz A; Horváth, Rita; Schneider, Hans-Christian; Schoser, Benedikt; Holinski-Feder, Elke; Czermin, Birgit; Freisinger, Peter; Sperl, Wolfgang

    2011-11-01

    In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia. One child died in infancy, two survived a clinically severe neonatal period. At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development. In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased. This protein is expressed in two tissue-specific isoforms generated by mutually exclusive alternative splicing of the SLC25A3 gene transcript. We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele.

  3. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

    PubMed Central

    Abdulhag, Ulla Najwa; Soiferman, Devorah; Schueler-Furman, Ora; Miller, Chaya; Shaag, Avraham; Elpeleg, Orly; Edvardson, Simon; Saada, Ann

    2015-01-01

    Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted. PMID:24781756

  4. A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    Lopez-Ayala, J M; Ortiz-Genga, M; Gomez-Milanes, I; Lopez-Cuenca, D; Ruiz-Espejo, F; Sanchez-Munoz, J J; Oliva-Sandoval, M J; Monserrat, L; Gimeno, J R

    2015-08-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.

  5. Mutations affecting enzymatic activity in liver arginase

    SciTech Connect

    Vockley, J.G.; Tabor, D.E.; Goodman, B.K.

    1994-09-01

    The hydrolysis of arginine to ornithine and urea is catalyzed by arginase in the last step of the urea cycle. We examined a group of arginase deficient patients by PCR-SSCP analysis to characterize the molecular basis of this disorder. A heterogeneous population of nonsense mutations, microdeletions, and missense mutations has been identified in our cohort. Microdeletions which introduce premature stop codons downstream of the deletion and nonsense mutations result in no arginase activity. These mutations occur randomly along the gene. The majority of missense mutations identified appear to occur in regions of high cross-species homology. To test the effect of these missense mutations on arginase activity, site-directed mutagenesis was used to re-create the patient mutations for in vivo expression studies in a prokaryotic fusion-protein expression system. Of 4 different missense mutations identified in 6 individuals, only one was located outside of a conserved region. The three substitution mutations within the conserved regions had a significant effect on enzymatic activity (0-3.1 nmole/30min, normal is 1300-1400 nmoles/30min, as determined by in vitro arginase assay), while the fourth mutation, a T to S substitution, did not. In addition, site-directed mutagenesis was utilized to create mutations not in residues postulated to play a significant role in the enzymatic function or active site formation in manganese-binding proteins such as arginase. We have determined that the substitution of glycine for a histidine residue, located in a very highly conserved region of exon 3, and the substitution of a histidine and an aspartic acid residue within a similarly conserved region in exon 4, totally abolishes enzymatic activity. Mutations substituting glycine for an additional histidine and aspartic acid residue in exon 4 and two aspartic acid residues in exon 7 have also been created. We are currently in the process of characterizing these mutations.

  6. Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function

    PubMed Central

    Sommese, Ruth F.; Sung, Jongmin; Nag, Suman; Sutton, Shirley; Deacon, John C.; Choe, Elizabeth; Leinwand, Leslie A.; Ruppel, Kathleen; Spudich, James A.

    2013-01-01

    Cardiovascular disorders are the leading cause of morbidity and mortality in the developed world, and hypertrophic cardiomyopathy (HCM) is among the most frequently occurring inherited cardiac disorders. HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including β-cardiac myosin. Here, we present a biomechanical analysis of the HCM-causing mutation, R453C, in the context of human β-cardiac myosin. We found that this mutation causes a ∼30% decrease in the maximum ATPase of the human β-cardiac subfragment 1, the motor domain of myosin, and a similar percent decrease in the in vitro velocity. The major change in the R453C human β-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap. These results predict that the overall force of the ensemble of myosin molecules in the muscle should be higher in the R453C mutant compared with wild type. Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle. PMID:23798412

  7. Factors affecting the nature of induced mutations

    SciTech Connect

    Russell, L.B.; Russell, W.L.; Rinchik, E.M.; Hunsicker, P.R.

    1989-01-01

    The recent considerable expansion of specific-locus-mutation data has made possible an examination of the effects of germ-cell stage on both quantity of mutation yield and nature of mutations. For chemicals mutagenic in poststem-cell stages, three patterns have been identified according to the stages in which they elicit maximum response: (1) early spermatozoa and late spermatids; (2) early spermatids; and (3) differentiating spermatogonia. The majority of chemicals tested fall into Pattern 1. Chemicals that are also mutagenic in stem-cell spermatogonia do not preferentially belong to any one of these three categories. For only one chemical (CHL) has an entire set of mutations been analyzed molecularly. However, the results of genetic and molecular analyses of genomic regions surrounding six of the specific-locus markers allow us to conclude that any mutation that causes lethality of homozygotes (in the case of d, prenatal lethality, specifically) must involve one or more loci in addition to the marked one. Such mutations have been classified as large lesions'' (LL), the remainder as other lesions'' (OL). Analysis of the data shows that, regardless of the nature of the chemical (Pattern-1, -2, or -3), (1) LLs constitute a very low proportion of the mutations induced in either stem-cell or differentiating spermatogonia, and (b) LLs constitute a high proportion of mutations induced in postmeiotic stages. Chemicals that are active in both pre- and postmeiotic stages produce LL or OL mutations depending on cell stage.

  8. Peripartum cardiomyopathy presenting with syncope due to Torsades de pointes: a case of long QT syndrome with a novel KCNH2 mutation.

    PubMed

    Nishimoto, Orie; Matsuda, Morihiro; Nakamoto, Kei; Nishiyama, Hirohiko; Kuraoka, Kazuya; Taniyama, Kiyomi; Tamura, Ritsu; Shimizu, Wataru; Kawamoto, Toshiharu

    2012-01-01

    Peripartum cardiomyopathy (PPCM) is a cardiomyopathy of unknown cause that occurs in the peripartum period. We report a case of PPCM presenting with syncope 1 month after an uncomplicated delivery. Electrocardiography showed Torsades de pointes (TdP) and QT interval prolongation. Echocardiography showed left ventricular systolic dysfunction and endomyocardial biopsy showed myocyte degeneration and fibrosis. Administration of magnesium sulfate and temporary pacing eliminated recurrent TdP. Genetic analyses revealed that recurrent TdP occurred via electrolyte disturbance and cardiac failure due to PPCM on the basis of a novel mutation in KCNH2, a gene responsible for inherited type 2 long QT syndrome.

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

    PubMed Central

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

    2015-01-01

    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

  10. Myocardial contractile and metabolic properties of familial hypertrophic cardiomyopathy caused by cardiac troponin I gene mutations: a simulation study.

    PubMed

    Wu, Bo; Wang, Longhui; Liu, Qian; Luo, Qingming

    2012-01-01

    Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is caused by sarcomeric protein gene mutations. The mechanism by which these mutant proteins cause disease is uncertain. Experimentally, cardiac troponin I (CTnI) gene mutations mainly alter myocardial performance via increases in the Ca(2+) sensitivity of cardiac contractility. In this study, we used an integrated simulation that links electrophysiology, contractile activity and energy metabolism of the myocardium to investigate alterations in myocardial contractile function and energy metabolism regulation as a result of increased Ca(2+) sensitivity in CTnI mutations. Simulation results reproduced the following typical features of FHC: (1) slower relaxation (diastolic dysfunction) caused by prolonged [Ca(2+)](i) and force transients; (2) higher energy consumption with the increase in Ca(2+) sensitivity; and (3) reduced fatty acid oxidation and enhanced glucose utilization in hypertrophied heart metabolism. Furthermore, the simulation indicated that in conditions of high energy consumption (that is, more than an 18.3% increase in total energy consumption), the myocardial energetic metabolic network switched from a net consumer to a net producer of lactate, resulting in a low coupling of glucose oxidation to glycolysis, which is a common feature of hypertrophied hearts. This study provides a novel systematic myocardial contractile and metabolic analysis to help elucidate the pathogenesis of FHC and suggests that the alterations in resting heart energy supply and demand could contribute to disease progression.

  11. 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.

  12. Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I

    PubMed Central

    Fleming, Jennifer R.; Anderson, Brian R.; Williams, Rhys; Franke, Barbara; Bullard, Belinda; Granzier, Henk

    2016-01-01

    Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected. PMID:27683155

  13. Targeted 46-gene and clinical exome sequencing for mutations causing cardiomyopathies.

    PubMed

    Waldmüller, Stephan; Schroeder, Christopher; Sturm, Marc; Scheffold, Thomas; Imbrich, Kerstin; Junker, Sandra; Frische, Christian; Hofbeck, Michael; Bauer, Peter; Bonin, Michael; Gawaz, Meinrad; Gramlich, Michael

    2015-10-01

    With the implementation of high-throughput sequencing protocols, the exhaustive scanning of known and candidate disease genes has become a feasible approach to genetic testing of patients with cardiomyopathy. A primary objective of the present study was to assess the performance characteristics of a 46-gene next-generation sequencing (NGS) assay that targets well-established cardiomyopathy genes. A total of 25 samples were analyzed. Twelve of those had previously been sequenced using resequencing arrays and served as reference samples for the assessment of the assay's performance characteristics. The remaining 13 samples were derived from consecutive patients. Both the analytical sensitivity and the specificity of the assay were 100% and the percentage of low-coverage bases was 0.4%, at an average read depth of 210×. In order to assess the diagnostic yield of the test, 13 consecutive samples representing cases of Dilated (n = 7), Hypertrophic (n = 4) and Left Ventricular Non-Compaction Cardiomyopathy (n = 2), were subjected to the 46-gene NGS assay. Including predicted pathogenic variants in the gene TTN, a total of 22 variants (11 novel) were detected in 10 patients, with a clear preponderance of variants of unknown pathogenicity (class 3 variants, 21/22, 95%). Of the seven DCM cases, two were digenic, involving variants in the genes MYH7 and RBM20 in one case and in DSP and TTN in the other case. Three other patients carried single TTN variants predicted to be pathogenic. Of the four HCM patients, one was trigenic (LAMA4, PKP2 and TTN) and three were digenic (DSP and TTN, MYH7 and NEXN, NEXN and TTN, respectively). As to LVNC, one of the two patients had one variant in the gene ABCC9 and two predicted pathogenic variants in the gene TTN. Strikingly, out of the thirteen investigated cases, only a single case exhibited a likely pathogenic or pathogenic variant justifying a positive test report. The percentage of inconclusive cases thus amounted to 69%. Three cases

  14. TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    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.

  15. Tissue Doppler imaging and plasma N-terminal probrain natriuretic peptide for the identification of hypertrophic cardiomyopathy mutation carriers.

    PubMed

    Silva, Doroteia; Madeira, Hugo; Almeida, Augusto; Brito, Dulce

    2013-10-01

    Previous studies have shown that tissue Doppler imaging (TDI) is able to identify mutation carriers of hypertrophic cardiomyopathy (HC) before the development of the clinical phenotype. However, data are scarce and have sometimes been controversial. We performed a systematic study that included conventional echocardiography, TDI, and plasma NT-probrain natriuretic peptide (NT-proBNP) measurement to evaluate the parameters that could identify HC mutation carriers. A total of 138 genotyped subjects were included and divided into 3 groups: group 1, those with HC (n = 62); group 2, mutation carriers (first-degree relatives with a positive genotype but negative phenotype; n = 34); and group 3, controls (first-degree relatives with a negative genotype and phenotype; n = 42). An echocardiographic study, including TDI, was performed on all subjects, and a TDI-derived index (global function index) was also determined. The age-adjusted mean differences in the echocardiographic and TDI parameters and NT-proBNP levels were compared among the 3 groups. Compared with the HC group, the carriers had significantly higher mean E' velocities, lower mean E/E' ratio, higher mean S' velocities, and lower mean global function index and NT-proBNP values. The carriers and controls did not differ significantly either in the echocardiographic parameters studied or in the NT-proBNP levels. In conclusion, the echocardiographic and TDI parameters and NT-proBNP levels cannot be used to identify the HC mutation carrier state and therefore do not appear to be reliable for the purpose of making a preclinical diagnosis of the disease.

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

    PubMed

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

    2015-10-01

    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 Ca(2+)-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 Ca(2+)-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 Ca(2+)-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.

  17. Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization

    PubMed Central

    Sharma, Ravi K.; Wang, David Wen Rui; Smith, Stephen H.; Banerjee, Sanjay K.; Huang, Xueyin N.; Gifford, Lindsey M.; Pruce, Michele L.; Gabris, Bethann E.; Saba, Samir; Shroff, Sanjeev G.; Ahmad, Ferhaan

    2016-01-01

    Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to β-adrenergic activation. PMID:27936050

  18. Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing.

    PubMed

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

    2016-11-01

    Pathogenic variants in the NONO gene have been most recently implicated in X-linked intellectual disability syndrome. This observation has been supported by studies of NONO-deficient mice showing that NONO has an important role in regulating inhibitory synaptic activity. Thus far, the phenotypic spectrum of affected patients remains limited. We applied whole exome sequencing to members of a family in which the proband was presented with a complex phenotype consisting of developmental delay, dysmorphism, and non-compaction cardiomyopathy. Exome analysis identified a novel de novo splice-site variant c.1171+1G>T in exon 11 of NONO gene that is suspected to abolish the donor splicing site. Thus, we propose that the phenotypic spectrum of NONO-related disorder is much broader than described and that pathogenic variants in NONO cause a recognizable phenotype.

  19. Restrictive cardiomyopathy

    MedlinePlus

    Cardiomyopathy - restrictive; Infiltrative cardiomyopathy; Idiopathic myocardial fibrosis ... In a case of restrictive cardiomyopathy, the heart muscle is of normal size or slightly enlarged. Most of the time, it also pumps normally. However, it does ...

  20. Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study

    PubMed Central

    Mattos, Beatriz Piva e; Scolari, Fernando Luís; Torres, Marco Antonio Rodrigues; Simon, Laura; de Freitas, Valéria Centeno; Giugliani, Roberto; Matte, Úrsula

    2016-01-01

    Background: Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country. Objective: To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations. Methods: Direct DNA sequencing of all encoding regions of three sarcomeric genes was conducted in 43 consecutive individuals of ten unrelated families. Results: Mutations for CMH have been found in 25 (58%) patients of seven (70%) of the ten study families. Fourteen (56%) individuals were phenotype-positive. All mutations were missense, four (66%) in MYH7 and two (33%) in MYBPC3. We have not found mutations in the TNNT2 gene. Mutations in MYH7 were identified in 20 (47%) patients of six (60%) families. Two of them had not been previously described. Mutations in MYBPC3 were found in seven (16%) members of two (20%) families. Two (5%) patients showed double heterozygosis for both genes. The mutations affected different domains of encoded proteins and led to variable phenotypic expression. A family history of HCM was identified in all genotype-positive individuals. Conclusions: In this first genetic-molecular analysis carried out in the south of Brazil, we found mutations in the sarcomeric genes MYH7 and MYBPC3 in 58% of individuals. MYH7-related disease was identified in the majority of cases with mutation. PMID:27737317

  1. 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.

  2. Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.

    PubMed

    Baertling, Fabian; A M van den Brand, Mariel; Hertecant, Jozef L; Al-Shamsi, Aisha; P van den Heuvel, Lambert; Distelmaier, Felix; Mayatepek, Ertan; Smeitink, Jan A; Nijtmans, Leo G J; Rodenburg, Richard J T

    2015-01-01

    COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits. Although monomeric complex IV is decreased in patient fibroblasts, the CI/CIII2 /CIVn -supercomplexes remain unaffected. Copper supplementation shows a partial rescue of complex IV deficiency in patient fibroblasts. We conclude that COA6 is required for complex IV subunit stability. Furthermore, the proposed role in the copper delivery pathway to complex IV subunits is substantiated and a therapeutic lead for COA6-deficient patients is provided.

  3. Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in α- and β-myosin heavy chain fibers.

    PubMed

    Mickelson, Alexis V; Gollapudi, Sampath K; Chandra, Murali

    2017-01-01

    The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation A28V in cardiac troponin T (TnT). The A28V mutation is located within the NH2 terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how α- and β-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH2 terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by α- and β-MHC isoforms. Recombinant wild-type mouse TnT (TnTWT) and the mouse equivalent of the human A28V mutation (TnTA30V) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (α-MHC) and transgenic (β-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnTA30V decreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges (ER) by 30% in α-MHC fibers. In sharp contrast, TnTA30V increased ER by 55% in β-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in ER in TnTA30V + α-MHC and TnTA30V + β-MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnTA30V-mediated effects on Ca(2+)-activated maximal tension and instantaneous muscle fiber stiffness (ED) were also divergently affected by α- and β-MHC. Our study demonstrates that TnTA30V + α-MHC and TnTA30V + β-MHC fibers show contrasting contractile phenotypes; however, only the observations from β-MHC fibers are consistent with the clinical data for A28V in humans.

  4. Genetics of inherited cardiomyopathy.

    PubMed

    Jacoby, Daniel; McKenna, William J

    2012-02-01

    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.

  5. 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.

  6. 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

    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.

  7. Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy.

    PubMed

    Meyer, Thomas; Pankuweit, Sabine; Richter, Anette; Maisch, Bernhard; Ruppert, Volker

    2013-09-15

    Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n=8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac β-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54-year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (>10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM.

  8. 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

  9. [Gender effect on cardiomyopathy].

    PubMed

    Biagini, Elena; Berardini, Alessandra; Graziosi, Maddalena; Rosmini, Stefania; Pazzi, Chiara; Rapezzi, Claudio

    2012-06-01

    The role of a gender effect (that means differences in clinical manifestations, access to therapies and response to treatments according to gender) in cardiomyopathies remains a matter of debate. Although recent studies have evaluated the differences in the clinical features and prognosis between the two sexes, many issues remain to be elucidated. At present, the only sex-specific condition that affects females is peripartum cardiomyopathy. Recent evidence suggests a pathogenetic role of a prolactin derivative, and ongoing clinical trials are investigating the possibility of targeted therapies using prolactin secretion inhibitors, such as bromocriptine and carbegoline. Although women were considered so far only carriers of X-linked diseases (Anderson-Fabry disease, Danon disease, Hunter syndrome and dystrophinopathies), clinical experience showed a wide spectrum of clinical manifestations in females due to random X chromosome inactivation. Conversely, in mitochondrial diseases (with matrilineal inheritance), cardiomyopathies may occur in the context of clinical multisystemic involvement without significant gender-related differences. Autosomal inherited cardiomyopathies also show different phenotypes and prognostic impact according to gender. The hypothesis of a premenopausal protective role of female hormones towards myocardial involvement has been raised by recent data on transtiretin-related amyloidosis and hypertrophic cardiomyopathy. Preexisting cardiomyopathies may affect pregnancy, labor and delivery in women, since all these conditions are associated with important hemodynamic changes. Women with low-risk hypertrophic cardiomyopathy (asymptomatic and without left ventricular outflow tract gradient) usually can tolerate pregnancy. Conversely, women who are symptomatic before pregnancy or have severe hypertrophy with important outflow tract gradient are at higher risk and should be referred to a tertiary center to be evaluated on a case by case basis

  10. Targets for therapy in sarcomeric cardiomyopathies.

    PubMed

    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

    2015-04-01

    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.

  11. 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

  12. 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.

  13. Peripartum cardiomyopathy.

    PubMed

    Grixti, Sarah; Magri, Caroline J; Xuereb, Robert; Fava, Stephen

    2015-02-01

    Peripartum cardiomyopathy is a form of dilated cardiomyopathy of indeterminate aetiology occurring in late pregnancy or the months following delivery. This article reviews current knowledge of its pathophysiology, therapeutic strategies and prognosis, as well as new treatments and future directions.

  14. Genetics of restrictive cardiomyopathy.

    PubMed

    Sen-Chowdhry, Srijita; Syrris, Petros; McKenna, William J

    2010-04-01

    Restrictive physiology, a severe form of diastolic dysfunction, is characteristically observed in the setting of constrictive pericarditis and myocardial restriction. The latter is commonly due to systemic diseases, some of which are inherited as mendelian traits (eg, hereditary amyloidosis), while others are multifactorial (eg, sarcoidosis). When restrictive physiology occurs as an early and dominant feature of a primary myocardial disorder, it may be termed restrictive cardiomyopathy. In the past decade, clinical and genetic studies have demonstrated that restrictive cardiomyopathy as such is part of the spectrum of sarcomeric disease and frequently coexists with hypertrophic cardiomyopathy in affected families.

  15. Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation

    PubMed Central

    Huang, Wei-Lin; Chou, Shih-Jie; Chang, Wei-Chao; Chang, Yuh-Lih; Leu, Hsin-Bang; Chen, Kuan-Hsuan; Wang, Kang-Ling; Lai, Ying-Hsiu; Liu, Yung-Yang; Lu, Kai-Hsi; Li, Hsin-Yang; Sung, Yen-Jen; Jong, Yuh-Jyh; Chen, Yann-Jang; Chen, Chung-Hsuan; Yu, Wen-Chung

    2016-01-01

    Rationale A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. Objective Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC. Results and methods The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients’ sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs. Conclusion Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation. PMID:27888626

  16. Mutations affecting xanthophore pigmentation in the zebrafish, Danio rerio.

    PubMed

    Odenthal, J; Rossnagel, K; Haffter, P; Kelsh, R N; Vogelsang, E; Brand, M; van Eeden, F J; Furutani-Seiki, M; Granato, M; Hammerschmidt, M; Heisenberg, C P; Jiang, Y J; Kane, D A; Mullins, M C; Nüsslein-Volhard, C

    1996-12-01

    In a large-scale screen for mutants with defects in embryonic development we identified 17 genes (65 mutants) specifically required for the development of xanthophores. We provide evidence that these genes are required for three different aspects of xanthophore development. (1) Pigment cell formation and migration (pfeffer and salz); (2) pigment synthesis (edison, yobo, yocca and brie) and (3) pigment translocation (esrom, tilsit and tofu). The number of xanthophore cells that appear in the body is reduced in embryos with mutations in the two genes, salz and pfeffer. In heterozygous and homozygous salz and pfeffer adults, the melanophore stripes are interrupted, indicating that xanthophore cells have an important function in adult melanophore pattern formation. Most other genes affect only larval pigmentation. In embryos mutant for edison, yobo, yocca and brie, differences in pteridine synthesis can be observed under UV light and by thin-layer chromatography. Homozygous mutant females of yobo show a recessive maternal effect. Embryonic development is slowed down and embryos display head and tail truncations. Xanthophores in larvae mutant in the three genes esrom, tilsit and tofu appear less spread out. In addition, these mutants display a defect in retinotectal axon pathfinding. These mutations may affect xanthophore pigment distribution within the cells or xanthophore cell shape. Mutations in seven genes affecting xanthophore pigmentation remain unclassified.

  17. Peripartum cardiomyopathy: a review.

    PubMed

    Bhattacharyya, Anirban; Basra, Sukhdeep Singh; Sen, Priyanka; Kar, Biswajit

    2012-01-01

    Peripartum cardiomyopathy is idiopathic heart failure occurring in the absence of any determinable heart disease during the last month of pregnancy or the first 5 months postpartum. The incidence varies worldwide but is high in developing nations; the cause of the disease might be a combination of environmental and genetic factors. Diagnostic echocardiographic criteria include left ventricular ejection fraction <0.45 or M-mode fractional shortening <30% (or both) and end-diastolic dimension >2.7 cm/m(2). Electrocardiography, magnetic resonance imaging, endomyocardial biopsy, and cardiac catheterization aid in the diagnosis and management of peripartum cardiomyopathy. Cardiac protein assays can also be useful, as suggested by reports of high levels of NT-proBNP, cardiac troponin, tumor necrosis factor-α, interleukin-6, interferon-γ, and C-reactive protein in peripartum cardiomyopathy. The prevalence of mutations associated with familial dilated-cardiomyopathy genes in patients with peripartum cardiomyopathy suggests an overlap in the clinical spectrum of these 2 diseases.Treatment for peripartum cardiomyopathy includes conventional pharmacologic heart-failure therapies-principally diuretics, angiotensin-converting enzyme inhibitors, vasodilators, digoxin, β-blockers, anticoagulants, and peripartum cardiomyopathy-targeted therapies. Therapeutic decisions are influenced by drug-safety profiles during pregnancy and lactation. Mechanical support and transplantation might be necessary in severe cases. Targeted therapies (such as intravenous immunoglobulin, pentoxifylline, and bromocriptine) have shown promise in small trials but require further evaluation. Fortunately, despite a mortality rate of up to 10% and a high risk of relapse in subsequent pregnancies, many patients with peripartum cardiomyopathy recover within 3 to 6 months of disease onset.

  18. Nav 1.5 mutations linked to dilated cardiomyopathy phenotypes: Is the gating pore current the missing link?

    PubMed

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

    2014-01-01

    Nav 1.5 dysfunctions are commonly linked to rhythms disturbances that include type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), sick sinus syndrome (SSS) and conduction defects. Recently, this channel protein has been also linked to structural heart diseases such as dilated cardiomyopathy (DCM).

  19. 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.

  20. Connecting Sarcomere Protein Mutations to Pathogenesis in Cardiomyopathies: The Development of “Disease in a Dish” Models

    PubMed Central

    Zaunbrecher, Rebecca; Regnier, Michael

    2016-01-01

    Recent technological and protocol developments have greatly increased the ability to utilize stem cells transformed into cardiomyocytes as models to study human heart muscle development and how this is affected by disease associated mutations in a variety of sarcomere proteins. In this perspective we provide an overview of these emerging technologies and how they are being used to create better models of “disease in a dish” for both research and screening assays. We also consider the value of these assays as models to explore the seminal processes in initiation of the disease development and the possibility of early interventions. PMID:27920728

  1. Mutations Affecting Expression of the rosy Locus in Drosophila melanogaster

    PubMed Central

    Lee, Chong Sung; Curtis, Daniel; McCarron, Margaret; Love, Carol; Gray, Mark; Bender, Welcome; Chovnick, Arthur

    1987-01-01

    The rosy locus in Drosophila melanogaster codes for the enzyme xanthine dehydrogenase (XDH). Previous studies defined a "control element" near the 5' end of the gene, where variant sites affected the amount of rosy mRNA and protein produced. We have determined the DNA sequence of this region from both genomic and cDNA clones, and from the ry+10 underproducer strain. This variant strain had many sequence differences, so that the site of the regulatory change could not be fixed. A mutagenesis was also undertaken to isolate new regulatory mutations. We induced 376 new mutations with 1-ethyl-1-nitrosourea (ENU) and screened them to isolate those that reduced the amount of XDH protein produced, but did not change the properties of the enzyme. Genetic mapping was used to find mutations located near the 5' end of the gene. DNA from each of seven mutants was cloned and sequenced through the 5' region. Mutant base changes were identified in all seven; they appear to affect splicing and translation of the rosy mRNA. In a related study (T. P. Keith et al. 1987), the genomic and cDNA sequences are extended through the 3' end of the gene; the combined sequences define the processing pattern of the rosy transcript and predict the amino acid sequence of XDH. PMID:3036645

  2. Mutations affecting expression of the rosy locus in Drosophila melanogaster

    SciTech Connect

    Lee, C.S.; Curtis, D.; McCarron, M.; Love, C.; Gray, M.; Bender, W.; Chovnick, A.

    1987-05-01

    The rosy locus in Drosophila melanogaster codes for the enzyme xanthine dehydrogenase (XDH). Previous studies defined a control element near the 5' end of the gene, where variant sites affected the amount of rosy mRNA and protein produced. The authors have determined the DNA sequence of this region from both genomic and cDNA clones, and from the ry/sup +10/ underproducer strain. This variant strain had many sequence differences, so that the site of the regulatory change could not be fixed. A mutagenesis was also undertaken to isolate new regulatory mutations. They induced 376 new mutations with 1-ethyl-1-nitrosourea (ENU) and screened them to isolate those that reduced the amount of XDH protein produced, but did not change the properties of the enzyme. Genetic mapping was used to find mutations located near the 5' end of the gene. DNA from each of seven mutants was cloned and sequenced through the 5' region. Mutant base changes were identified in all seven; they appear to affect splicing and translation of the rosy mRNA. In a related study, the genomic and cDNA sequences are extended through the 3' end of the gene; the combined sequences define the processing pattern of the rosy transcript and predict the amino acid sequence of XDH.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Optic neuropathy, cardiomyopathy, cognitive disability in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant.

    PubMed

    Charif, Majida; Titah, Salah Mohamed Cherif; Roubertie, Agathe; Desquiret-Dumas, Valérie; Gueguen, Naig; Meunier, Isabelle; Leid, Jean; Massal, Frédéric; Zanlonghi, Xavier; Mercier, Jacques; Raynaud de Mauverger, Eric; Procaccio, Vincent; Mousson de Camaret, Bénédicte; Lenaers, Guy; Hamel, Christian P

    2015-10-01

    We report on clinical, genetic and metabolic investigations in a family with optic neuropathy, non-progressive cardiomyopathy and cognitive disability. Ophthalmic investigations (slit lamp examination, funduscopy, OCT scan of the optic nerve, ERG and VEP) disclosed mild or no decreased visual acuity, but pale optic disc, loss of temporal optic fibers and decreased VEPs. Mitochondrial DNA and exome sequencing revealed a novel homozygous mutation in the nuclear MTO1 gene and the homoplasmic m.593T>G mutation in the mitochondrial MT-TF gene. Muscle biopsy analyses revealed decreased oxygraphic Vmax values for complexes I+III+IV, and severely decreased activities of the respiratory chain complexes (RCC) I, III and IV, while muscle histopathology was normal. Fibroblast analysis revealed decreased complex I and IV activity and assembly, while cybrid analysis revealed a partial complex I deficiency with normal assembly of the RCC. Thus, in patients with a moderate clinical presentation due to MTO1 mutations, the presence of an optic atrophy should be considered. The association with the mitochondrial mutation m.593T>G could act synergistically to worsen the complex I deficiency and modulate the MTO1-related disease.

  8. 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.

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

    PubMed

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

    2015-02-01

    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 Na(v)1.5 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 Na(v)1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers.

  10. 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

  11. Peripartum Cardiomyopathy.

    PubMed

    Arany, Zolt; Elkayam, Uri

    2016-04-05

    Peripartum cardiomyopathy is a potentially life-threatening pregnancy-associated disease that typically arises in the peripartum period and is marked by left ventricular dysfunction and heart failure. The disease is relatively uncommon, but its incidence is rising. Women often recover cardiac function, but long-lasting morbidity and mortality are not infrequent. Management of peripartum cardiomyopathy is largely limited to the same neurohormonal antagonists used in other forms of cardiomyopathy, and no proven disease-specific therapies exist yet. Research in the past decade has suggested that peripartum cardiomyopathy is caused by vascular dysfunction, triggered by late-gestational maternal hormones. Most recently, information has also indicated that many cases of peripartum cardiomyopathy have genetic underpinnings. We review here the known epidemiology, clinical presentation, and management of peripartum cardiomyopathy, as well as the current knowledge of the pathophysiology of the disease.

  12. Doxorubicin Cardiomyopathy

    PubMed Central

    Chatterjee, Kanu; Zhang, Jianqing; Honbo, Norman; Karliner, Joel S.

    2010-01-01

    Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered. PMID:20016174

  13. Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae.

    PubMed Central

    Adams, A K; Holm, C

    1996-01-01

    To investigate the relationship between the DNA replication apparatus and the control of telomere length, we examined the effects of several DNA replication mutations on telomere length in Saccharomyces cerevisiae. We report that a mutation in the structural gene for the large subunit of DNA replication factor C (cdc44/rfc1) causes striking increases in telomere length. A similar effect is seen with mutations in only one other DNA replication gene: the structural gene for DNA polymerase alpha (cdc17/pol1) (M.J. Carson and L. Hartwell, Cell 42:249-257, 1985). For both genes, the telomere elongation phenotype is allele specific and appears to correlate with the penetrance of the mutations. Furthermore, fluorescence-activated cell sorter analysis reveals that those alleles that cause elongation also exhibit a slowing of DNA replication. To determine whether elongation is mediated by telomerase or by slippage of the DNA polymerase, we created cdc17-1 mutants carrying deletions of the gene encoding the RNA component of telomerase (TLC1). cdc17-1 strains that would normally undergo telomere elongation failed to do so in the absence of telomerase activity. This result implies that telomere elongation in cdc17-1 mutants is mediated by the action of telomerase. Since DNA replication involves transfer of the nascent strand from polymerase alpha to replication factor C (T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1950-1960, 1991; T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1961-1968, 1991; S. Waga and B. Stillman, Nature [London] 369:207-212, 1994), one possibility is that this step affects the regulation of telomere length. PMID:8756617

  14. 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

  15. Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

    PubMed

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

    2015-03-01

    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 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device 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_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although 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 the siblings developed progressive HF 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 level (>13 000 IU l(-1)) 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 HF during early adolescence.

  16. 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

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

    PubMed Central

    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

  18. Dilated cardiomyopathy.

    PubMed

    Weintraub, Robert G; Semsarian, Christopher; Macdonald, Peter

    2017-02-09

    Dilated cardiomyopathy is defined by the presence of left ventricular dilatation and contractile dysfunction. Genetic mutations involving genes that encode cytoskeletal, sarcomere, and nuclear envelope proteins, among others, account for up to 35% of cases. Acquired causes include myocarditis and exposure to alcohol, drugs and toxins, and metabolic and endocrine disturbances. The most common presenting symptoms relate to congestive heart failure, but can also include circulatory collapse, arrhythmias, and thromboembolic events. Secondary neurohormonal changes contribute to reverse remodelling and ongoing myocyte damage. The prognosis is worst for individuals with the lowest ejection fractions or severe diastolic dysfunction. Treatment of chronic heart failure comprises medications that improve survival and reduce hospital admission-namely, angiotensin converting enzyme inhibitors and β blockers. Other interventions include enrolment in a multidisciplinary heart failure service, and device therapy for arrhythmia management and sudden death prevention. Patients who are refractory to medical therapy might benefit from mechanical circulatory support and heart transplantation. Treatment of preclinical disease and the potential role of stem-cell therapy are being investigated.

  19. Peripartum cardiomyopathy.

    PubMed

    Sundin, Courtney Stanley

    2014-01-01

    Peripartum cardiomyopathy is a very rare, but serious life-threatening emergency. Early recognition of signs and symptoms, along with radiologic imaging and blood work, can facilitate timely diagnosis. Once peripartum cardiomyopathy is diagnosed, a multidisciplinary team can facilitate the delivery of quality care to promote optimal outcomes.

  20. [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.

  1. Dilated Cardiomyopathy Mutation (R134W) in Mouse Cardiac Troponin T Induces Greater Contractile Deficits against α-Myosin Heavy Chain than against β-Myosin Heavy Chain.

    PubMed

    Gollapudi, Sampath K; Chandra, Murali

    2016-01-01

    Many studies have demonstrated that depressed myofilament Ca(2+) sensitivity is common to dilated cardiomyopathy (DCM) in humans. However, it remains unclear whether a single determinant-such as myofilament Ca(2+) sensitivity-is sufficient to characterize all cases of DCM because the severity of disease varies widely with a given mutation. Because dynamic features dominate in the heart muscle, alterations in dynamic contractile parameters may offer better insight on the molecular mechanisms that underlie disparate effects of DCM mutations on cardiac phenotypes. Dynamic features are dominated by myofilament cooperativity that stem from different sources. One such source is the strong tropomyosin binding region in troponin T (TnT), which is known to modulate crossbridge (XB) recruitment dynamics in a myosin heavy chain (MHC)-dependent manner. Therefore, we hypothesized that the effects of DCM-linked mutations in TnT on contractile dynamics would be differently modulated by α- and β-MHC. After reconstitution with the mouse TnT equivalent (TnTR134W) of the human DCM mutation (R131W), we measured dynamic contractile parameters in detergent-skinned cardiac muscle fiber bundles from normal (α-MHC) and transgenic mice (β-MHC). TnTR134W significantly attenuated the rate constants of tension redevelopment, XB recruitment dynamics, XB distortion dynamics, and the magnitude of length-mediated XB recruitment only in α-MHC fiber bundles. TnTR134W decreased myofilament Ca(2+) sensitivity to a greater extent in α-MHC (0.14 pCa units) than in β-MHC fiber bundles (0.08 pCa units). Thus, our data demonstrate that TnTR134W induces a more severe DCM-like contractile phenotype against α-MHC than against β-MHC background.

  2. Dilated Cardiomyopathy Mutation (R134W) in Mouse Cardiac Troponin T Induces Greater Contractile Deficits against α-Myosin Heavy Chain than against β-Myosin Heavy Chain

    PubMed Central

    Gollapudi, Sampath K.; Chandra, Murali

    2016-01-01

    Many studies have demonstrated that depressed myofilament Ca2+ sensitivity is common to dilated cardiomyopathy (DCM) in humans. However, it remains unclear whether a single determinant—such as myofilament Ca2+ sensitivity—is sufficient to characterize all cases of DCM because the severity of disease varies widely with a given mutation. Because dynamic features dominate in the heart muscle, alterations in dynamic contractile parameters may offer better insight on the molecular mechanisms that underlie disparate effects of DCM mutations on cardiac phenotypes. Dynamic features are dominated by myofilament cooperativity that stem from different sources. One such source is the strong tropomyosin binding region in troponin T (TnT), which is known to modulate crossbridge (XB) recruitment dynamics in a myosin heavy chain (MHC)-dependent manner. Therefore, we hypothesized that the effects of DCM-linked mutations in TnT on contractile dynamics would be differently modulated by α- and β-MHC. After reconstitution with the mouse TnT equivalent (TnTR134W) of the human DCM mutation (R131W), we measured dynamic contractile parameters in detergent-skinned cardiac muscle fiber bundles from normal (α-MHC) and transgenic mice (β-MHC). TnTR134W significantly attenuated the rate constants of tension redevelopment, XB recruitment dynamics, XB distortion dynamics, and the magnitude of length-mediated XB recruitment only in α-MHC fiber bundles. TnTR134W decreased myofilament Ca2+ sensitivity to a greater extent in α-MHC (0.14 pCa units) than in β-MHC fiber bundles (0.08 pCa units). Thus, our data demonstrate that TnTR134W induces a more severe DCM-like contractile phenotype against α-MHC than against β-MHC background. PMID:27757084

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

    PubMed

    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

    2015-10-01

    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 Ca(2+)-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.

  4. Genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal gene mutations: A systematic review and meta-analysis

    PubMed Central

    Xu, Zhenyan; Zhu, Wengen; Wang, Cen; Huang, Lin; Zhou, Qiongqiong; Hu, Jinzhu; Cheng, Xiaoshu; Hong, Kui

    2017-01-01

    The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1–3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1–3 leads and a strong family history of ARVC. PMID:28120905

  5. 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

  6. 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.

  7. What's Cardiomyopathy

    MedlinePlus

    ... blood effectively and heart failure or irregular heartbeats (arrhythmias or dysrhythmia) may occur. Cardiomyopathy is classified as ... HCM are also at an increased risk of arrhythmias and sudden cardiac arrest. In advanced HCM (seen ...

  8. A Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy Associated Mutation in Human Cardiac Troponin I (K206I)

    PubMed Central

    Warren, Chad M.; Karam, Chehade N.; Wolska, Beata M.; Kobayashi, Tomoyoshi; de Tombe, Pieter P.; Arteaga, Grace M.; Bos, J. Martijn; Ackerman, Michael J.; Solaro, R. John

    2015-01-01

    Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease characterized by thickening of ventricular walls and decreased left ventricular chamber volume. The majority of HCM-associated mutations are found in genes encoding sarcomere proteins. Herein, we set out to functionally characterize a novel HCM-associated mutation (K206I-TNNI3), and elucidate the mechanism of dysfunction at the level of myofilament proteins. Methods and Results The male index case was diagnosed with HCM after an out-of-hospital cardiac arrest which was followed by comprehensive clinical evaluation, transthoracic echocardiography, and clinical genetic testing. To determine molecular mechanism(s) of the mutant human cardiac troponin I (K206I), we tested the Ca2+ dependence of thin filament-activated myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system comparing wildtype human troponin complex, 50% mix of K206I/wildtype, or 100% K206I. We also exchanged native troponin detergent extracted fibers with reconstituted troponin containing either wildtype or a 65% mix of K206I/wildtype, and measured force generation. The Ca2+ sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 μM EGCG (green tea) was restored back to wildtype levels in ATPase and force measurements. The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of Ca-hcTnC (calcium-bound-human cardiac troponin C). The ability of Ca-hcTnC to neutralize the inhibition of K206I was greater than with wildtype TnI. Conclusions Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM. PMID:26553696

  9. Anthracycline cardiomyopathy.

    PubMed

    Kobrinsky, N L; Ramsay, N K; Krivit, W

    1982-01-01

    Life-threatening irreversible cardiomyopathy is a major complication of anthracycline therapy, particularly in the pediatric population. The pediatric cardiologist, in concert with the primary oncologist, should therefore play a major role in the care of patients receiving these agents and in clinical trials involving their use. Many risk factors and their relationships to drug pharmacokinetics, mechanisms of action, and toxicity have been identified. These data provide a rational basis for present-day recommendations regarding anthracycline administration and dosage scheduling. They furthermore provide potential avenues for clinical investigation aimed at improving the therapeutic index of these agents: alpha-tocopherol, cytochrome Q10, and other free radical scavengers may decrease the deleterious effects of free radical generation on the myocardium without apparent interference with tumoricidal effect. The cardiac glycosides may decrease cardiac toxicity by specific myocardial exclusion. Anthracycline analogs have been designed to specifically inhibit myocardial binding and/or free radical generation. Clinical trials involving these agents are difficult to interpret because of variability in front end risk factors and dosage schedules in the study population. Furthermore, the relatively low (5 to 10%) incidence of affected patients implies the need for large numbers to demonstrate a statistically significant benefit. Pediatric protocols addressing these issues are urgently needed. Guidelines for present-day management and future studies are outlined.

  10. 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.

  11. Mutations Affecting the Chemosensory Neurons of Caenorhabditis Elegans

    PubMed Central

    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-filling defective mutants are important for the differentiation of amphid and phasmid chemosensilla. PMID:7705621

  12. 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.

  13. 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...

  14. Dominance of mutations affecting viability in Drosophila melanogaster.

    PubMed Central

    Fry, James D; Nuzhdin, Sergey V

    2003-01-01

    There have been several attempts to estimate the average dominance (ratio of heterozygous to homozygous effects) of spontaneous deleterious mutations in Drosophila melanogaster, but these have given inconsistent results. We investigated whether transposable element (TE) insertions have higher average dominance for egg-to-adult viability than do point mutations, a possibility suggested by the types of fitness-depressing effects that TEs are believed to have. If so, then variation in dominance estimates among strains and crosses would be expected as a consequence of variation in TE activity. As a first test, we estimated the average dominance of all mutations and of copia insertions in a set of lines that had accumulated spontaneous mutations for 33 generations. A traditional regression method gave a dominance estimate for all mutations of 0.17, whereas average dominance of copia insertions was 0.51; the difference between these two estimates approached significance (P = 0.08). As a second test, we reanalyzed Ohnishi 1974 data on dominance of spontaneous and EMS-induced mutations. Because a considerable fraction of spontaneous mutations are caused by TE insertions, whereas EMS induces mainly point mutations, we predicted that average dominance would decline with increasing EMS concentration. This pattern was observed, but again fell short of formal significance (P = 0.07). Taken together, however, the two results give modest support for the hypothesis that TE insertions have greater average dominance in their viability effects than do point mutations, possibly as a result of deleterious effects of expression of TE-encoded genes. PMID:12702680

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

    PubMed

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

    2010-04-01

    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.

  16. [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.

  17. Hypertrophic cardiomyopathy in Friedreich's ataxia.

    PubMed

    Fayssoil, A; Nardi, O; Orlikowski, D; Annane, D

    2008-07-21

    Friedreich's ataxia is an autosomal recessive disorder characterized by spinocerebellar degeneration. It is caused by a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9 (9q13). We reported a case of hypertrophic cardiomyopathy associated with Friedreich's ataxia in a twenty year old patient.

  18. 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.

  19. 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

  20. Fast diastolic swinging motion of the mitral valve as a clinical marker of familial hypertrophic cardiomyopathy in genetically affected young children without left ventricular hypertrophy: a new role for noninvasive imaging?

    PubMed

    Udink ten Cate, Floris E A; Junghaenel, Shino; Brockmeier, Konrad; Sreeram, Narayanswami

    2013-08-01

    Structural mitral valve (MV) abnormalities are common in patients with hypertrophic cardiomyopathy (HCM). This is the first report demonstrating MV abnormalities in very young children as the sole overt clinical feature of a known HCM-causing sarcomere protein gene mutation. Due to MV leaflet elongation, we also noticed a typical fast diastolic swinging motion of the MV in our patients. This novel echocardiographic feature may be used as a clinical marker of HCM disease in the absence of left ventricular hypertrophy.

  1. Research priorities in sarcomeric cardiomyopathies.

    PubMed

    van der Velden, Jolanda; Ho, Carolyn Y; Tardiff, Jil C; Olivotto, Iacopo; Knollmann, Bjorn C; Carrier, Lucie

    2015-04-01

    The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is harmless in a family member. Moreover, the clinical phenotype varies ranging from asymmetric hypertrophy to severe dilatation of the heart. Identification of a single phenotype-associated disease mechanism would facilitate the design of targeted treatments for patient groups with different clinical phenotypes. However, evidence from both the clinic and basic knowledge of functional and structural properties of the sarcomere argues against a 'one size fits all' therapy for treatment of one clinical phenotype. Meticulous clinical and basic studies are needed to unravel the initial and progressive changes initiated by sarcomere mutations to better understand why mutations in the same gene can lead to such opposing phenotypes. Ultimately, we need to design an 'integrative physiology' approach to fully realize patient/gene-tailored therapy. Expertise within different research fields (cardiology, genetics, cellular biology, physiology, and pharmacology) must be joined to link longitudinal clinical studies with mechanistic insights obtained from molecular and functional studies in novel cardiac muscle systems. New animal models, which reflect both initial and more advanced stages of sarcomeric cardiomyopathy, will also aid in achieving these goals. Here, we discuss current priorities in clinical and preclinical investigation aimed at increasing our understanding of pathophysiological mechanisms leading from mutation to disease. Such information will provide the basis to improve risk stratification and to develop therapies to prevent/rescue cardiac dysfunction and remodelling caused by sarcomere mutations.

  2. Cirrhotic cardiomyopathy.

    PubMed

    Ruiz-del-Árbol, Luis; Serradilla, Regina

    2015-11-07

    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.

  3. Restrictive cardiomyopathies.

    PubMed

    Nihoyannopoulos, Petros; Dawson, David

    2009-12-01

    Restrictive cardiomyopathies constitute a heterogenous group of heart muscle conditions that all have, in common, the symptoms of heart failure. Diastolic dysfunction with preserved systolic function is often the only echocardiographic abnormality that may be noted, although systolic dysfunction may also be an integral part of some specific pathologies, particularly in the most advanced cases such as amyloid infiltration of the heart. By far, the majority of restrictive cardiomyopathies are secondary to a systemic disorder such as amyloidosis, sarcoidosis, scleroderma, haemochromatosis, eosinophilic heart disease, or as a result of radiation treatment. The much more rare diagnosis of idiopathic restrictive cardiomyopathy is supported only by the absence of specific pathology on either endomyocardial biopsies or at post-mortem. Restrictive cardiomyopathy is diagnosed based on medical history, physical examination, and tests: such as blood tests, electrocardiogram, chest X-ray, echocardiography, and magnetic resonance imaging. With its wide availability, echocardiography is probably the most important investigation to identify the left ventricular dysfunction and should be performed early and by groups that are familiar with the wide variety of aetiologies. Finally, on rare occasions, the differential diagnosis from constrictive pericarditis may be necessary.

  4. LMNA cardiomyopathy: cell biology and genetics meet clinical medicine.

    PubMed

    Lu, Jonathan T; Muchir, Antoine; Nagy, Peter L; Worman, Howard J

    2011-09-01

    Mutations in the LMNA gene, which encodes A-type nuclear lamins (intermediate filament proteins expressed in most differentiated somatic cells), cause a diverse range of diseases, called laminopathies, that selectively affect different tissues and organ systems. The most prevalent laminopathy is cardiomyopathy with or without different types of skeletal muscular dystrophy. LMNA cardiomyopathy has an aggressive clinical course with higher rates of deadly arrhythmias and heart failure than most other heart diseases. As awareness among physicians increases, and advances in DNA sequencing methods make the genetic diagnosis of LMNA cardiomyopathy more common, cardiologists are being faced with difficult questions regarding patient management. These questions concern the optimal use of intracardiac cardioverter defibrillators to prevent sudden death from arrhythmias, and medical interventions to prevent heart damage and ameliorate heart failure symptoms. Data from a mouse model of LMNA cardiomyopathy suggest that inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways are beneficial in preventing and treating cardiac dysfunction; this basic research discovery needs to be translated to human patients.

  5. Cardiomyopathy in neurological disorders.

    PubMed

    Finsterer, Josef; Stöllberger, Claudia; Wahbi, Karim

    2013-01-01

    According to the American Heart Association, cardiomyopathies are classified as primary (solely or predominantly confined to heart muscle), secondary (those showing pathological myocardial involvement as part of a neuromuscular disorder) and those in which cardiomyopathy is the first/predominant manifestation of a neuromuscular disorder. Cardiomyopathies may be further classified as hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or unclassified cardiomyopathy (noncompaction, Takotsubo-cardiomyopathy). This review focuses on secondary cardiomyopathies and those in which cardiomyopathy is the predominant manifestation of a myopathy. Any of them may cause neurological disease, and any of them may be a manifestation of a neurological disorder. Neurological disease most frequently caused by cardiomyopathies is ischemic stroke, followed by transitory ischemic attack, syncope, or vertigo. Neurological disease, which most frequently manifests with cardiomyopathies are the neuromuscular disorders. Most commonly associated with cardiomyopathies are muscular dystrophies, myofibrillar myopathies, congenital myopathies and metabolic myopathies. Management of neurological disease caused by cardiomyopathies is not at variance from the same neurological disorders due to other causes. Management of secondary cardiomyopathies is not different from that of cardiomyopathies due to other causes either. Patients with neuromuscular disorders require early cardiologic investigations and close follow-ups, patients with cardiomyopathies require neurological investigation and avoidance of muscle toxic medication if a neuromuscular disorder is diagnosed. Which patients with cardiomyopathy profit most from primary stroke prevention is unsolved and requires further investigations.

  6. 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

  7. What Is 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. ...

  8. Nemaline myopathy with dilated cardiomyopathy in childhood.

    PubMed

    Gatayama, Ryohei; Ueno, Kentaro; Nakamura, Hideaki; Yanagi, Sadamitsu; Ueda, Hideaki; Yamagishi, Hiroyuki; Yasui, Seiyo

    2013-06-01

    We present a case of a 9-year-old boy with nemaline myopathy and dilated cardiomyopathy. The combination of nemaline myopathy and cardiomyopathy is rare, and this is the first reported case of dilated cardiomyopathy associated with childhood-onset nemaline myopathy. A novel mutation, p.W358C, in ACTA1 was detected in this patient. An unusual feature of this case was that the patient's cardiac failure developed during early childhood with no delay of gross motor milestones. The use of a β-blocker did not improve his clinical course, and the patient died 6 months after diagnosis of dilated cardiomyopathy. Congenital nonprogressive nemaline myopathy is not necessarily a benign disorder: deterioration can occur early in the course of dilated cardiomyopathy with neuromuscular disease, and careful clinical evaluation is therefore necessary.

  9. Heart failure and tachycardia-induced cardiomyopathy.

    PubMed

    Ellis, Ethan R; Josephson, Mark E

    2013-12-01

    Congestive heart failure is a major health care concern affecting almost six million Americans and an estimated 23 million people worldwide, and its prevalence is increasing with time. Long-standing tachycardia is a well-recognized cause of heart failure and left ventricular dysfunction and has led to the nomenclature, tachycardia-induced cardiomyopathy. Tachycardia-induced cardiomyopathy is generally a reversible cardiomyopathy with effective treatment of the causative arrhythmia, either with medications, surgery, or catheter ablation. Tachycardia-induced cardiomyopathy remains poorly understood and is likely under-diagnosed. A better understanding of tachycardia-induced cardiomyopathy and improved recognition of its presence in clinical practice is vital to the health of patients with this disorder. The goal of this review is to discuss the pathogenesis and clinical manifestations of tachycardia-induced cardiomyopathy, as well as approaches to its diagnosis and treatment.

  10. Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature.

    PubMed

    Hedberg-Oldfors, Carola; Glamuzina, Emma; Ruygrok, Peter; Anderson, Lisa J; Elliott, Perry; Watkinson, Oliver; Occleshaw, Chris; Abernathy, Malcolm; Turner, Clinton; Kingston, Nicola; Murphy, Elaine; Oldfors, Anders

    2017-01-01

    We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.

  11. Kem Mutations Affect Nuclear Fusion in Saccharomyces Cerevisiae

    PubMed Central

    Kim, J.; Ljungdahl, P. O.; Fink, G. R.

    1990-01-01

    We have identified mutations in three genes of Saccharomyces cerevisiae, KEM1, KEM2 and KEM3, that enhance the nuclear fusion defect of kar1-1 yeast during conjugation. The KEM1 and KEM3 genes are located on the left arm of chromosome VII. Kem mutations reduce nuclear fusion whether the kem and the kar1-1 mutations are in the same or in different parents (i.e., in both kem kar1-1 X wild-type and kem X kar1-1 crosses). kem1 X kem1 crosses show a defect in nuclear fusion, but kem1 X wild-type crosses do not. Mutant kem1 strains are hypersensitive to benomyl, lose chromosomes at a rate 10-20-fold higher than KEM(+) strains, and lose viability upon nitrogen starvation. In addition, kem1/kem1 diploids are unable to sporulate. Cells containing a kem1 null allele grow very poorly, have an elongated rod-shape and are defective in spindle pole body duplication and/or separation. The KEM1 gene, which is expressed as a 5.5-kb mRNA transcript, contains a 4.6-kb open reading frame encoding a 175-kD protein. PMID:2076815

  12. Genetic Variations Leading to Familial Dilated Cardiomyopathy.

    PubMed

    Cho, Kae Won; Lee, Jongsung; Kim, Youngjo

    2016-10-01

    Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions.

  13. Genetic Variations Leading to Familial Dilated Cardiomyopathy

    PubMed Central

    Cho, Kae Won; Lee, Jongsung; Kim, Youngjo

    2016-01-01

    Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions. PMID:27802374

  14. 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

  15. 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

  16. Peripartum cardiomyopathy: a review

    PubMed Central

    Capriola, Michael

    2013-01-01

    Peripartum cardiomyopathy (PPCM) is a form of dilated cardiomyopathy of unclear etiology affecting women without preexisting heart disease during the last month of pregnancy or during the first 5 months postpartum. Its incidence shows marked geographic and ethnic variation, being most common in Africa and among women of African descent. Most women present in the first month postpartum with typical heart failure symptoms such as dyspnea, lower extremity edema, and fatigue. These symptoms are often initially erroneously diagnosed as part of the normal puerperal process. Diagnosis can be aided by the finding of a significantly elevated serum brain natriuretic peptide. The etiology of PPCM is unclear; however, recent research suggests abnormal prolactin metabolism is seminal in its development, and prolactin antagonism with bromocriptine shows promise as a novel treatment for PPCM. PMID:23300351

  17. Factors affecting mutational specificity induced by ionizing radiation and oxidizing radicals

    SciTech Connect

    Strauss, B.S.

    1992-01-01

    We propose to analyze the factors affecting the specificity of mutational change as induced by ionizing radiation and oxidizing radicals. We want to understand not only the rules that affect base substitution, but also the mechanism(s) by which additions and deletions are produced, since detections are a common consequence of radiation. We wish to carry out this analysis in an in vitro mutation system that permits us to analyze the role of base sequence, of polymerase and of mutagenic agent. Our system is designed to screen out most direct breaks as a cause of mutation and should indicate the changes resulting from base damage to the DNA.

  18. The genetics of dilated cardiomyopathy

    PubMed Central

    Dellefave, Lisa; McNally, Elizabeth M.

    2010-01-01

    Purpose of review More than forty different individual genes have been implicated in the inheritance of dilated cardiomyopathy. For a subset of these genes, mutations can lead to a spectrum of cardiomyopathy that extends to hypertrophic cardiomyopathy and left ventricular noncompaction. In nearly all cases, there is an increased risk of arrhythmias. With some genetic mutations, extracardiac manifestations are likely to be present. The precise genetic etiology can usually not be discerned from the cardiac and/or extracardiac manifestations and requires molecular genetic diagnosis for prognostic determination and cardiac care. Recent findings Newer technologies are influencing genetic testing, especially cardiomyopathy genetic testing, where an increased number of genes are now routinely being tested simultaneously. While this approach to testing multiple genes is increasing the diagnostic yield, the analysis of multiple genes in one test is also resulting in a large amount of genetic information of unclear significance. Summary Genetic testing is highly useful in the care of patients and families, since it guides diagnosis, influences care and aids in prognosis. However, the large amount of benign human genetic variation may complicate genetic results, and often requires a skilled team to accurately interpret the findings. PMID:20186049

  19. Myocardial Fibrosis as an Early Manifestation of Hypertrophic Cardiomyopathy

    PubMed Central

    Ho, Carolyn Y.; López, Begoña; Coelho-Filho, Otavio R.; Lakdawala, Neal K.; Cirino, Allison L.; Jarolim, Petr; Kwong, Raymond; González, Arantxa; Colan, Steven D.; Seidman, J.G.; Díez, Javier; Seidman, Christine E.

    2011-01-01

    BACKGROUND Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy and a proposed substrate for arrhythmias and heart failure. In animal models, profibrotic genetic pathways are activated early, before hypertrophic remodeling. Data showing early profibrotic responses to sarcomere-gene mutations in patients with hypertrophic cardiomyopathy are lacking. METHODS We used echocardiography, cardiac magnetic resonance imaging (MRI), and serum biomarkers of collagen metabolism, hemodynamic stress, and myocardial injury to evaluate subjects with hypertrophic cardiomyopathy and a confirmed genotype. RESULTS The study involved 38 subjects with pathogenic sarcomere mutations and overt hypertrophic cardiomyopathy, 39 subjects with mutations but no left ventricular hypertrophy, and 30 controls who did not have mutations. Levels of serum C-terminal propeptide of type I procollagen (PICP) were significantly higher in mutation carriers without left ventricular hypertrophy and in subjects with overt hypertrophic cardiomyopathy than in controls (31% and 69% higher, respectively; P<0.001). The ratio of PICP to C-terminal telopeptide of type I collagen was increased only in subjects with overt hypertrophic cardiomyopathy, suggesting that collagen synthesis exceeds degradation. Cardiac MRI studies showed late gadolinium enhancement, indicating myocardial fibrosis, in 71% of subjects with overt hypertrophic cardiomyopathy but in none of the mutation carriers without left ventricular hypertrophy. CONCLUSIONS Elevated levels of serum PICP indicated increased myocardial collagen synthesis in sarcomere-mutation carriers without overt disease. This profibrotic state preceded the development of left ventricular hypertrophy or fibrosis visible on MRI. (Funded by the National Institutes of Health and others.) PMID:20818890

  20. 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

  1. Factors affecting mutational specificity induced by ionizing radiation and oxidizing radicals. Progress report

    SciTech Connect

    Strauss, B.

    1992-07-01

    We propose to analyze the factors affecting the specificity of mutational change as induced by ionizing radiation and oxidizing radicals. We want to understand not only the rules the affect base substitution but also the mechanisms(s) by which additions and deletions are produced, since deletions are a common consequence of radiation. We wish to carry out this analysis in an in vitro mutation system that permits us to analyze the role of base sequence, of polymerase and of mutagenic agent. Our system is designed to screen out most direct breaks as a cause of mutation and should indicate the changes resulting from base damage to the DNA. Questions addressed include: 1. What types of base substitution mutations are induced by ionizing radiation and oxidizing radicals? 2. Are deletions and/or additions produced? 3. Is there a difference in type of mutation produced dependent on the polymerase used? Do mammalian polymerase plus their accessory factors result in different patterns of mutation. 4. What is the mechanism by which base damage is converted to mutation. Our proposal was based on utilization of an in vitro system in which mutations generated by the in vitro copying of a reporter gene sequence could be readily scored.

  2. Factors affecting mutational specificity induced by ionizing radiation and oxidizing radicals

    SciTech Connect

    Strauss, B.

    1992-01-01

    We propose to analyze the factors affecting the specificity of mutational change as induced by ionizing radiation and oxidizing radicals. We want to understand not only the rules the affect base substitution but also the mechanisms(s) by which additions and deletions are produced, since deletions are a common consequence of radiation. We wish to carry out this analysis in an in vitro mutation system that permits us to analyze the role of base sequence, of polymerase and of mutagenic agent. Our system is designed to screen out most direct breaks as a cause of mutation and should indicate the changes resulting from base damage to the DNA. Questions addressed include: 1. What types of base substitution mutations are induced by ionizing radiation and oxidizing radicals 2. Are deletions and/or additions produced 3. Is there a difference in type of mutation produced dependent on the polymerase used Do mammalian polymerase plus their accessory factors result in different patterns of mutation. 4. What is the mechanism by which base damage is converted to mutation. Our proposal was based on utilization of an in vitro system in which mutations generated by the in vitro copying of a reporter gene sequence could be readily scored.

  3. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines.

    PubMed

    Chappuis-Flament, S; Pasini, A; De Vita, G; Ségouffin-Cariou, C; Fusco, A; Attié, T; Lenoir, G M; Santoro, M; Billaud, M

    1998-12-03

    The RET gene encodes a receptor tyrosine kinase whose function is essential during the development of kidney and the intestinal nervous system. Germline mutations affecting one of five cysteines (Cys609, 611, 618, 620 and 634) located in the juxtamembrane domain of the RET receptor are responsible for the vast majority of two cancer-prone disorders, multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC). These mutations lead to the replacement of a cysteine by an alternate amino acid. Mutations of the RET gene are also the underlying genetic cause of Hirschsprung disease (HSCR), a congenital aganglionosis of the hindgut. In a fraction of kindreds, MEN 2A cosegregate with HSCR and affected individuals carry a single mutation at codons 609, 618 or 620. To examine the consequences of cysteine substitution on RET function, we have introduced a Cys to Arg mutation into the wild-type RET at either codons 609, 618, 620, 630 or 634. We now report that each mutation induces a constitutive catalytic activity due to the aberrant disulfide homodimerization of RET. However, mutations 630 and 634 activate RET more strongly than mutations 609, 618 or 620 as demonstrated by quantitative assays in rodent fibroblasts and pheochromocytoma PC12 cells. Biochemical analysis revealed that mutations 618 and 620, and to a lesser extent mutation 609, result in a marked reduction of the level of RET at the cell surface and as a consequence decrease the amount of RET covalent dimer. These findings provide a molecular basis explaining the range of phenotype engendered by alterations of RET cysteines and suggest a novel mechanism whereby mutations of cysteines 609, 618 and 620 exert both activating and inactivating effects.

  4. Tumor-specific mutations in low-frequency genes affect their functional properties.

    PubMed

    Erdem-Eraslan, Lale; Heijsman, Daphne; de Wit, Maurice; Kremer, Andreas; Sacchetti, Andrea; van der Spek, Peter J; Sillevis Smitt, Peter A E; French, Pim J

    2015-05-01

    Causal genetic changes in oligodendrogliomas (OD) with 1p/19q co-deletion include mutations in IDH1, IDH2, CIC, FUBP1, TERT promoter and NOTCH1. However, it is generally assumed that more somatic mutations are required for tumorigenesis. This study aimed to establish whether genes mutated at low frequency can be involved in OD initiation and/or progression. We performed whole-genome sequencing on three anaplastic ODs with 1p/19q co-deletion. To estimate mutation frequency, we performed targeted resequencing on an additional 39 ODs. Whole-genome sequencing identified a total of 55 coding mutations (range 8-32 mutations per tumor), including known abnormalities in IDH1, IDH2, CIC and FUBP1. We also identified mutations in genes, most of which were previously not implicated in ODs. Targeted resequencing on 39 additional ODs confirmed that these genes are mutated at low frequency. Most of the mutations identified were predicted to have a deleterious functional effect. Functional analysis on a subset of these genes (e.g. NTN4 and MAGEH1) showed that the mutation affects the subcellular localization of the protein (n = 2/12). In addition, HOG cells stably expressing mutant GDI1 or XPO7 showed altered cell proliferation compared to those expressing wildtype constructs. Similarly, HOG cells expressing mutant SASH3 or GDI1 showed altered migration. The significantly higher rate of predicted deleterious mutations, the changes in subcellular localization and the effects on proliferation and/or migration indicate that many of these genes functionally may contribute to gliomagenesis and/or progression. These low-frequency genes and their affected pathways may provide new treatment targets for this tumor type.

  5. The genetic basis of hypertrophic cardiomyopathy in cats and humans.

    PubMed

    Kittleson, Mark D; Meurs, Kathryn M; Harris, Samantha P

    2015-12-01

    Mutations in genes that encode for muscle sarcomeric proteins have been identified in humans and two breeds of domestic cats with hypertrophic cardiomyopathy (HCM). This article reviews the history, genetics, and pathogenesis of HCM in the two species in order to give veterinarians a perspective on the genetics of HCM. Hypertrophic cardiomyopathy in people is a genetic disease that has been called a disease of the sarcomere because the preponderance of mutations identified that cause HCM are in genes that encode for sarcomeric proteins (Maron and Maron, 2013). Sarcomeres are the basic contractile units of muscle and thus sarcomeric proteins are responsible for the strength, speed, and extent of muscle contraction. In people with HCM, the two most common genes affected by HCM mutations are the myosin heavy chain gene (MYH7), the gene that encodes for the motor protein β-myosin heavy chain (the sarcomeric protein that splits ATP to generate force), and the cardiac myosin binding protein-C gene (MYBPC3), a gene that encodes for the closely related structural and regulatory protein, cardiac myosin binding protein-C (cMyBP-C). To date, the two mutations linked to HCM in domestic cats (one each in Maine Coon and Ragdoll breeds) also occur in MYBPC3 (Meurs et al., 2005, 2007). This is a review of the genetics of HCM in both humans and domestic cats that focuses on the aspects of human genetics that are germane to veterinarians and on all aspects of feline HCM genetics.

  6. Diaphanous gene mutation affects spiral cleavage and chirality in snails

    PubMed Central

    Kuroda, Reiko; Fujikura, Kohei; Abe, Masanori; Hosoiri, Yuji; Asakawa, Shuichi; Shimizu, Miho; Umeda, Shin; Ichikawa, Futaba; Takahashi, Hiromi

    2016-01-01

    L-R (left and right) symmetry breaking during embryogenesis and the establishment of asymmetric body plan are key issues in developmental biology, but the onset including the handedness-determining gene locus still remains unknown. Using pure dextral (DD) and sinistral (dd) strains of the pond snail Lymnaea stagnalis as well as its F2 through to F10 backcrossed lines, the single handedness-determining-gene locus was mapped by genetic linkage analysis, BAC cloning and chromosome walking. We have identified the actin-related diaphanous gene Lsdia1 as the strongest candidate. Although the cDNA and derived amino acid sequences of the tandemly duplicated Lsdia1 and Lsdia2 genes are very similar, we could discriminate the two genes/proteins in our molecular biology experiments. The Lsdia1 gene of the sinistral strain carries a frameshift mutation that abrogates full-length LsDia1 protein expression. In the dextral strain, it is already translated prior to oviposition. Expression of Lsdia1 (only in the dextral strain) and Lsdia2 (in both chirality) decreases after the 1-cell stage, with no asymmetric localization throughout. The evolutionary relationships among body handedness, SD/SI (spiral deformation/spindle inclination) at the third cleavage, and expression of diaphanous proteins are discussed in comparison with three other pond snails (L. peregra, Physa acuta and Indoplanorbis exustus). PMID:27708420

  7. The callipyge mutation and other genes that affect muscle hypertrophy in sheep

    PubMed Central

    2005-01-01

    Genetic strategies to improve the profitability of sheep operations have generally focused on traits for reproduction. However, natural mutations exist in sheep that affect muscle growth and development, and the exploitation of these mutations in breeding strategies has the potential to significantly improve lamb-meat quality. The best-documented mutation for muscle development in sheep is callipyge (CLPG), which causes a postnatal muscle hypertrophy that is localized to the pelvic limbs and loin. Enhanced skeletal muscle growth is also observed in animals with the Carwell (or rib-eye muscling) mutation, and a double-muscling phenotype has been documented for animals of the Texel sheep breed. However, the actual mutations responsible for these muscular hypertrophy phenotypes in sheep have yet to be identified, and further characterization of the genetic basis for these phenotypes will provide insight into the biological control of muscle growth and body composition. PMID:15601596

  8. 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.

  9. Hypertrophic cardiomyopathy: a heart in need of an energy bar?

    PubMed Central

    Vakrou, Styliani; Abraham, M. Roselle

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) has been recently recognized as the most common inherited cardiovascular disorder, affecting 1 in 500 adults worldwide. HCM is characterized by myocyte hypertrophy resulting in thickening of the ventricular wall, myocyte disarray, interstitial and/or replacement fibrosis, decreased ventricular cavity volume and diastolic dysfunction. HCM is also the most common cause of sudden death in the young. A large proportion of patients diagnosed with HCM have mutations in sarcomeric proteins. However, it is unclear how these mutations lead to the cardiac phenotype, which is variable even in patients carrying the same causal mutation. Abnormalities in calcium cycling, oxidative stress, mitochondrial dysfunction and energetic deficiency have been described constituting the basis of therapies in experimental models of HCM and HCM patients. This review focuses on evidence supporting the role of cellular metabolism and mitochondria in HCM. PMID:25191275

  10. 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.

  11. The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy

    PubMed Central

    Spudich, James A.

    2015-01-01

    No matter how many times one explores the structure of the myosin molecule, there is always something new to discover. Here, I describe the myosin mesa, a structural feature of the motor domain that has the characteristics of a binding domain for another protein, possibly myosin-binding protein C (MyBP-C). Interestingly, many well-known hypertrophic cardiomyopathy (HCM) mutations lie along this surface and may affect the putative interactions proposed here. A potential unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy is discussed here. It involves increased power output of the cardiac muscle as a result of HCM mutations causing the release of inhibition by myosin binding protein C. PMID:25619247

  12. Mutations in arrestin-3 differentially affect binding to neuropeptide Y receptor subtypes.

    PubMed

    Gimenez, Luis E; Babilon, Stefanie; Wanka, Lizzy; Beck-Sickinger, Annette G; Gurevich, Vsevolod V

    2014-07-01

    Based on the identification of residues that determine receptor selectivity in arrestins and the phylogenetic analysis of the arrestin (arr) family, we introduced fifteen mutations of receptor-discriminator residues in arr-3, which were identified previously using mutagenesis, in vitro binding, and BRET-based recruitment assay in intact cells. The effects of these mutations were tested using neuropeptide Y receptors Y1R and Y2R. NPY-elicited arr-3 recruitment to Y1R was not affected by these mutations, or even alanine substitution of all ten residues (arr-3-NCA), which prevented arr-3 binding to other receptors tested so far. However, NCA and two other mutations prevented agonist-independent arr-3 pre-docking to Y1R. In contrast, eight out of 15 mutations significantly reduced agonist-dependent arr-3 recruitment to Y2R. NCA eliminated arr-3 binding to active Y2R, whereas Tyr239Thr reduced it ~7-fold. Thus, manipulation of key residues on the receptor-binding surface generates arr-3 with high preference for Y1R over Y2R. Several mutations differentially affect arr-3 pre-docking and agonist-induced recruitment. Thus, arr-3 recruitment to the receptor involves several mechanistically distinct steps. Targeted mutagenesis can fine-tune arrestins directing them to specific receptors and particular activation states of the same receptor.

  13. Mutations in arrestin-3 differentially affect binding to neuropeptide Y receptor subtypes

    PubMed Central

    Gimenez, Luis E.; Babilon, Stefanie; Wanka, Lizzy; Beck-Sickinger, Annette G.; Gurevich, Vsevolod V.

    2014-01-01

    Based on the identification of residues that determine receptor selectivity in arrestins and the phylogenetic analysis of the arrestin (arr) family, we introduced fifteen mutations of receptor-discriminator residues in arr-3, which were identified previously using mutagenesis, in vitro binding, and BRET-based recruitment assay in intact cells. The effects of these mutations were tested using neuropeptide Y receptors Y1R and Y2R. NPY-elicited arr-3 recruitment to Y1R was not affected by these mutations, or even alanine substitution of all ten residues (arr-3-NCA), which prevented arr-3 binding to other receptors tested so far. However, NCA and two other mutations prevented agonist-independent arr-3 pre-docking to Y1R. In contrast, eight out of 15 mutations significantly reduced agonist-dependent arr-3 recruitment to Y2R. NCA eliminated arr-3 binding to active Y2R, whereas Tyr239Thr reduced it ~7-fold. Thus, manipulation of key residues on the receptor-binding surface generates arr-3 with high preference for Y1R over Y2R. Several mutations differentially affect arr-3 pre-docking and agonist-induced recruitment. Thus, arr-3 recruitment to the receptor involves several mechanistically distinct steps. Targeted mutagenesis can fine-tune arrestins directing them to specific receptors and particular activation states of the same receptor. PMID:24686081

  14. Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.

    PubMed

    Breuss, Martin W; Nguyen, Thai; Srivatsan, Anjana; Leca, Ines; Tian, Guoling; Fritz, Tanja; Hansen, Andi H; Musaev, Damir; McEvoy-Venneri, Jennifer; James, Kiely N; Rosti, Rasim O; Scott, Eric; Tan, Uner; Kolodner, Richard D; Cowan, Nicholas J; Keays, David A; Gleeson, Joseph G

    2016-12-23

    The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the α/β-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of β-tubulin to fold or become assembled into the α/β-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.

  15. Mutations affecting a putative MutLα endonuclease motif impact multiple mismatch repair functions

    PubMed Central

    Erdeniz, Naz; Nguyen, Megan; Deschênes, Suzanne M.; Liskay, R. Michael

    2008-01-01

    Mutations in DNA mismatch repair (MMR) lead to increased mutation rates and higher recombination between similar, but not identical sequences, as well as resistance to certain DNA methylating agents. Recently, a component of human MMR machinery, MutLα, has been shown to display a latent endonuclease activity. The endonuclease active site appears to include a conserved motif, DQHA(X)2E(X)4E, within the COOH-terminus of human PMS2. Substitution of the glutamic acid residue (E705) abolished the endonuclease activity and mismatch-dependent excision in vitro. Previously, we showed that the PMS2-E705K mutation and the corresponding mutation in Saccharomyces cerevisiae were both recessive loss of function alleles for mutation avoidance in vivo. Here, we show that mutations impacting this endonuclease motif also significantly affect MMR-dependent suppression of homeologous recombination in yeast and responses to Sn1-type methylating agents in both yeast and mammalian cells. Thus, our in vivo results suggest that the endonuclease activity of MutLα is important not only in MMR-dependent mutation avoidance but also for recombination and damage response functions. PMID:17567544

  16. Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes.

    PubMed

    Ochs, Hans D

    2009-01-01

    Mutations of the Wiskott-Aldrich Syndrome Protein (WASP) are responsible for classic Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and in rare instances congenital X-linked neutropenia (XLN). WASP is a regulator of actin polymerization in hematopoietic cells with well-defined functional domains that are involved in cell signaling and cell locomotion, immune synapse formation, and apoptosis. Mutations of WASP are located throughout the gene and either inhibit or disregulate normal WASP function. Analysis of a large patient population demonstrates a strong phenotype-genotype correlation. Classic WAS occurs when WASP is absent, XLT when mutated WASP is expressed and XLN when missense mutations occur in the Cdc42-binding site. However, because there are exceptions to this rule it is difficult to predict the long-term prognosis of a given affected boy solely based on the analysis of WASP expression.

  17. Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy.

    PubMed

    Hershberger, Ray E; Cowan, Jason; Morales, Ana; Siegfried, Jill D

    2009-05-01

    This review focuses on the genetic cardiomyopathies: principally dilated cardiomyopathy, with salient features of hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia/cardiomyopathy, regarding genetic etiology, genetic testing, and genetic counseling. Enormous progress has recently been made in identifying genetic causes for each cardiomyopathy, and key phenotype and genotype information is reviewed. Clinical genetic testing is rapidly emerging with a principal rationale of identifying at-risk asymptomatic or disease-free relatives. Knowledge of a disease-causing mutation can guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions. Genetic counseling is also indicated for patients and their family members regarding the symptoms of their cardiomyopathy, its inheritance pattern, family screening recommendations, and genetic testing options and possible results.

  18. 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

  19. Mutations Affecting RNA Polymerase I-Stimulated Exchange and Rdna Recombination in Yeast

    PubMed Central

    Lin, Y. H.; Keil, R. L.

    1991-01-01

    HOT1 is a cis-acting recombination-stimulatory sequence isolated from the rDNA repeat unit of yeast. The ability of HOT1 to stimulate mitotic exchange appears to depend on its ability to promote high levels of RNA polymerase I transcription. A qualitative colony color sectoring assay was developed to screen for trans-acting mutations that alter the activity of HOT1. Both hypo-recombination and hyper-recombination mutants were isolated. Genetic analysis of seven HOT1 recombination mutants (hrm) that decrease HOT1 activity shows that they behave as recessive nuclear mutations and belong to five linkage groups. Three of these mutations, hrm1, hrm2, and hrm3, also decrease rDNA exchange but do not alter recombination in the absence of HOT1. Another mutation, hrm4, decreases HOT1-stimulated recombination but does not affect rDNA recombination or exchange in the absence of HOT1. Two new alleles of RAD52 were also isolated using this screen. With regard to HOT1 activity, rad52 is epistatic to all four hrm mutations indicating that the products of the HRM genes and of RAD52 mediate steps in the same recombination pathway. Finding mutations that decrease both the activity of HOT1 and exchange in the rDNA supports the hypothesis that HOT1 plays a role in rDNA recombination. PMID:2016045

  20. 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.

  1. 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.

  2. Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG)

    PubMed Central

    Laine, C M; Chung, B D; Susic, M; Prescott, T; Semler, O; Fiskerstrand, T; D'Eufemia, P; Castori, M; Pekkinen, M; Sochett, E; Cole, W G; Netzer, C; Mäkitie, O

    2011-01-01

    Osteoporosis-pseudoglioma sydrome (OPPG) is an autosomal recessive disorder with early-onset severe osteoporosis and blindness, caused by biallelic loss-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Heterozygous carriers exhibit a milder bone phenotype. Only a few splice mutations in LRP5 have been published. We present clinical and genetic data for four patients with novel LRP5 mutations, three of which affect splicing. Patients were evaluated clinically and by radiography and bone densitometry. Genetic screening of LRP5 was performed on the basis of the clinical diagnosis of OPPG. Splice aberrances were confirmed by cDNA sequencing or exon trapping. The effect of one splice mutation on LRP5 protein function was studied. A novel splice-site mutation c.1584+4A>T abolished the donor splice site of exon 7 and activated a cryptic splice site, which led to an in-frame insertion of 21 amino acids (p.E528_V529ins21). Functional studies revealed severely impaired signal transduction presumably caused by defective intracellular transport of the mutated receptor. Exon trapping was used on two samples to confirm that splice-site mutations c.4112-2A>G and c.1015+1G>T caused splicing-out of exons 20 and 5, respectively. One patient carried a homozygous deletion of exon 4 causing the loss of exons 4 and 5, as demonstrated by cDNA analysis. Our results broaden the spectrum of mutations in LRP5 and provide the first functional data on splice aberrations. PMID:21407258

  3. Identification and Functional Characterization of GAA Mutations in Colombian Patients Affected by Pompe Disease.

    PubMed

    Niño, Mónica Yasmín; Mateus, Heidi Eliana; Fonseca, Dora Janeth; Kroos, Marian A; Ospina, Sandra Yaneth; Mejía, Juan Fernando; Uribe, Jesús Alfredo; Reuser, Arnold J J; Laissue, Paul

    2013-01-01

    Pompe disease (PD) is a recessive metabolic disorder characterized by acid α-glucosidase (GAA) deficiency, which results in lysosomal accumulation of glycogen in all tissues, especially in skeletal muscles. PD clinical course is mainly determined by the nature of the GAA mutations. Although ~400 distinct GAA sequence variations have been described, the genotype-phenotype correlation is not always evident.In this study, we describe the first clinical and genetic analysis of Colombian PD patients performed in 11 affected individuals. GAA open reading frame sequencing revealed eight distinct mutations related to PD etiology including two novel missense mutations, c.1106 T > C (p.Leu369Pro) and c.2236 T > C (p.Trp746Arg). In vitro functional studies showed that the structural changes conferred by both mutations did not inhibit the synthesis of the 110 kD GAA precursor form but affected the processing and intracellular transport of GAA. In addition, analysis of previously described variants located at this position (p.Trp746Gly, p.Trp746Cys, p.Trp746Ser, p.Trp746X) revealed new insights in the molecular basis of PD. Notably, we found that p.Trp746Cys mutation, which was previously described as a polymorphism as well as a causal mutation, displayed a mild deleterious effect. Interestingly and by chance, our study argues in favor of a remarkable Afro-American and European ancestry of the Colombian population. Taken together, our report provides valuable information on the PD genotype-phenotype correlation, which is expected to facilitate and improve genetic counseling of affected individuals and their families.

  4. Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    Roberts, Jason D; Veinot, John P; Rutberg, Julie; Gollob, Michael H

    2010-01-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) represents an inherited cardiomyopathy that manifests clinically with malignant ventricular arrhythmias, sudden cardiac death, and less commonly heart failure. The condition is characterized by replacement of the myocardium, primarily of the right ventricle, with fibrofatty tissue. Extensive fibrofatty replacement of the myocardium has been previously thought to be pathognomonic of ARVC; however, this report details two other forms of inherited cardiomyopathy, namely hypertrophic cardiomyopathy (HCM) and the PRKAG2 cardiac syndrome, that were found to have significant fibrofatty myocardial replacement at pathologic examination. This report represents the first documentation of inherited cardiomyopathies mimicking ARVC and highlights the concept that other cardiac conditions can be associated with fibrofatty replacement of the myocardium.

  5. [Classification of cardiomyopathy].

    PubMed

    Asakura, Masanori; Kitakaze, Masafumi

    2014-01-01

    Cardiomyopathy is a group of cardiovascular diseases with poor prognosis. Some patients with dilated cardiomyopathy need heart transplantations due to severe heart failure. Some patients with hypertrophic cardiomyopathy die unexpectedly due to malignant ventricular arrhythmias. Various phenotypes of cardiomyopathies are due to the heterogeneous group of diseases. The classification of cardiomyopathies is important and indispensable in the clinical situation. However, their classification has not been established, because the causes of cardiomyopathies have not been fully elucidated. We usually use definition and classification offered by WHO/ISFC task force in 1995. Recently, several new definitions and classifications of the cardiomyopathies have been published by American Heart Association, European Society of Cardiology and Japanese Circulation Society.

  6. Neonatal dilated cardiomyopathy.

    PubMed

    Soares, Paulo; Rocha, Gustavo; Pissarra, Susana; Soares, Henrique; Flôr-de-Lima, Filipa; Costa, Sandra; Moura, Cláudia; Dória, Sofia; Guimarães, Hercília

    2017-03-01

    Cardiomyopathies are rare diseases of the heart muscle, of multiple causes, that manifest with various structural and functional phenotypes but are invariably associated with cardiac dysfunction. Dilated cardiomyopathy is the commonest cardiomyopathy in children, and the majority present before one year of age. Its etiology may be acquired or genetic. Myocarditis is an important cause and is responsible for the majority of acquired cases. Inherited (familial) forms of dilated cardiomyopathy may occur in 25-50% of patients. Echocardiographic and tissue Doppler studies are the basis for diagnosis of dilated cardiomyopathy in most patients. Marked dilatation of the left ventricle with global hypokinesis is the hallmark of the disease. This review will cover the classification, epidemiology and management of newborns with dilated cardiomyopathy. In particular, a comprehensive and up-to-date review of the genetic study of dilated cardiomyopathy and of detailed echocardiographic assessment of these patients will be presented.

  7. A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.

    PubMed

    Davis, Jennifer; Davis, L Craig; Correll, Robert N; Makarewich, Catherine A; Schwanekamp, Jennifer A; Moussavi-Harami, Farid; Wang, Dan; York, Allen J; Wu, Haodi; Houser, Steven R; Seidman, Christine E; Seidman, Jonathan G; Regnier, Michael; Metzger, Joseph M; Wu, Joseph C; Molkentin, Jeffery D

    2016-05-19

    The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model, the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent-stem-cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

  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.

  9. Two different cardiomyopathies in a single patient : hypertrophic cardiomyopathy and left ventricular noncompaction.

    PubMed

    Sunbul, M; Ozben, B; Mutlu, B

    2013-05-01

    Hypertrophic cardiomyopathy is a complex and relatively common genetic disorder characterized by left ventricular (LV) hypertrophy, usually associated with a nondilated and hyperdynamic chamber with heterogeneous phenotypic expression and clinical course. On the other hand, LV noncompaction is an uncommon cardiomyopathy characterized by the persistence of fetal myocardium with a pattern of prominent trabecular meshwork and deep intertrabecular recesses, systolic dysfunction, and LV dilatation. We report a 29-year-old man with these two different inherent conditions. Our case raises the possibility of a genetic mutation common to these two clinical entities or different gene mutations existing in the same individual.

  10. Mutations affecting mitotic recombination frequency in haploids and diploids of the filamentous fungus Aspergillus nidulans.

    PubMed

    Parag, Y; Parag, G

    1975-01-01

    A haploid strain of Asp. nidulans with a chromosome segment in duplicate (one in normal position on chromosome I, one translocated to chromosome II) shows mitotic recombination, mostly by conversion, in adE in a frequency slightly higher than in the equivalent diploid. A method has been devised, using this duplication, for the selection of rec and uvs mutations. Six rec mutations have been found which decrease recombination frequency in the haploid. One mutation selected as UV sensitive showed a hundred fold increase in recombination frequency in the haploid (pop mutation) and probably the same in diploids. The increased frequency is both in gene conversion and in crossing over, and the exchanges appear in clusters of two or more. pop is allelic to uvsB (Jansen, 1970) which had been found to affect mitotic but not meiotic recombination. It is suggested that mutations of this type interfere with the control mechanism which determines that high recombination is confirmed to the meiotic nuclei and avoided in somatic nuclei.

  11. Human junctophilin-2 undergoes a structural rearrangement upon binding PtdIns(3,4,5)P3 and the S101R mutation identified in hypertrophic cardiomyopathy obviates this response.

    PubMed

    Bennett, Hayley J; Davenport, John Bernard; Collins, Richard F; Trafford, Andrew W; Pinali, Christian; Kitmitto, Ashraf

    2013-12-01

    JP2 (junctophilin-2) is believed to hold the transverse tubular and jSR (junctional sarcoplasmic reticulum) membranes in a precise geometry that facilitates excitation-contraction coupling in cardiomyocytes. We have expressed and purified human JP2 and shown using electron microscopy that the protein forms elongated structures ~15 nm long and 2 nm wide. Employing lipid-binding assays and quartz crystal microbalance with dissipation we have determined that JP2 is selective for PS (phosphatidylserine), with a Kd value of ~0.5 μM, with the N-terminal domain mediating this interaction. JP2 also binds PtdIns(3,4,5)P3 at a different site than PS, resulting in the protein adopting a more flexible conformation; this interaction is modulated by both Ca(2+) and Mg(2+) ions. We show that the S101R mutation identified in patients with hypertrophic cardiomyopathy leads to modification of the protein secondary structure, forming a more flexible molecule with an increased affinity for PS, but does not undergo a structural transition in response to binding PtdIns(3,4,5)P3. In conclusion, the present study provides new insights into the structural and lipid-binding properties of JP2 and how the S101R mutation may have an effect upon the stability of the dyad organization with the potential to alter JP2-protein interactions regulating Ca(2+) cycling.

  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. Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing

    SciTech Connect

    Akeson, A.L.; Wiginton, D.A.; States, C.J.; Perme, C.M.; Dusing, M.R.; Hutton, J.J.

    1987-08-01

    Adenosine deaminase deficiency is one cause of the genetic disease severe combined immunodeficiency. To identify mutations responsible for ADA deficiency, the authors synthesized cDNAs to ADA mRNAs from two cell lines, GM2756 and GM2825A, derived from ADA-deficient immunodeficient patients. Sequence analysis of GM2756 cDNA clones revealed a different point mutation in each allele that causes amino acid changes of alanine to valine and arginine to histidine. One allele of GM2825A also has a point mutation that causes an alanine to valine substitution. The other allele of GM2825A was found to produce an mRNA in which exon 4 had been spliced out but had no other detrimental mutations. S1 nuclease mapping of GM2825A mRNA showed equal abundance of the full-length ADA mRNA and the ADA mRNA that was missing exon 4. Several of the ADA cDNA clones extended 5' of the major initiation start site, indicating multiple start sites for ADA transcription. The point mutations in GM2756 and GM2825A and the absence of exon 4 in GM2825A appear to be directly responsible for the ADA deficiency. Comparison of a number of normal and mutant ADA cDNA sequences showed a number of changes in the third base of codons. These change do not affect the amino acid sequence. Analyses of ADA cDNAs from different cell lines detected aberrant RNA species that either included intron 7 or excluded exon 7. Their presence is a result of aberrant splicing of pre-mRNAs and is not related to mutations that cause ADA deficiency.

  14. GENETIC MUTATIONS AFFECTING THE FIRST LINE ERADICATION THERAPY OF Helicobacter pylori-INFECTED EGYPTIAN PATIENTS

    PubMed Central

    RAMZY, Iman; ELGAREM, Hassan; HAMZA, Iman; GHAITH, Doaa; ELBAZ, Tamer; ELHOSARY, Waleed; MOSTAFA, Gehan; ELZAHRY, Mohammad A. Mohey Eldin

    2016-01-01

    SUMMARY Introduction: Several genetic mutations affect the first-line triple therapy for Helicobacter pylori. We aimed to study the most common genetic mutations affecting the metronidazole and clarithromycin therapy for H. pylori-infected Egyptian patients. Patients and Methods: In our study, we included 100 successive dyspeptic patients scheduled for diagnosis through upper gastroscopy at Cairo's University Hospital, Egypt. Gastric biopsies were tested for the presence of H. pylori by detection of the 16S rRNA gene. Positive biopsies were further studied for the presence of the rdxA gene deletion by Polymerase Chain Reaction (PCR), while clarithromycin resistance was investigated by the presence of nucleotide substitutions within H. pylori 23S rRNA V domain using MboII and BsaI to carry out a Restricted Fragment Length Polymorphism (RFLP) assay. Results: Among 70 H. pylori positive biopsies, the rdxA gene deletion was detected in 44/70 (62.9%) samples, while predominance of the A2142G mutations within the H. pylori 23S rRNA V domain was evidenced in 39/70 (55.7%) of the positive H. pylori cases. No statistically significant difference was found between the presence of gene mutations and different factors such as patients 'age, gender, geographic distribution, symptoms and endoscopic findings. Conclusion: Infection with mutated H. pylori strains is considerably high, a finding that imposes care in the use of the triple therapy to treat H. pylori in Egypt, since the guidelines recommend to abandon the standard triple therapy when the primary clarithromycin resistance rate is over 20%1. PMID:27982354

  15. Ventricular hypertrophy in cardiomyopathy.

    PubMed

    Oakley, C

    1971-01-01

    Semantic difficulties arise when hypertrophic obstructive cardiomyopathy is seen without obstruction and with congestive failure, and also when congestive cardiomyopathy is seen with gross hypertrophy but without heart failure. Retention of a small left ventricular cavity and a normal ejection fraction characterizes hypertrophic cardiomyopathy at all stages of the disorder. Congestive cardiomyopathy is recognized by the presence of a dilated left ventricular cavity and reduced ejection fraction regardless of the amount of hypertrophy and the presence or not of heart failure. Longevity in congestive cardiomyopathy seems to be promoted when hypertrophy is great relative to the amount of pump failure as measured by increase in cavity size. Conversely, death in hypertrophic cardiomyopathy is most likely when hypertrophy is greatest at a time when outflow tract obstruction has been replaced by inflow restriction caused by diminishing ventricular distensibility. Hypertrophy is thus beneficial and compensatory in congestive cardiomyopathy, whereas it may be the primary disorder and eventual cause of death in hypertrophic cardiomyopathy. Reasons are given for believing that hypertension may have been the original cause of left ventricular dilatation in some case of congestive cardiomyopathy in which loss of stroke output thenceforward is followed by normotension. Development of severe hypertension in these patients after recovery from a prolonged period of left ventricular failure with normotension lends weight to this hypothesis. No fault has been found in the large or small coronary arteries in either hypertrophic cardiomyopathy or congestive cardiomyopathy when they have been examined in life by selective coronary angiography, or by histological methods in biopsy or post-mortem material. Coronary blood supply may be a limiting factor in the compensatory hypertrophy of congestive cardiomyopathy, and the ability to hypertrophy may explain the better prognosis of some

  16. Peripartum Cardiomyopathy Presenting as Bradycardia

    PubMed Central

    Rose, Carl H.; Tweet, Marysia S.; Hayes, Sharonne N.; Best, Patricia J. M.; Blauwet, Lori A.

    2017-01-01

    Peripartum cardiomyopathy (PPCM) is a disease that typically affects young otherwise healthy women. As PPCM is associated with significant mortality, timely diagnosis is necessary to ensure appropriate care. To our knowledge, this represents the first reported case of PPCM presenting as symptomatic bradycardia. We describe the patient's clinical presentation and relevant findings and review the potential etiology and ramifications of bradycardia in patients with PPCM. PMID:28255481

  17. Human viral cardiomyopathy.

    PubMed

    Maisch, Bernhard; Ristic, Arsen D; Portig, Irene; Pankuweit, Sabine

    2003-01-01

    Viral infection of the heart is relatively common, usually asymptomatic and has a spontaneous and complete resolution. It can, however, in rare cases, lead to substantial cardiac damage, development of viral cardiomyopathy and congestive heart failure. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (<14 lymphocytes and macrophages/mm ) the term viral cardiomyopathy or viral persistence in dilated cardiomyopathy should be applied. The diagnosis of myocarditis and viral cardiomyopathy can be made only by endomyocardial biopsy, implementing the WHO/WHF criteria, and PCR techniques for identification of viral genome. The most frequent cardiotropic viruses detected by endomyocardial biopsy are Parvo B19, enteroviruses, adenoviruses, cytomegalovirus, and less frequently Epstein-Barr virus, and influenza virus.

  18. Dynamics of a Recurrent Buchnera Mutation That Affects Thermal Tolerance of Pea Aphid Hosts

    PubMed Central

    Burke, Gaelen R.; McLaughlin, Heather J.; Simon, Jean-Christophe; Moran, Nancy A.

    2010-01-01

    Mutations in maternally transmitted symbionts can affect host fitness. In this study we investigate a mutation in an obligate bacterial symbiont (Buchnera), which has dramatic effects on the heat tolerance of pea aphid hosts (Acyrthosiphon pisum). The heat-sensitive allele arises through a single base deletion in a homopolymer within the promoter of ibpA, which encodes a universal small heat-shock protein. In laboratory cultures reared under cool conditions (20°), the rate of fixation (1.4 × 10−3 substitutions per Buchnera replication) is much higher than the previously estimated mutation rate for single base deletions in homopolymers in the Buchnera genome, implying a strong selective benefit. This mutation recurs in natural populations, but seldom reaches high frequencies, implying that it is only rarely favored by selection. Another potential source of physiological stress in pea aphids is infection by other microorganisms, including facultative bacterial symbionts, which occur in a majority of pea aphids in field populations. Frequency of the heat-sensitive Buchnera allele is negatively correlated with presence of facultative symbionts in both laboratory colonies and field populations, suggesting that these infections impose stress that is ameliorated by ibpA expression. This single base polymorphism in Buchnera has the potential to allow aphid populations to adapt quickly to prevailing conditions. PMID:20610410

  19. Mutations in the West Nile prM protein affect VLP and virion secretion in vitro.

    PubMed

    Calvert, Amanda E; Huang, Claire Y-H; Blair, Carol D; Roehrig, John T

    2012-11-10

    Mutation of the West Nile virus-like particle (WN VLP) prM protein (T20D, K31A, K31V, or K31T) results in undetectable VLP secretion from transformed COS-1 cells. K31 mutants formed intracellular prM-E heterodimers; however these proteins remained in the ER and ER-Golgi intermediary compartments of transfected cells. The T20D mutation affected glycosylation, heterodimer formation, and WN VLP secretion. When infectious viruses bearing the same mutations were used to infect COS-1 cells, K31 mutant viruses exhibited delayed growth and reduced infectivity compared to WT virus. Epitope maps of WN VLP and WNV prM were also different. These results suggest that while mutations in the prM protein can reduce or eliminate secretion of WN VLPs, they have less effect on virus. This difference may be due to the quantity of prM in WN VLPs compared to WNV or to differences in maturation, structure, and symmetry of these particles.

  20. [Desmin-related cardiomyopathy].

    PubMed

    Rybakova, M G; Kuznetsova, I A; Gudkova, A Ia; Kostareva, A A; Semernin, E N

    2011-01-01

    The observation of 26 years old patient with desminopathy declared itself by hypertrophied cardiomyopathy with its transformation into restrictive phenotype is presented. The features of pathologic course at the patient were a dominance and diversity of cardiac manifestations. Endomyocardiac biopsy allowed suspecting the desminopathy confirmed by genetic analysis. Morphological features of desmin-related cardiomyopathy were irregular desmin conglomerates mainly located under sarcolemma and an indirect histological signs of idiopathic cardiomyopathy as well nuclear polymorphism, perinuclear "nimbus", chaotic located myofibrils.

  1. 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.

  2. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

    PubMed Central

    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

    2016-01-01

    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

  3. Familial cardiomyopathy in Norwegian Forest cats.

    PubMed

    März, Imke; Wilkie, Lois J; Harrington, Norelene; Payne, Jessie R; Muzzi, Ruthnea A L; Häggström, Jens; Smith, Ken; Luis Fuentes, Virginia

    2015-08-01

    Norwegian Forest cats (NFCs) are often listed as a breed predisposed to cardiomyopathy, but the characteristics of cardiomyopathy in this breed have not been described. The aim of this preliminary study was to report the features of NFC cardiomyopathy based on prospective echocardiographic screening of affected family groups; necropsy findings; and open-source breed screening databases. Prospective examination of 53 NFCs revealed no murmur or left ventricular (LV) outflow tract obstruction in any screened cat, though mild LV hypertrophy (defined as diastolic LV wall thickness ≥5.5mm) was present in 13/53 cats (25%). Gross pathology results and histopathological sections were analysed in eight NFCs, six of which had died of a cardiac cause. Myocyte hypertrophy, myofibre disarray and interstitial fibrosis typical of hypertrophic cardiomyopathy were present in 7/8 cats, but endomyocardial fibrosis suggestive of restrictive cardiomyopathy was also present in the same cats. Pedigree data analysis from 871 NFCs was supportive of a familial cardiomyopathy in this breed.

  4. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation

    PubMed Central

    Svensson, Lena; Howarth, Kimberley; McDowall, Alison; Patzak, Irene; Evans, Rachel; Ussar, Siegfried; Moser, Markus; Metin, Ayse; Fried, Mike; Tomlinson, Ian; Hogg, Nancy

    2009-01-01

    Integrins are the major adhesion receptors of leukocytes and platelets. β1 and β2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin αIIbβ3 initiates the process of blood clotting through binding fibrinogen1-3. Integrins on circulating cells bind poorly to their ligands but become active after ‘inside-out’ signaling through other membrane receptors4,5. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express β2 integrins because of mutations in the gene specifying the β2 subunit, and they suffer recurrent bacterial infections6,7. Mutations affecting αIIbβ3 integrin cause the bleeding disorder termed Glanzmann’s thrombasthenia3. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann’s thrombasthenia. Their hematopoietically-derived cells express β1, β2 and β3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems8. The LAD-III lesion has been attributed to a C→A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein9, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects’ lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration. PMID:19234463

  5. 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 ...

  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. ramR mutations affecting fluoroquinolone susceptibility in epidemic multidrug-resistant Salmonella enterica serovar Kentucky ST198.

    PubMed

    Baucheron, Sylvie; Le Hello, Simon; Doublet, Benoît; Giraud, Etienne; Weill, François-Xavier; Cloeckaert, Axel

    2013-01-01

    A screening for non-target mutations affecting fluoroquinolone susceptibility was conducted in epidemic multidrug-resistant Salmonella enterica serovar Kentucky ST198. Among a panel of representative isolates (n = 27), covering the epidemic, only three showed distinct mutations in ramR resulting in enhanced expression of genes encoding the AcrAB-TolC efflux system and low increase in ciprofloxacin MIC. No mutations were detected in other regulatory regions of this efflux system. Ciprofloxacin resistance in serovar Kentucky ST198 is thus currently mainly due to multiple target gene mutations.

  9. 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.

  10. Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases.

    PubMed

    Rickelt, Steffen; Pieperhoff, Sebastian

    2012-05-01

    In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies.

  11. Mutations affecting catabolite repression of the L-arabinose regulon in Escherichia coli B/r.

    PubMed

    Heffernan, L; Bass, R; Englesberg, E

    1976-06-01

    Expression of the L-arabinose regulon in Escherichia coli B/r requires, among other things, cyclic adenosine-3', 5'-monophosphate (cAMP) and the cAMP receptor protein (CRP). Mutants deficient in adenyl cyclase (cya-), the enzyme which synthesizes cAMP, or CRP (crp-) are unable to utilize a variety of carbohydrates, including L-arabinose. Ara+ revertants of a cya-crp- strain were isolated on 0.2% minimal L-arabinose plates, conditions which require the entire ara regulon to be activated in the absence of cAMP and CRP. Evidence from genetic and physiological studies is consistent with placing these mutations in the araC regulatory gene. Deletion mapping with one mutant localized the site within either araO or araC, and complementation tests indicated the mutants acted trans to confer the ability to utilize L-arabinose in a cya-crp- genetic background. Since genetic analysis supports the conclusion, that the mutant sites are in the araC regulatory gene, the mutants were designated araCi, indicating a mutation in the regulatory gene affecting the cAMP-CRP requirement. Physiological analysis of one mutant, araCi1, illustrates the trans-acting nature of the mutation. In a cya-crp- genetic background, araCi1 promoted synthesis of both isomerase, a product of the araBAD operon, and permease, a product of the araE operon. Isomerase and permease levels in araCi1 cya+ crp+ were hyperinducible, and the sensitivity of each to cAMP was altered. Two models are presented that show the possible mutational lesion in the araCi strains.

  12. Factors affecting mutational specificity induced by ionizing radiation and oxidizing radicals. Technical progress report, February 1, 1992--October 15, 1992

    SciTech Connect

    Strauss, B.S.

    1992-01-01

    We propose to analyze the factors affecting the specificity of mutational change as induced by ionizing radiation and oxidizing radicals. We want to understand not only the rules that affect base substitution, but also the mechanism(s) by which additions and deletions are produced, since detections are a common consequence of radiation. We wish to carry out this analysis in an in vitro mutation system that permits us to analyze the role of base sequence, of polymerase and of mutagenic agent. Our system is designed to screen out most direct breaks as a cause of mutation and should indicate the changes resulting from base damage to the DNA.

  13. Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies.

    PubMed

    Hoedemaekers, Yvonne M; Caliskan, Kadir; Majoor-Krakauer, Danielle; van de Laar, Ingrid; Michels, Michelle; Witsenburg, Maarten; ten Cate, Folkert J; Simoons, Maarten L; Dooijes, Dennis

    2007-11-01

    Cardiomyopathies are classified according to distinct morphological characteristics. They occur relatively frequent and are an important cause of mortality and morbidity. Isolated ventricular non-compaction or non-compaction cardiomyopathy (NCCM) is characterized by an excessively thickened endocardial layer with deep intertrabecular recesses, reminiscent of the myocardium during early embryogenesis. Aims Autosomal-dominant as well as X-linked inheritance for NCCM has been described and several loci have been associated with the disease. Nevertheless, a major genetic cause for familial NCCM remains to be identified. Methods and Results We describe, in two separate autosomal-dominant NCCM families, the identification of mutations in the sarcomeric cardiac beta-myosin heavy chain gene (MYH7), known to be associated with hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). Conclusion These results confirm the genetic heterogeneity of NCCM and suggest that the molecular classification of cardiomyopathies includes an MYH7-associated spectrum of NCCM with HCM, RCM, and DCM.

  14. 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.

  15. Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature.

    PubMed

    Smigiel, Robert; Jakubiak, Aleksandra; Esteves-Vieira, Vera; Szela, Katarzyna; Halon, Agnieszka; Jurek, Tomasz; Lévy, Nicolas; De Sandre-Giovannoli, Annachiara

    2010-02-01

    Restrictive dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made.

  16. A Novel Forward Genetic Screen for Identifying Mutations Affecting Larval Neuronal Dendrite Development in Drosophila melanogaster

    PubMed Central

    Medina, Paul Mark B.; Swick, Lance L.; Andersen, Ryan; Blalock, Zachary; Brenman, Jay E.

    2006-01-01

    Vertebrate and invertebrate dendrites are information-processing compartments that can be found on both central and peripheral neurons. Elucidating the molecular underpinnings of information processing in the nervous system ultimately requires an understanding of the genetic pathways that regulate dendrite formation and maintenance. Despite the importance of dendrite development, few forward genetic approaches have been used to analyze the latest stages of dendrite development, including the formation of F-actin-rich dendritic filopodia or dendritic spines. We developed a forward genetic screen utilizing transgenic Drosophila second instar larvae expressing an actin, green fluorescent protein (GFP) fusion protein (actin∷GFP) in subsets of sensory neurons. Utilizing this fluorescent transgenic reporter, we conducted a forward genetic screen of >4000 mutagenized chromosomes bearing lethal mutations that affected multiple aspects of larval dendrite development. We isolated 13 mutations on the X and second chromosomes composing 11 complementation groups affecting dendrite outgrowth/branching, dendritic filopodia formation, or actin∷GFP localization within dendrites in vivo. In a fortuitous observation, we observed that the structure of dendritic arborization (da) neuron dendritic filopodia changes in response to a changing environment. PMID:16415365

  17. A fatal case of peripartum cardiomyopathy.

    PubMed

    Cohen, Ronny; Mallet, Thierry; Mirrer, Brooks; Loarte, Pablo; Gale, Michael; Kastell, Paul

    2014-06-01

    Peripartum cardiomyopathy is a life-threatening cardiac condition affecting pregnant women either late in pregnancy or early in the post-partum period. The latest studies show a dramatic improvement in the mortality rates of women affected with this disorder, which has been correlated with advances in medical therapy for heart failure. However, patients continue to die of this condition. The following case report describes a typical patient with peripartum cardiomyopathy diagnosed on clinical grounds, along with echocardiogram findings of severe systolic dysfunction and global hypokinesis consistent with dilated cardiomyopathy. Emergency cesarean delivery had to be performed for fetal distress. There was significant improvement of the patient's condition with standard pharmacological management for heart failure at the time of discharge. However, five weeks after discharge, fatal cardiac arrest occurred. It is hoped that this article will raise awareness about this rare but potentially fatal condition and promote understanding of its main clinical features, diagnostic criteria, and conventional pharmacological management.

  18. Factors affecting germline mutations in a hypervariable microsatellite: a comparative analysis of six species of swallows (Aves: Hirundinidae).

    PubMed

    Anmarkrud, Jarl A; Kleven, Oddmund; Augustin, Jakob; Bentz, Kristofer H; Blomqvist, Donald; Fernie, Kim J; Magrath, Michael J L; Pärn, Henrik; Quinn, James S; Robertson, Raleigh J; Szép, Tibor; Tarof, Scott; Wagner, Richard H; Lifjeld, Jan T

    2011-03-15

    Microsatellites mutate frequently by replication slippage. Empirical evidence shows that the probability of such slippage mutations may increase with the length of the repeat region as well as exposure to environmental mutagens, but the mutation rate can also differ between the male and female germline. It has been hypothesized that more intense sexual selection or sperm competition can also lead to elevated mutation rates, but the empirical evidence is inconclusive. Here, we analyzed the occurrence of germline slippage mutations in the hypervariable pentanucleotide microsatellite locus HrU10 across six species of swallow (Aves: Hirundinidae). These species exhibit marked differences in the length range of the microsatellite, as well as differences in the intensity of sperm competition. We found a strong effect of microsatellite length on the probability of mutation, but no residual effect of species or their level of sperm competition when the length effect was accounted for. Neither could we detect any difference in mutation rate between tree swallows (Tachycineta bicolor) breeding in Hamilton Harbour, Ontario, an industrial site with previous documentation of elevated mutation rates for minisatellite DNA, and a rural reference population. However, our cross-species analysis revealed two significant patterns of sex differences in HrU10 germline mutations: (1) mutations in longer alleles occurred typically in the male germline, those in shorter alleles in the female germline, and (2) male germline mutations were more often expansions than contractions, whereas no directional bias was evident in the female germline. These results indicate some fundamental differences in male and female gametogenesis affecting the probability of slippage mutations. Our study also reflects the value of a comparative, multi-species approach for locus-specific mutation analyses, through which a wider range of influential factors can be assessed than in single-species studies.

  19. SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome.

    PubMed

    Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A; Landau, Daniel; Birk, Ohad S

    2017-02-09

    A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through

  20. 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

  1. 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

  2. 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

  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. Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy

    PubMed Central

    Chang, Alex Chia Yu; Ong, Sang-Ging; LaGory, Edward L.; Kraft, Peggy E.; Giaccia, Amato J.; Wu, Joseph C.; Blau, Helen M.

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx4cv/mTRG2 mouse model with “humanized” telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions. PMID:27799523

  5. Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy

    PubMed Central

    Dunning, Mark D.; Brownlie, Serena

    2016-01-01

    Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with dilated cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH) is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human dilated cardiomyopathy (DCM), yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH. PMID:28070514

  6. Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy.

    PubMed

    Wang, Libin; Seidman, Jonathan G; Seidman, Christine E

    2010-04-20

    Unexplained cardiac hypertrophy, the diagnostic criterion for hypertrophic cardiomyopathy (HCM), occurs in 1 in 500 adults. Insights into the genetic cause and molecular pathophysiology of HCM are reshaping clinical paradigms for diagnosis and treatment of this common myocardial disorder. Human genetic studies have established that dominant mutations in the proteins that make up the contractile apparatus (the sarcomere) cause HCM. With the current availability of clinical gene-based diagnostics, pathogenic mutations in affected patients can be defined, which can suggest a clinical course and allow definitive preclinical identification of family members at risk for HCM. Genetic discoveries have also fostered mechanistic investigations in model organisms that are engineered to carry human HCM mutations. Novel therapeutic targets have emerged from these fundamental studies and are currently under clinical assessment in humans. The combination of contemporary gene-based diagnosis with new strategies to attenuate disease development and progression is changing the natural history of lifelong cardiac symptoms, arrhythmias, and heart failure from HCM.

  7. Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

    PubMed Central

    Yue, Yongping; Binalsheikh, Ibrahim M.; Leach, Stacey B.; Domeier, Timothy L.; Duan, Dongsheng

    2016-01-01

    Introduction Cardiac involvement is a common feature in muscular dystrophies. It presents as heart failure and/or arrhythmia. Traditionally, dystrophic cardiomyopathy is treated with symptom-relieving medications. Identification of disease-causing genes and investigation on pathogenic mechanisms have opened new opportunities to treat dystrophic cardiomyopathy with gene therapy. Replacing/repairing the mutated gene and/or targeting the pathogenic process/mechanisms using alternative genes may attenuate heart disease in muscular dystrophies. Areas covered Duchenne muscular dystrophy is the most common muscular dystrophy. Duchenne cardiomyopathy has been the primary focus of ongoing dystrophic cardiomyopathy gene therapy studies. Here, we use Duchenne cardiomyopathy gene therapy to showcase recent developments and to outline the path forward. We also discuss gene therapy status for cardiomyopathy associated with limb-girdle and congenital muscular dystrophies, and myotonic dystrophy. Expert opinion Gene therapy for dystrophic cardiomyopathy has taken a slow but steady path forward. Preclinical studies over the last decades have addressed many fundamental questions. Adeno-associated virus-mediated gene therapy has significantly improved the outcomes in rodent models of Duchenne and limb girdle muscular dystrophies. Validation of these encouraging results in large animal models will pave the way to future human trials. PMID:27340611

  8. TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish.

    PubMed

    Reverendo, Marisa; Soares, Ana R; Pereira, Patrícia M; Carreto, Laura; Ferreira, Violeta; Gatti, Evelina; Pierre, Philippe; Moura, Gabriela R; Santos, Manuel A

    2014-01-01

    Mutations in genes that encode tRNAs, aminoacyl-tRNA syntheases, tRNA modifying enzymes and other tRNA interacting partners are associated with neuropathies, cancer, type-II diabetes and hearing loss, but how these mutations cause disease is unclear. We have hypothesized that levels of tRNA decoding error (mistranslation) that do not fully impair embryonic development can accelerate cell degeneration through proteome instability and saturation of the proteostasis network. To test this hypothesis we have induced mistranslation in zebrafish embryos using mutant tRNAs that misincorporate Serine (Ser) at various non-cognate codon sites. Embryo viability was affected and malformations were observed, but a significant proportion of embryos survived by activating the unfolded protein response (UPR), the ubiquitin proteasome pathway (UPP) and downregulating protein biosynthesis. Accumulation of reactive oxygen species (ROS), mitochondrial and nuclear DNA damage and disruption of the mitochondrial network, were also observed, suggesting that mistranslation had a strong negative impact on protein synthesis rate, ER and mitochondrial homeostasis. We postulate that mistranslation promotes gradual cellular degeneration and disease through protein aggregation, mitochondrial dysfunction and genome instability.

  9. 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.

  10. P-element mutations affecting embryonic peripheral nervous system development in Drosophila melanogaster

    SciTech Connect

    Kania, A.; Salzberg, A.; Bhat, M.

    1995-04-01

    The Drosophila embryonic peripheral nervous system (PNS) is an excellent model system to study the molecular mechanisms governing neural development. To identify genes controlling PNS development, we screened 2000 lethal P-element insertion strains. The PNS of mutant embryos was examined using the neural specific marker MAb 22C10, and 92 mutant strains were retained for further analysis. Genetic and cytological analysis of these strains shows that 42 mutations affect previously isolated genes that are known to be required for PNS development: longitudinals lacking (19), mastermind (15), numb (4), big brain (2), and spitz (2). The remaining 50 mutations were classified into 29 complementation groups and the P-element insertions were cytologically mapped. The mutants were classified in five major classes on the basis of their phenotype: gain of neurons, loss of neurons, organizational defects, pathfinding defects and morphological defects. Herein we report the preliminary phenotypic characterization of each of these complementation groups as well as the embryonic lacZ expression pattern of each P-element strain. Our analysis indicates that in most of the P-element insertion strains, the lacZ reporter gene is not expressed in the developing PNS. 52 refs., 5 figs., 5 tabs.

  11. Glutamine synthetase-constitutive mutation affecting the glnALG upstream promoter of Escherichia coli.

    PubMed

    León, P; Romero, D; Garciarrubio, A; Bastarrachea, F; Covarrubias, A A

    1985-12-01

    The spontaneous gln-76 mutation of Escherichia coli (Osorio et al., Mol. Gen. Genet. 194:114-123, 1984) was previously shown to be responsible for the cis-dominant constitutive expression of the glnA gene in the absence of a glnG-glnF activator system. Nucleotide sequence analysis has now revealed that gln-76 is a single transversion T.A to A.T, an up-promoter mutation affecting the -10 region of glnAp1, the upstream promoter of the glnALG control region. Both, wild-type and gln-76 DNA control regions were cloned into the promoter-probe plasmid pKO1. Galactokinase activity determinations of cells carrying the fused plasmids showed 10-fold more effective expression mediated by gln-76 than by the glnA wild-type control region. Primer extension experiments with RNA from strains carrying the gln-76 control region indicated that the transcription initiation sites were the same in both the gln-76 mutant and the wild type.

  12. Glutamine synthetase-constitutive mutation affecting the glnALG upstream promoter of Escherichia coli.

    PubMed Central

    León, P; Romero, D; Garciarrubio, A; Bastarrachea, F; Covarrubias, A A

    1985-01-01

    The spontaneous gln-76 mutation of Escherichia coli (Osorio et al., Mol. Gen. Genet. 194:114-123, 1984) was previously shown to be responsible for the cis-dominant constitutive expression of the glnA gene in the absence of a glnG-glnF activator system. Nucleotide sequence analysis has now revealed that gln-76 is a single transversion T.A to A.T, an up-promoter mutation affecting the -10 region of glnAp1, the upstream promoter of the glnALG control region. Both, wild-type and gln-76 DNA control regions were cloned into the promoter-probe plasmid pKO1. Galactokinase activity determinations of cells carrying the fused plasmids showed 10-fold more effective expression mediated by gln-76 than by the glnA wild-type control region. Primer extension experiments with RNA from strains carrying the gln-76 control region indicated that the transcription initiation sites were the same in both the gln-76 mutant and the wild type. Images PMID:2866175

  13. Social defeat interacts with Disc1 mutations in the mouse to affect behavior.

    PubMed

    Haque, F Nipa; Lipina, Tatiana V; Roder, John C; Wong, Albert H C

    2012-08-01

    DISC1 (Disrupted-in-schizophrenia 1) is a strong candidate susceptibility gene for psychiatric disease that was originally discovered in a family with a chromosomal translocation severing this gene. Although the family members with the translocation had an identical genetic mutation, their clinical diagnosis and presentation varied significantly. Gene-environment interactions have been proposed as a mechanism underlying the complex heritability and variable phenotype of psychiatric disorders such as major depressive disorder and schizophrenia. We hypothesized that gene-environment interactions would affect behavior in a mutant Disc1 mouse model. We examined the effect of chronic social defeat (CSD) as an environmental stressor in two lines of mice carrying different Disc1 point mutations, on behaviors relevant to psychiatric illness: locomotion in a novel open field (OF), pre-pulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI), elevated plus maze (EPM), forced swim test (FST), sucrose consumption (SC), and the social interaction task for sociability and social novelty (SSN). We found that Disc1-L100P +/- and wild-type mice have similar anxiety responses to CSD, while Q31L +/- mice had a very different response. We also found evidence of significant gene-environment interactions in the OF, EPM and SSN.

  14. Mutation in fucose synthesis gene of Klebsiella pneumoniae affects capsule composition and virulence in mice.

    PubMed

    Pan, Po-Chang; Chen, Hui-Wen; Wu, Po-Kuan; Wu, Yu-Yang; Lin, Chun-Hung; Wu, June H

    2011-02-01

    The emerging pathogenicity of Klebsiella pneumoniae (KP) is evident by the increasing number of clinical cases of liver abscess (LA) due to KP infection. A unique property of KP is its thick mucoid capsule. The bacterial capsule has been found to contain fucose in KP strains causing LA but not in those causing urinary tract infections. The products of the gmd and wcaG genes are responsible for converting mannose to fucose in KP. A KP strain, KpL1, which is known to have a high death rate in infected mice, was mutated by inserting an apramycin-resistance gene into the gmd. The mutant expressed genes upstream and downstream of gmd, but not gmd itself, as determined by reverse transcriptase polymerase chain reaction. The DNA mapping confirmed the disruption of the gmd gene. This mutant decreased its ability to kill infected mice and showed decreased virulence in infected HepG2 cells. Compared with wild-type KpL1, the gmd mutant lost fucose in capsular polysaccharides, increased biofilm formation and interacted more readily with macrophages. The mutant displayed morphological changes with long filament forms and less uniform sizes. The mutation also converted the serotype from K1 of wild-type to K2 and weak K3. The results indicate that disruption of the fucose synthesis gene affected the pathophysiology of this bacterium and may be related to the virulence of this KpL1 strain.

  15. Lessons learned from the Pediatric Cardiomyopathy Registry (PCMR) Study Group.

    PubMed

    Wilkinson, James D; Westphal, Joslyn A; Bansal, Neha; Czachor, Jason D; Razoky, Hiedy; Lipshultz, Steven E

    2015-08-01

    Cardiomyopathy is a rare disorder of the heart muscle, affecting 1.13 cases per 100,000 children, from birth to 18 years of age. Cardiomyopathy is the leading cause of heart transplantation in children over the age of 1. The Pediatric Cardiomyopathy Registry funded in 1994 by the National Heart, Lung, and Blood Institute was established to examine the epidemiology of the disease in children below 18 years of age. More than 3500 children across the United States and Canada have been enrolled in the Pediatric Cardiomyopathy Registry, which has followed-up these patients until death, heart transplantation, or loss to follow-up. The Pediatric Cardiomyopathy Registry has provided the most in-depth illustration of this disease regarding its aetiology, clinical course, associated risk factors, and patient outcomes. Data from the registry have helped in guiding the clinical management of cardiomyopathy in children under 18 years of age; however, questions still remain regarding the most clinically effective diagnostic and treatment approaches for these patients. Future directions of the registry include the use of next-generation whole-exome sequencing and cardiac biomarkers to identify aetiology-specific treatments and improve diagnostic strategies. This article provides a brief synopsis of the work carried out by the Pediatric Cardiomyopathy Registry since its inception, including the current knowledge on the aetiologies, outcomes, and treatments of cardiomyopathy in children.

  16. Cardiomyopathies in Noonan syndrome and the other RASopathies

    PubMed Central

    Gelb, Bruce D.; Roberts, Amy E.; Tartaglia, Marco

    2015-01-01

    Noonan syndrome and related disorders (Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies. PMID:26380542

  17. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia

    PubMed Central

    Alaa el Din, Ferdos; Patri, Sylvie; Thoreau, Vincent; Rodriguez-Ballesteros, Montserrat; Hamade, Eva; Bailly, Sabine; Gilbert-Dussardier, Brigitte; Abou Merhi, Raghida; Kitzis, Alain

    2015-01-01

    Hereditary Hemorrhagic Telangiectasia syndrome (HHT) or Rendu-Osler-Weber (ROW) syndrome is an autosomal dominant vascular disorder. Two most common forms of HHT, HHT1 and HHT2, have been linked to mutations in the endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1or ALK1) genes respectively. This work was designed to examine the pathogenicity of 23 nucleotide variations in ACVRL1 gene detected in more than 400 patients. Among them, 14 missense mutations and one intronic variant were novels, and 8 missense mutations were previously identified with questionable implication in HHT2. The functionality of missense mutations was analyzed in response to BMP9 (specific ligand of ALK1), the maturation of the protein products and their localization were analyzed by western blot and fluorescence microscopy. The splicing impairment of the intronic and of two missense mutations was examined by minigene assay. Functional analysis showed that 18 out of 22 missense mutations were defective. Splicing analysis revealed that one missense mutation (c.733A>G, p.Ile245Val) affects the splicing of the harboring exon 6. Similarly, the intronic mutation outside the consensus splicing sites (c.1048+5G>A in intron 7) was seen pathogenic by splicing study. Both mutations induce a frame shift creating a premature stop codon likely resulting in mRNA degradation by NMD surveillance mechanism. Our results confirm the haploinsufficiency model proposed for HHT2. The affected allele of ACVRL1 induces mRNA degradation or the synthesis of a protein lacking the receptor activity. Furthermore, our data demonstrate that functional and splicing analyses together, represent two robust diagnostic tools to be used by geneticists confronted with novel or conflicted ACVRL1 mutations. PMID:26176610

  18. Four novel cystic fibrosis mutations in splice junction sequences affecting the CFTR nucleotide binding folds

    SciTech Connect

    Doerk, T.; Wulbrand, U.; Tuemmler, B. )

    1993-03-01

    Single cases of the four novel splice site mutations 1525[minus]1 G [r arrow] A (intron 9), 3601[minus]2 A [r arrow] G (intron 18), 3850[minus]3 T [r arrow] G (intron 19), and 4374+1 G [r arrow] T (intron 23) were detected in the CFTR gene of cystic fibrosis patients of Indo-Iranian, Turkish, Polish, and Germany descent. The nucleotide substitutions at the +1, [minus]1, and [minus]2 positions all destroy splice sites and lead to severe disease alleles associated with features typical of gastrointestinal and pulmonary cystic fibrosis disease. The 3850[minus]3 T-to-G change was discovered in a very mildly affected 33-year-old [Delta]F508 compound heterozygote, suggesting that the T-to-G transversion at the less conserved [minus]3 position of the acceptor splice site may retain some wildtype function. 13 refs., 1 fig., 2 tabs.

  19. Mitochondrial Diseases and Cardiomyopathies.

    PubMed

    Brunel-Guitton, Catherine; Levtova, Alina; Sasarman, Florin

    2015-11-01

    Mitochondrial cardiomyopathies are clinically and genetically heterogeneous. An integrative approach encompassing clinical, biochemical, and molecular investigations is required to reach a specific diagnosis. In this review we summarize the clinical and genetic aspects of mitochondrial disorders associated with cardiomyopathy, including disorders of oxidative phosphorylation. It also describes groups of disorders that, although not usually classified as mitochondrial disorders, stem from defects in mitochondrial function (eg, disorders of β-oxidation and the carnitine cycle), are associated with secondary mitochondrial impairment (eg, organic acidurias), and are important diagnostically because they are treatable. Current biochemical and molecular techniques for the diagnosis of mitochondrial cardiomyopathies are described, and a diagnostic algorithm is proposed, to help clinicians in their approach to cardiomyopathies in the context of mitochondrial diseases.

  20. Types of Cardiomyopathy

    MedlinePlus

    ... Links Related Topics Arrhythmia Heart Failure Heart Murmur Heart Valve Disease Sudden Cardiac Arrest Send a link to NHLBI ... effectively. Dilated cardiomyopathy can lead to heart failure , heart valve disease , irregular heart rate , and blood clots in the ...

  1. Children's Cardiomyopathy Foundation

    MedlinePlus

    ... A Cause for Today… A Cure for Tomorrow” Join Us for 2 Online Events Join CCF for ... benefit programs for children with cardiomyopathy. LEARN MORE Join CCF's Family Network! Become a CCF member and ...

  2. Ubiquitin-proteasome system and hereditary cardiomyopathies.

    PubMed

    Schlossarek, Saskia; Frey, Norbert; Carrier, Lucie

    2014-06-01

    Adequate protein turnover is essential for cardiac homeostasis. Different protein quality controls are involved in the maintenance of protein homeostasis, including molecular chaperones and co-chaperones, the autophagy-lysosomal pathway, and the ubiquitin-proteasome system (UPS). In the last decade, a series of evidence has underlined a major function of the UPS in cardiac physiology and disease. Particularly, recent studies have shown that dysfunctional proteasomal function leads to cardiac disorders. Hypertrophic and dilated cardiomyopathies are the two most prevalent inherited cardiomyopathies. Both are primarily transmitted as an autosomal-dominant trait and mainly caused by mutations in genes encoding components of the cardiac sarcomere, including a relevant striated muscle-specific E3 ubiquitin ligase. A growing body of evidence indicates impairment of the UPS in inherited cardiomyopathies as determined by measurement of the level of ubiquitinated proteins, the activities of the proteasome and/or the use of fluorescent UPS reporter substrates. The present review will propose mechanisms of UPS impairment in inherited cardiomyopathies, summarize the potential consequences of UPS impairment, including activation of the unfolded protein response, and underline some therapeutic options available to restore proteasome function and therefore cardiac homeostasis and function. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

  3. Error-prone and error-restrictive mutations affecting ribosomal protein S12.

    PubMed

    Agarwal, Deepali; Gregory, Steven T; O'Connor, Michael

    2011-07-01

    Ribosomal protein S12 plays a pivotal role in decoding functions on the ribosome. X-ray crystallographic analyses of ribosomal complexes have revealed that S12 is involved in the inspection of codon-anticodon pairings in the ribosomal A site, as well as in the succeeding domain rearrangements of the 30S subunit that are essential for accommodation of aminoacyl-tRNA. A role for S12 in tRNA selection is also well supported by classical genetic analyses; mutations affecting S12 are readily isolated in bacteria and organelles, since specific alterations in S12 confer resistance to the error-inducing antibiotic streptomycin, and the ribosomes from many such streptomycin-resistant S12 mutants display decreased levels of miscoding. However, substitutions that confer resistance to streptomycin likely represent a very distinct class of all possible S12 mutants. Until recently, the technical difficulties in generating random, unselectable mutations in essential genes in complex operons have generally precluded the analysis of other classes of S12 alterations. Using a recombineering approach, we have targeted the Escherichia coli rpsL gene, encoding S12, for random mutagenesis and screened the resulting mutants for effects on decoding fidelity. We have recovered over 40 different substitutions located throughout the S12 protein that alter the accuracy of translation without substantially affecting the sensitivity to streptomycin. Moreover, this collection includes mutants that promote miscoding, as well as those that restrict decoding errors. These results affirm the importance of S12 in decoding processes and indicate that alterations in this essential protein can have diverse effects on the accuracy of decoding.

  4. A Promoter Region Mutation Affecting Replication of the Tetrahymena Ribosomal DNA Minichromosome

    PubMed Central

    Gallagher, Renata C.; Blackburn, Elizabeth H.

    1998-01-01

    In the ciliated protozoan Tetrahymena thermophila the ribosomal DNA (rDNA) minichromosome replicates partially under cell cycle control and is also subject to a copy number control mechanism. The relationship between rDNA replication and rRNA gene transcription was investigated by the analysis of replication, transcription, and DNA-protein interactions in a mutant rDNA, the rmm3 rDNA. The rmm3 (for rDNA maturation or maintenance mutant 3) rDNA contains a single-base deletion in the rRNA promoter region, in a phylogenetically conserved sequence element that is repeated in the replication origin region of the rDNA minichromosome. The multicopy rmm3 rDNA minichromosome has a maintenance defect in the presence of a competing rDNA allele in heterozygous cells. No difference in the level of rRNA transcription was found between wild-type and rmm3 strains. However, rmm3 rDNA replicating intermediates exhibited an enhanced pause in the region of the replication origin, roughly 750 bp upstream from the rmm3 mutation. In footprinting of isolated nuclei, the rmm3 rDNA lacked the wild-type dimethyl sulfate (DMS) footprint in the promoter region adjacent to the base change. In addition, a DMS footprint in the origin region was lost in the rmm3 rDNA minichromosome. This is the first reported correlation in this system between an rDNA minichromosome maintenance defect and an altered footprint in the origin region. Our results suggest that a promoter region mutation can affect replication without detectably affecting transcription. We propose a model in which interactions between promoter and origin region complexes facilitate replication and maintenance of the Tetrahymena rDNA minichromosome. PMID:9566921

  5. An initiator protein for plasmid R6K DNA replication. Mutations affecting the copy-number control.

    PubMed

    Inuzuka, M; Wada, Y

    1988-02-08

    Two kinds of mutations affecting the copy-number control of plasmid R6K were isolated and identified in an initiator pi protein by DNA sequencing. Firstly, a temperature-sensitive replication mutation, ts22, with decreased copy number results in a substitution of threonine to isoleucine at position 138 of the 305-amino-acid pi protein. Secondly, a high-copy-number (cop21) mutant was isolated from this ts mutant and was identified by an alteration of alanine to serine at position 162. This cop21 mutation suppressed the Ts character and was recessive to the wild-type allele in the copy control.

  6. Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1.

    PubMed

    Pilz, D T; Kuc, J; Matsumoto, N; Bodurtha, J; Bernadi, B; Tassinari, C A; Dobyns, W B; Ledbetter, D H

    1999-09-01

    Subcortical band heterotopia (SBH) are bilateral and symmetric ribbons of gray matter found in the central white matter between the cortex and the ventricular surface, which comprises the less severe end of the lissencephaly (agyria-pachygyria-band) spectrum of malformations. Mutations in DCX (also known as XLIS ) have previously been described in females with SBH. We have now identified mutations in either the DCX or LIS1 gene in three of 11 boys studied, demonstrating for the first time that mutations of either DCX or LIS1 can cause SBH or mixed pachygyria-SBH (PCH-SBH) in males. All three changes detected are missense mutations, predicted to be of germline origin. They include a missense mutation in exon 4 of DCX in a boy with PCH-SBH (R78H), a different missense mutation in exon 4 of DCX in a boy with mild SBH and in his mildly affected mother (R89G) and a missense mutation in exon 6 of LIS1 in a boy with SBH (S169P). The missense mutations probably account for the less severe brain malformations, although other patients with missense mutations in the same exons have had diffuse lissencephaly. Therefore, it appears likely that the effect of the specific amino acid change on the protein determines the severity of the phenotype, with some mutations enabling residual protein function and allowing normal migration in a larger proportion of neurons. However, we expect that somatic mosaic mutations of both LIS1 and DCX will also prove to be an important mechanism in causing SBH in males.

  7. Familial Hypertrophic Cardiomyopathy Related Cardiac Troponin C L29Q Mutation Alters Length-Dependent Activation and Functional Effects of Phosphomimetic Troponin I*

    PubMed Central

    Li, Alison Y.; Stevens, Charles M.; Liang, Bo; Rayani, Kaveh; Little, Sean; Davis, Jonathan; Tibbits, Glen F.

    2013-01-01

    The Ca2+ binding properties of the FHC-associated cardiac troponin C (cTnC) mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted thin filament preparations, and skinned cardiomyocytes. While higher Ca2+ binding affinity was apparent for the L29Q mutant in isolated cTnC, this phenomenon was not observed in the cTn complex. At the level of the thin filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the Ca2+ affinity by 27% in the steady-state measurement and increased the Ca2+ dissociation rate by 20% in the kinetic studies. Molecular dynamics simulations suggest that L29Q destabilizes the conformation of cNTnC in the presence of phosphomimetic cTnI and potentially modulates the Ca2+ sensitivity due to the changes of the opening/closing equilibrium of cNTnC. In the skinned cardiomyocyte preparation, L29Q cTnC increased Ca2+ sensitivity in a highly sarcomere length (SL)-dependent manner. The well-established reduction of Ca2+ sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the mutation and it also depressed the SL-dependent increase in myofilament Ca2+ sensitivity. This might result from its modified interaction with cTnI which altered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex. This study demonstrates that the L29Q mutation alters the contractility and the functional effects of the phosphomimetic cTnI in both thin filament and single skinned cardiomyocytes and importantly that this effect is highly sarcomere length dependent. PMID:24260207

  8. Balancing protein stability and activity in cancer: a new approach for identifying driver mutations affecting CBL ubiquitin ligase activation

    PubMed Central

    Li, Minghui; Kales, Stephen C.; Ma, Ke; Shoemaker, Benjamin A.; Crespo-Barreto, Juan; Cangelosi, Andrew L.; Lipkowitz, Stanley; Panchenko, Anna R.

    2015-01-01

    Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved depicting the protein at different stages of its activation cycle and thus provide mechanistic insight underlying how stability-activity tradeoffs in cancer-related proteins may influence disease onset and progression. In this study, we computationally modeled the effects of missense cancer mutations on structures representing four stages of the CBL activation cycle to identify driver mutations that affect CBL stability, binding, and activity. We found that recurrent, homozygous, and leukemia-specific mutations had greater destabilizing effects on CBL states than did random non-cancer mutations. We further tested the ability of these computational models assessing the changes in CBL stability and its binding to ubiquitin conjugating enzyme E2, by performing blind CBL-mediated EGFR ubiquitination assays in cells. Experimental CBL ubiquitin ligase activity was in agreement with the predicted changes in CBL stability and, to a lesser extent, with CBL-E2 binding affinity. Two-thirds of all experimentally tested mutations affected the ubiquitin ligase activity by either destabilizing CBL or disrupting CBL-E2 binding, whereas about one-third of tested mutations were found to be neutral. Collectively, our findings demonstrate that computational methods incorporating multiple protein conformations and stability and binding affinity evaluations can successfully predict the functional consequences of cancer mutations on protein activity, and provide a proof of concept for mutations in CBL. PMID:26676746

  9. Interaction between mutations in the suppressor of Hairy wing and modifier of mdg4 genes of Drosophila melanogaster affecting the phenotype of gypsy-induced mutations

    SciTech Connect

    Georgiev, P.; Kozycina, M.

    1996-02-01

    The suppressor of Hairy-wing [su(Hw)] protein mediates the mutagenic effect of the gypsy retrotransposon by repressing the function of transcriptional enhancers located distally from the promoter with respect to the position of the su(Hw)-binding region. Mutations in a second gene, modifier of mdg4, also affect the gypsy-induced phenotype. Two major effects of the mod(mdg4){sup lu1} mutation can be distinguished: the interference with insulation by the su(Hw)-binding region and direct inhibition of gene expression that is not dependent on the su(Hw)-binding region position. The mod(mdg4){sup lu1} mutation partially suppresses ct{sup 6}, sc{sup D1} and Hw{sup 1} mutations, possibly by interfering with the insulation effect of the su(Hw)-binding region. An example of the second effect of mod(mdg4){sup lu1} is a complete inactivation of yellow expression in combination with the y{sup 2} allele. Phenotypic analyses of flies with combinations of mdg(mdg4){sup lu1} and different su(Hw) mutations, or with constructions carrying deletions of the acidic domains of the su(Hw) protein, suggest that the carboxy-terminal acidic domain is important for direct inhibition of yellow transcription in bristles, while the amino-terminal acidic domain is more essential for insulation. 31 refs., 1 fig., 6 tabs.

  10. Dietary taurine deficiency and dilated cardiomyopathy in the fox.

    PubMed

    Moise, N S; Pacioretty, L M; Kallfelz, F A; Stipanuk, M H; King, J M; Gilmour, R F

    1991-02-01

    Taurine deficiency has been implicated as a potential cause of dilated cardiomyopathy. However, the relationship between taurine and myocardial function is presently unclear. The purpose of this study was to determine whether dilated cardiomyopathy in the fox is associated with dietary taurine deficiency. A total of 68 foxes from farms with a history of death caused by dilated cardiomyopathy and 14 foxes from a farm with no history of dilated cardiomyopathy were studied. Dilated cardiomyopathy was diagnosed by echocardiography in 48% of the foxes from one farm with a positive history and in none of the foxes from the control farm. Foxes less than 9 months of age were more commonly affected than older foxes (p = 0.03). Plasma taurine concentrations were significantly less (p less than 0.01) in foxes that had dilated cardiomyopathy (26.8 +/- 16.4 nmol/ml) than in the control foxes (99.3 +/- 60.2 nmol/ml). A significantly higher (p less than 0.01) incidence of dilated cardiomyopathy was present in foxes with a history of a sibling or offspring that died of dilated cardiomyopathy than in foxes without a family history of cardiac death. In one fox with dilated cardiomyopathy that was tested, the myocardial taurine concentration was lower (1.7 mumol/gm wet weight) than that of control foxes (7.3 +/- 1.6 mumol/gm wet weight). Hepatic cysteinesulfinic acid decarboxylase activity was significantly less (p less than 0.001) in foxes with dilated cardiomyopathy (0.97 +/- 0.2 nmol/mm.mg protein) than in control foxes (2.11 +/- 0.07 nmol CO2/mm.mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Functional Assessment of Human Coding Mutations Affecting Skin Pigmentation Using Zebrafish

    PubMed Central

    Tsetskhladze, Zurab R.; Canfield, Victor A.; Ang, Khai C.; Wentzel, Steven M.; Reid, Katherine P.; Berg, Arthur S.; Johnson, Stephen L.; Kawakami, Koichi; Cheng, Keith C.

    2012-01-01

    A major challenge in personalized medicine is the lack of a standard way to define the functional significance of the numerous nonsynonymous, single nucleotide coding variants that are present in each human individual. To begin to address this problem, we have used pigmentation as a model polygenic trait, three common human polymorphisms thought to influence pigmentation, and the zebrafish as a model system. The approach is based on the rescue of embryonic zebrafish mutant phenotypes by “humanized” zebrafish orthologous mRNA. Two hypomorphic polymorphisms, L374F in SLC45A2, and A111T in SLC24A5, have been linked to lighter skin color in Europeans. The phenotypic effect of a second coding polymorphism in SLC45A2, E272K, is unclear. None of these polymorphisms had been tested in the context of a model organism. We have confirmed that zebrafish albino fish are mutant in slc45a2; wild-type slc45a2 mRNA rescued the albino mutant phenotype. Introduction of the L374F polymorphism into albino or the A111T polymorphism into slc24a5 (golden) abolished mRNA rescue of the respective mutant phenotypes, consistent with their known contributions to European skin color. In contrast, the E272K polymorphism had no effect on phenotypic rescue. The experimental conclusion that E272K is unlikely to affect pigmentation is consistent with a lack of correlation between this polymorphism and quantitatively measured skin color in 59 East Asian humans. A survey of mutations causing human oculocutaneous albinism yielded 257 missense mutations, 82% of which are theoretically testable in zebrafish. The developed approach may be extended to other model systems and may potentially contribute to our understanding the functional relationships between DNA sequence variation, human biology, and disease. PMID:23071798

  12. Stress-related cardiomyopathies

    PubMed Central

    2011-01-01

    Stress-related cardiomyopathies can be observed in the four following situations: Takotsubo cardiomyopathy or apical ballooning syndrome; acute left ventricular dysfunction associated with subarachnoid hemorrhage; acute left ventricular dysfunction associated with pheochromocytoma and exogenous catecholamine administration; acute left ventricular dysfunction in the critically ill. Cardiac toxicity was mediated more by catecholamines released directly into the heart via neural connection than by those reaching the heart via the bloodstream. The mechanisms underlying the association between this generalized autonomic storm secondary to a life-threatening stress and myocardial toxicity are widely discussed. Takotsubo cardiomyopathy has been reported all over the world and has been acknowledged by the American Heart Association as a form of reversible cardiomyopathy. Four "Mayo Clinic" diagnostic criteria are required for the diagnosis of Takotsubo cardiomyopathy: 1) transient left ventricular wall motion abnormalities involving the apical and/or midventricular myocardial segments with wall motion abnormalities extending beyond a single epicardial coronary artery distribution; 2) absence of obstructive epicardial coronary artery disease that could be responsible for the observed wall motion abnormality; 3) ECG abnormalities, such as transient ST-segment elevation and/or diffuse T wave inversion associated with a slight troponin elevation; and 4) the lack of proven pheochromocytoma and myocarditis. ECG changes and LV dysfunction occur frequently following subarachnoid hemorrhage and ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic stress-related cardiomyopathy. Stress-related cardiomyopathy has been reported in patients with pheochromocytoma and in patients receiving intravenous exogenous catecholamine administration. The role of a huge increase in endogenous and/or exogenous catecholamine level in critically ill patients

  13. Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases.

    PubMed

    Kaneko, Maki; Desai, Bela S; Cook, Boaz

    2014-02-01

    Type II P-type ATPases (PAIIs) constitute a family of conserved proteins that actively generate ionic gradients across membranes. Mutations in genes encoding PAIIs can cause heritable dominant diseases, with suggested etiology of haploinsufficiency. Using a Drosophila melanogaster genetic screen, we identified a dominant mutation altering the PAII member sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA). This mutation conferred temperature-sensitive uncoordination in a gain-of-function manner. We established that this gain-of-function phenotype is linked to dominant disease-causing mutations affecting various human PAIIs. We further found that heterologous expression of mutant PAIIs elicited ion leakage that was exacerbated at elevated temperatures. Therefore, these dominant mutations result in ionic leakage and render PAIIs susceptible to deleterious effects from elevated temperatures. Accordingly, it was recently reported that missense mutations affecting the Na(+)/K(+) ATPase can elicit ionic leakage. We propose that ionic leakage is a pervasive gain-of-function mechanism that can underlie a variety of dominant PAII-related diseases.

  14. Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems

    PubMed Central

    Vulto-van Silfhout, Anneke T.; Rajamanickam, Shivakumar; Jensik, Philip J.; Vergult, Sarah; de Rocker, Nina; Newhall, Kathryn J.; Raghavan, Ramya; Reardon, Sara N.; Jarrett, Kelsey; McIntyre, Tara; Bulinski, Joseph; Ownby, Stacy L.; Huggenvik, Jodi I.; McKnight, G. Stanley; Rose, Gregory M.; Cai, Xiang; Willaert, Andy; Zweier, Christiane; Endele, Sabine; de Ligt, Joep; van Bon, Bregje W.M.; Lugtenberg, Dorien; de Vries, Petra F.; Veltman, Joris A.; van Bokhoven, Hans; Brunner, Han G.; Rauch, Anita; de Brouwer, Arjan P.M.; Carvill, Gemma L.; Hoischen, Alexander; Mefford, Heather C.; Eichler, Evan E.; Vissers, Lisenka E.L.M.; Menten, Björn; Collard, Michael W.; de Vries, Bert B.A.

    2014-01-01

    Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1. PMID:24726472

  15. Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.

    PubMed

    Vulto-van Silfhout, Anneke T; Rajamanickam, Shivakumar; Jensik, Philip J; Vergult, Sarah; de Rocker, Nina; Newhall, Kathryn J; Raghavan, Ramya; Reardon, Sara N; Jarrett, Kelsey; McIntyre, Tara; Bulinski, Joseph; Ownby, Stacy L; Huggenvik, Jodi I; McKnight, G Stanley; Rose, Gregory M; Cai, Xiang; Willaert, Andy; Zweier, Christiane; Endele, Sabine; de Ligt, Joep; van Bon, Bregje W M; Lugtenberg, Dorien; de Vries, Petra F; Veltman, Joris A; van Bokhoven, Hans; Brunner, Han G; Rauch, Anita; de Brouwer, Arjan P M; Carvill, Gemma L; Hoischen, Alexander; Mefford, Heather C; Eichler, Evan E; Vissers, Lisenka E L M; Menten, Björn; Collard, Michael W; de Vries, Bert B A

    2014-05-01

    Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.

  16. Arrhythmogenic right ventricular cardiomyopathy: new insights into mechanisms of disease.

    PubMed

    Saffitz, Jeffrey E; Asimaki, Angeliki; Huang, Hayden

    2010-01-01

    Arrhythmogenic right ventricular cardiomyopathy is a primary heart muscle disorder characterized by the early occurrence of arrhythmias often out of proportion to the extent of structural remodeling and contractile derangement. Approximately 40% of patients with arrhythmogenic right ventricular cardiomyopathy have one or more mutations in genes encoding proteins in desmosomes, intercellular adhesion junctions which, in cardiac myocytes, reside within intercalated disks. Some desmosomal proteins fulfill roles both as structural proteins in cell-cell adhesion junctions and as signaling molecules in pathways mediated by Wnt ligands. Evidence is increasing that mutations in desmosomal proteins can perturb the normal balance of critical proteins in junctions and the cytosol which, in turn, could alter gene expression by circumventing normal Wnt signaling pathways. This review highlights recent advances in understanding the pathogenesis of arrhythmogenic right ventricular cardiomyopathy and presents evidence suggesting that the disease is caused by a combination of altered cellular biomechanical behavior and altered signaling.

  17. Psychological Distress, Anxiety, and Depression of Cancer-Affected BRCA1/2 Mutation Carriers: a Systematic Review.

    PubMed

    Ringwald, Johanna; Wochnowski, Christina; Bosse, Kristin; Giel, Katrin Elisabeth; Schäffeler, Norbert; Zipfel, Stephan; Teufel, Martin

    2016-10-01

    Understanding the intermediate- and long-term psychological consequences of genetic testing for cancer patients has led to encouraging research, but a clear consensus of the psychosocial impact and clinical routine for cancer-affected BRCA1 and BRCA2 mutation carriers is still missing. We performed a systematic review of intermediate- and long-term studies investigating the psychological impact like psychological distress, anxiety, and depression in cancer-affected BRCA mutation carriers compared to unaffected mutation carriers. This review included the screening of 1243 studies. Eight intermediate- and long-term studies focusing on distress, anxiety, and depression symptoms among cancer-affected mutation carriers at least six months after the disclosure of genetic testing results were included. Studies reported a great variety of designs, methods, and patient outcomes. We found evidence indicating that cancer-affected mutation carriers experienced a negative effect in relation to psychological well-being in terms of an increase in symptoms of distress, anxiety, and depression in the first months after test disclosure. In the intermediate- and long-term, no significant clinical relevant symptoms occurred. However, none of the included studies used specific measurements, which can clearly identify psychological burdens of cancer-affected mutation carriers. We concluded that current well-implemented distress screening instruments are not sufficient for precisely identifying the psychological burden of genetic testing. Therefore, future studies should implement coping strategies, specific personality structures, the impact of genetic testing, supportive care needs and disease management behaviour to clearly screen for the possible intermediate- and long-term psychological impact of a positive test disclosure.

  18. Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression.

    PubMed

    Zeraati, Mahdi; Moye, Aaron L; Wong, Jason W H; Perera, Dilmi; Cowley, Mark J; Christ, Daniel U; Bryan, Tracy M; Dinger, Marcel E

    2017-04-06

    Cancer is a multifactorial disease driven by a combination of genetic and environmental factors. Many cancer driver mutations have been characterised in protein-coding regions of the genome. However, mutations in noncoding regions associated with cancer have been less investigated. G-quadruplex (G4) nucleic acids are four-stranded secondary structures formed in guanine-rich sequences and prevalent in the regulatory regions. In this study, we used published whole cancer genome sequence data to find mutations in cancer patients that overlap potential RNA G4-forming sequences in 5' UTRs. Using RNAfold, we assessed the effect of these mutations on the thermodynamic stability of predicted RNA G4s in the context of full-length 5' UTRs. Of the 217 identified mutations, we found that 33 are predicted to destabilise and 21 predicted to stabilise potential RNA G4s. We experimentally validated the effect of destabilising mutations in the 5' UTRs of BCL2 and CXCL14 and one stabilising mutation in the 5' UTR of TAOK2. These mutations resulted in an increase or a decrease in translation of these mRNAs, respectively. These findings suggest that mutations that modulate the G4 stability in the noncoding regions could act as cancer driver mutations, which present an opportunity for early cancer diagnosis using individual sequencing information.

  19. Cardiomyopathy in pregnancy.

    PubMed

    Lewey, Jennifer; Haythe, Jennifer

    2014-08-01

    Cardiomyopathy during pregnancy is uncommon but potentially catastrophic to maternal health, accounting for up to 11% of maternal deaths. Peripartum cardiomyopathy is diagnosed in women without a history of heart disease 1 month before delivery or within 5 months postpartum. About half of all women will have full myocardial recovery within 6 months of diagnosis, but complications such as severe heart failure or death are not rare. African-American women have higher rates of diagnosis and adverse events. Women with preexisting cardiomyopathy, such as dilated or hypertrophic cardiomyopathy, followed closely during pregnancy often tolerate pregnancy and delivery. Risk factors for adverse outcomes include functional status at baseline, severity of systolic dysfunction or outflow tract gradient, or history of prior cardiac event, such as arrhythmia or stroke. The level of brain natriuretic peptide (BNP) can be used to risk stratify women for adverse events. Pregnant women with cardiomyopathy should be followed closely by a multidisciplinary team comprised of nurses, obstetricians, neonatologists, cardiologists, anesthesiologists, and cardiac surgeons.

  20. Diagnosis and management of inherited cardiomyopathies.

    PubMed

    Millar, Lynne; Sharma, Sanjay

    2014-10-01

    Inherited heart conditions are the most common cause of sudden cardiac death in those under the age of 35 and the leading cause of non-traumatic death in young athletes. Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease affecting 1 in 500 of the population. Some patients may exhibit severe left ventricular hypertrophy, others may show nothing more than an abnormal ECG. Left ventricular hypertrophy most commonly manifests in the second decade of life. Sudden death is rare and usually affects patients in the first three decades whereas older patients present with heart failure, atrial fibrillation and stroke. Arrhythmogenic right ventricular cardiomyopathy is a rare, autosomal dominant heart muscle disorder which affects between 1 in 1,000 and 1 in 5,000 of the population. Dilated cardiomyopathy (DCM) is characterised by a dilated left ventricle with impaired function that cannot be explained by ischaemic heart disease, hypertension or valvular heart disease. At least 25% of cases of DCM are familial. DCM may be associated with multisystem conditions such as muscular dystrophy. Chemotherapy and certain other drugs, alcohol abuse and myocarditis may also lead to a dilated and poorly contracting left ventricle. In many cases the first manifestation of an inherited cardiomyopathy can be a sudden cardiac arrest. Other presentations include chest pain or breathlessness during exertion, palpitations and syncope. In many of the cardiomyopathies, the diagnosis can be made with a standard ECG and echocardiogram. However if the diagnosis is not certain or the cardiologist wishes to look at the heart structure in greater detail, a cardiac MRI may be performed.

  1. Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis.

    PubMed

    Zhao, Linjie; Sun, Tanlin; Pei, Jianfeng; Ouyang, Qi

    2015-07-28

    It has been a consensus in cancer research that cancer is a disease caused primarily by genomic alterations, especially somatic mutations. However, the mechanism of mutation-induced oncogenesis is not fully understood. Here, we used the mitochondrial apoptotic pathway as a case study and performed a systematic analysis of integrating pathway dynamics with protein interaction kinetics to quantitatively investigate the causal molecular mechanism of mutation-induced oncogenesis. A mathematical model of the regulatory network was constructed to establish the functional role of dynamic bifurcation in the apoptotic process. The oncogenic mutation enrichment of each of the protein functional domains involved was found strongly correlated with the parameter sensitivity of the bifurcation point. We further dissected the causal mechanism underlying this correlation by evaluating the mutational influence on protein interaction kinetics using molecular dynamics simulation. We analyzed 29 matched mutant-wild-type and 16 matched SNP--wild-type protein systems. We found that the binding kinetics changes reflected by the changes of free energy changes induced by protein interaction mutations, which induce variations in the sensitive parameters of the bifurcation point, were a major cause of apoptosis pathway dysfunction, and mutations involved in sensitive interaction domains show high oncogenic potential. Our analysis provided a molecular basis for connecting protein mutations, protein interaction kinetics, network dynamics properties, and physiological function of a regulatory network. These insights provide a framework for coupling mutation genotype to tumorigenesis phenotype and help elucidate the logic of cancer initiation.

  2. Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis

    PubMed Central

    Zhao, Linjie; Sun, Tanlin; Pei, Jianfeng; Ouyang, Qi

    2015-01-01

    It has been a consensus in cancer research that cancer is a disease caused primarily by genomic alterations, especially somatic mutations. However, the mechanism of mutation-induced oncogenesis is not fully understood. Here, we used the mitochondrial apoptotic pathway as a case study and performed a systematic analysis of integrating pathway dynamics with protein interaction kinetics to quantitatively investigate the causal molecular mechanism of mutation-induced oncogenesis. A mathematical model of the regulatory network was constructed to establish the functional role of dynamic bifurcation in the apoptotic process. The oncogenic mutation enrichment of each of the protein functional domains involved was found strongly correlated with the parameter sensitivity of the bifurcation point. We further dissected the causal mechanism underlying this correlation by evaluating the mutational influence on protein interaction kinetics using molecular dynamics simulation. We analyzed 29 matched mutant–wild-type and 16 matched SNP—wild-type protein systems. We found that the binding kinetics changes reflected by the changes of free energy changes induced by protein interaction mutations, which induce variations in the sensitive parameters of the bifurcation point, were a major cause of apoptosis pathway dysfunction, and mutations involved in sensitive interaction domains show high oncogenic potential. Our analysis provided a molecular basis for connecting protein mutations, protein interaction kinetics, network dynamics properties, and physiological function of a regulatory network. These insights provide a framework for coupling mutation genotype to tumorigenesis phenotype and help elucidate the logic of cancer initiation. PMID:26170328

  3. Oakleaf: an S locus-linked mutation of Primula vulgaris that affects leaf and flower development.

    PubMed

    Cocker, Jonathan M; Webster, Margaret A; Li, Jinhong; Wright, Jonathan; Kaithakottil, Gemy; Swarbreck, David; Gilmartin, Philip M

    2015-10-01

    In Primula vulgaris outcrossing is promoted through reciprocal herkogamy with insect-mediated cross-pollination between pin and thrum form flowers. Development of heteromorphic flowers is coordinated by genes at the S locus. To underpin construction of a genetic map facilitating isolation of these S locus genes, we have characterised Oakleaf, a novel S locus-linked mutant phenotype. We combine phenotypic observation of flower and leaf development, with classical genetic analysis and next-generation sequencing to address the molecular basis of Oakleaf. Oakleaf is a dominant mutation that affects both leaf and flower development; plants produce distinctive lobed leaves, with occasional ectopic meristems on the veins. This phenotype is reminiscent of overexpression of Class I KNOX-homeodomain transcription factors. We describe the structure and expression of all eight P. vulgaris PvKNOX genes in both wild-type and Oakleaf plants, and present comparative transcriptome analysis of leaves and flowers from Oakleaf and wild-type plants. Oakleaf provides a new phenotypic marker for genetic analysis of the Primula S locus. We show that none of the Class I PvKNOX genes are strongly upregulated in Oakleaf leaves and flowers, and identify cohorts of 507 upregulated and 314 downregulated genes in the Oakleaf mutant.

  4. Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations.

    PubMed Central

    Léveillard, T; Andera, L; Bissonnette, N; Schaeffer, L; Bracco, L; Egly, J M; Wasylyk, B

    1996-01-01

    The p53 tumour suppressor is mutated in the majority of human tumours. p53's proposed role as the guardian of the genome is reflected in its multiple effects on transcription genome stability, cell growth and survival. We show that p53 interacts both physically and functionally with the TFIIH complex. There are multiple protein-protein contacts, involving two regions of p53 and three subunits of TFIIH, ERCC2 (XPD), ERCC3 (XPB) and p62. p53 and its C-terminus (amino acids 320-393) inhibit both of the TFIIH helicases and in vitro transcription in the absence of TFIIH. Transcription inhibition is overcome by TFIIH. The N-terminal region of p53 (1-320), lacking the C-terminus, is inactive on its own, yet apparently affects the activity of the C-terminus in the native protein. Interestingly, mutant p53s that are frequently found in tumours are less efficient inhibitors of the helicases and transcription. We hypothesize that the interactions provide an immediate and direct link for p53 to the multiple functions of TFIIH in transcription, DNA repair and possibly the cell cycle. Images PMID:8612585

  5. Mutations affecting the cAMP transduction pathway modify olfaction in Drosophila.

    PubMed

    Martín, F; Charro, M J; Alcorta, E

    2001-06-01

    The rutabaga and dunce genes, encode two enzymes of the cyclic adenosine monophosphate transduction pathway in Drosophila, adenylyl cyclase and cyclic adenosine monophosphate phosphodiesterase, respectively. Two main second messenger systems, depending on inositol 1,4,5-triphosphate and cyclic adenosine monophosphate, have been associated with olfaction in vertebrates as well as invertebrates. A relationship between the cyclic adenosine monophosphate signaling pathway and olfactory reception in Drosophila is suggested by the presence of cyclic nucleotide gated channels and cyclic-nucleotide modulated K+ channels in the antennae, the main olfactory organs. In this report, molecular, electrophysiological and behavioral data support the role of cyclic adenosine monophosphate in olfactory function for this species. Expression of both genes in the antennae has been shown by messenger ribonucleic acid analysis. Changes in the electroantennogram kinetics have been observed specifically on the slope of the initial rising phase, as predicted for processes that affect cyclic adenosine monophosphate concentration. Olfactory behavior changes due to both mutations were coherent with a functional meaning of the reported electrophysiological phenotype in olfactory perception. Sensitivity level increases or decreases for the mutants compared to the control line depending on the odorant. These results are compatible with some olfactory coding at the reception level by differential activation of a dual transduction system involving the inositol 1,4,5-triphosphate and cyclic adenosine monophosphate cascades.

  6. Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis

    PubMed Central

    Samuelov, Liat; Bertolini, Marta; Weissglas-Volkov, Daphna; Eskin-Schwartz, Marina; Malchin, Natalia; Bochner, Ron; Fainberg, Gilad; Goldberg, Ilan; Sugawara, Koji; Tsuruta, Daisuke; Morasso, Maria; Shalev, Stavit; Gallo, Richard L.; Shomron, Noam; Paus, Ralf; Sprecher, Eli

    2016-01-01

    Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway. PMID:27736875

  7. Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor [gamma] chain gene in SCIDX1 that differently affect the mRNA processing

    SciTech Connect

    Markiewicz, S.; Fischer, A.; Saint Basile, G. de ); Subtil, A.; Dautry-Varsat, A. )

    1994-05-01

    The interleukin-2 receptor [gamma] (IL-2R[gamma]) chain gene encodes a 64-kDa protein that not only composes the high-affinity form of the IL-2 binding receptor in association with the 2R [alpha] and [beta] chains, but also participates in at least the IL-4 and IL-7 receptor complexes. Mutations in this gene have recently been shown to cause X-linked severe combined immunodeficiency (SCIDX1). This disease of the immune system results from an early block of T lymphocyte and natural killer (NK) cell differentiation, which leads to a severe cellular and humoral immune defect that is lethal unless treated by bone marrow transplantation. Analysis of the IL-2R[gamma] gene in SCIDX1 patients has revealed the presence of heterogeneous mutations principally located in the extracellular domain of the molecule. We report here three intraexonic mutations and one deletion in the IL-2R[gamma] gene in four SCIDX1 patients. These mutations appear to differentially affect RNA processing, either by decreasing IL-2R[gamma] mRNA level or by the skipping of a constitutive exon. 16 refs., 1 fig.

  8. Mutations affecting export and activity of cytolysin A from Escherichia coli.

    PubMed

    Ludwig, Albrecht; Völkerink, Guido; von Rhein, Christine; Bauer, Susanne; Maier, Elke; Bergmann, Birgit; Goebel, Werner; Benz, Roland

    2010-08-01

    Cytolysin A (known as ClyA, HlyE, and SheA) is a cytolytic pore-forming protein toxin found in several Escherichia coli and Salmonella enterica strains. The structure of its water-soluble monomeric form and that of dodecameric ClyA pores is known, but the mechanisms of ClyA export from bacterial cells and of pore assembly are only partially understood. Here we used site-directed mutagenesis to study the importance of different regions of the E. coli ClyA protein for export and activity. The data indicate that ClyA translocation to the periplasm requires several protein segments located closely adjacent to each other in the "tail" domain of the ClyA monomer, namely, the N- and C-terminal regions and the hydrophobic sequence ranging from residues 89 to 101. Deletion of most of the "head" domain of the monomer (residues 181 to 203), on the other hand, did not strongly affect ClyA secretion, suggesting that the tail domain plays a particular role in export. Furthermore, we found that the N-terminal amphipathic helix alphaA1 of ClyA is crucial for the formation and the properties of the transmembrane channel, and hence for hemolytic activity. Several mutations affecting the C-terminal helix alphaG, the "beta-tongue" region in the head domain, or the hydrophobic region in the tail domain of the ClyA monomer strongly impaired the hemolytic activity and reduced the activity toward planar lipid bilayer membranes but did not totally prevent formation of wild-type-like channels in these artificial membranes. The latter regions thus apparently promote membrane interaction without being directly required for pore formation in a lipid bilayer.

  9. Treatment of Chagas Cardiomyopathy

    PubMed Central

    Botoni, Fernando A.; Ribeiro, Antonio Luiz P.; Marinho, Carolina Coimbra; Lima, Marcia Maria Oliveira; Nunes, Maria do Carmo Pereira; Rocha, Manoel Otávio C.

    2013-01-01

    Chagas' disease (ChD), caused by the protozoa Trypanosoma cruzi (T. cruzi), was discovered and described by the Brazilian physician Carlos Chagas in 1909. After a century of original description, trypanosomiasis still brings much misery to humanity and is classified as a neglected tropical disease prevalent in underdeveloped countries, particularly in South America. It is an increasing worldwide problem due to the number of cases in endemic areas and the migration of infected subjects to more developed regions, mainly North America and Europe. Despite its importance, chronic chagas cardiomyopathy (CCC) pathophysiology is yet poorly understood, and independently of its social, clinical, and epidemiological importance, the therapeutic approach of CCC is still transposed from the knowledge acquired from other cardiomyopathies. Therefore, the objective of this review is to describe the treatment of Chagas cardiomyopathy with emphasis on its peculiarities. PMID:24350293

  10. Alcoholic cardiomyopathy: Pathophysiologic insights

    PubMed Central

    Piano, Mariann R.; Phillips, Shane A.

    2014-01-01

    Alcoholic cardiomyopathy is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. Alcoholic cardiomyopathy is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of alcoholic cardiomyopathy. PMID:24671642

  11. Hypertrophic Cardiomyopathy Registry (HCMR): The rationale and design of an international, observational study of hypertrophic cardiomyopathy

    PubMed Central

    Kramer, Christopher M.; Appelbaum, Evan; Desai, Milind Y.; Desvigne-Nickens, Patrice; DiMarco, John P.; Friedrich, Matthias G.; Geller, Nancy; Heckler, Sarahfaye; Ho, Carolyn Y.; Jerosch-Herold, Michael; Ivey, Elizabeth A.; Keleti, Julianna; Kim, Dong-Yun; Kolm, Paul; Kwong, Raymond Y.; Maron, Martin S.; Schulz-Menger, Jeanette; Piechnik, Stefan; Watkins, Hugh; Weintraub, William S.; Wu, Pan; Neubauer, Stefan

    2015-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. HCM is characterized by unexplained left ventricular hypertrophy (LVH), myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. While the majority of patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death (SCD) or progress to refractory heart failure (HF). The HCMR study is a National Heart Lung and Blood Institute (NHLBI)-sponsored 2750 patient, 41 site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance (CMR) for assessment of left ventricular (LV) mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analysis will be performed. HCMR has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk. PMID:26299218

  12. Hypertrophic and dilated cardiomyopathy: four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases.

    PubMed

    Spudich, James A

    2014-03-18

    With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases.

  13. Hypertrophic and Dilated Cardiomyopathy: Four Decades of Basic Research on Muscle Lead to Potential Therapeutic Approaches to These Devastating Genetic Diseases

    PubMed Central

    Spudich, James A.

    2014-01-01

    With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases. PMID:24655499

  14. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

    PubMed

    Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Guarino, Estrella; Guarino Almeida, Estrella; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher C; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw J W; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

    2013-02-01

    Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.

  15. High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

    PubMed Central

    Ezquerra-Inchausti, Maitane; Barandika, Olatz; Anasagasti, Ander; Irigoyen, Cristina; López de Munain, Adolfo; Ruiz-Ederra, Javier

    2017-01-01

    Retinitis pigmentosa is the most frequent group of inherited retinal dystrophies. It is highly heterogeneous, with more than 80 disease-causing genes 27 of which are known to cause autosomal dominant RP (adRP), having been identified. In this study a total of 29 index cases were ascertained based on a family tree compatible with adRP. A custom panel of 31 adRP genes was analysed by targeted next-generation sequencing using the Ion PGM platform in combination with Sanger sequencing. This allowed us to detect putative disease-causing mutations in 14 out of the 29 (48.28%) families analysed. Remarkably, around 38% of all adRP cases analysed showed mutations affecting the splicing process, mainly due to mutations in genes coding for spliceosome factors (SNRNP200 and PRPF8) but also due to splice-site mutations in RHO. Twelve of the 14 mutations found had been reported previously and two were novel mutations found in PRPF8 in two unrelated patients. In conclusion, our results will lead to more accurate genetic counselling and will contribute to a better characterisation of the disease. In addition, they may have a therapeutic impact in the future given the large number of studies currently underway based on targeted RNA splicing for therapeutic purposes. PMID:28045043

  16. High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa.

    PubMed

    Ezquerra-Inchausti, Maitane; Barandika, Olatz; Anasagasti, Ander; Irigoyen, Cristina; López de Munain, Adolfo; Ruiz-Ederra, Javier

    2017-01-03

    Retinitis pigmentosa is the most frequent group of inherited retinal dystrophies. It is highly heterogeneous, with more than 80 disease-causing genes 27 of which are known to cause autosomal dominant RP (adRP), having been identified. In this study a total of 29 index cases were ascertained based on a family tree compatible with adRP. A custom panel of 31 adRP genes was analysed by targeted next-generation sequencing using the Ion PGM platform in combination with Sanger sequencing. This allowed us to detect putative disease-causing mutations in 14 out of the 29 (48.28%) families analysed. Remarkably, around 38% of all adRP cases analysed showed mutations affecting the splicing process, mainly due to mutations in genes coding for spliceosome factors (SNRNP200 and PRPF8) but also due to splice-site mutations in RHO. Twelve of the 14 mutations found had been reported previously and two were novel mutations found in PRPF8 in two unrelated patients. In conclusion, our results will lead to more accurate genetic counselling and will contribute to a better characterisation of the disease. In addition, they may have a therapeutic impact in the future given the large number of studies currently underway based on targeted RNA splicing for therapeutic purposes.

  17. Genetic advances in sarcomeric cardiomyopathies: state of the art.

    PubMed

    Ho, Carolyn Y; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y; Pinto, Yigal

    2015-04-01

    Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine.

  18. Genetic and biochemical characterization of mutations affecting the ability of the yeast Pachysolen tannophilus to metabolize D-xylose

    SciTech Connect

    James, A.P.; Zahab, D.M.; Mahmourides, G.; Maleszka, R.; Schneider, H. )

    1989-11-01

    Induced mutants, selected for their defective growth on D-xylose while retaining the ability to grow normally on D-glucose, were studied in Pachysolen tannophilus, a yeast capable of converting D-xylose to ethanol. Fourteen of the mutations were found to occur at nine distinct loci, and data indicated that many more loci remain to be detected. Most of the mutations were pleiotropic in character, and the expression of some of them was much affected by nutritional conditions and by genetic background. Mutations at several loci resulted in poor growth on at least one compound that was either an intermediate of the tricarboxylic acid cycle, succinate or {alpha}-ketoglutarate, or on compounds metabolizable via this cycle, ethanol or glycerol. An initial biochemical characterization of the mutants was undertaken. Analysis for xylose reductase, xylitol dehydrogenase, and xylulose kinase activity showed that one or more of these activities was affected in 12 of 13 mutants. However, drastic reduction in activity of a single enzyme was confined to that of xylitol dehydrogenase by mutations at three different loci and to that of D-xylose reductase by mutation at another locus. Growth of these latter four mutants was normal on all carbon sources tested that were not five-carbon sugars.

  19. Arrhythmias in peripartum cardiomyopathy.

    PubMed

    Honigberg, Michael C; Givertz, Michael M

    2015-06-01

    Peripartum cardiomyopathy (PPCM) is a complication of late pregnancy and the early postpartum period characterized by dilated cardiomyopathy and heart failure with reduced ejection fraction. Approximately half of women fail to recover left ventricular function. Standard management of heart failure is indicated, with some exceptions for women who are predelivery or breastfeeding. Atrial and ventricular arrhythmias are reported in PPCM, but the frequency of arrhythmias in this condition is not well characterized. Management of PPCM-associated arrhythmias may include antiarrhythmic drugs, catheter ablation, and wearable or implantable cardioverter-defibrillators. Further research is needed on the prevalence, natural history, and optimal management of arrhythmias in PPCM.

  20. A Mutator Affecting the Region of the Iso-1-Cytochrome c Gene in Yeast

    PubMed Central

    Liebman, Susan W.; Singh, Arjun; Sherman, Fred

    1979-01-01

    The mutator gene DEL1 in the yeast Saccharomyces cerevisiae causes a high rate of formation of multisite mutations that encompass the following three adjacent genes: CYC1, which determines the structure of iso-1-cytochrome c; RAD7, which controls UV sensitivity; and OSM1, which controls osomotic sensitivity. The simplest hypothesis is that these multisite mutations are deletions, although it has not been excluded that they may involve other types of gross chromosomal aberrations. In contrast, normal strains do not produce such multisite mutations even after mutagenic treatments.—The multisite mutations arise at a rate of approximately 10-5 to 10-6 per cell per division in DEL1 strains, which is much higher than rates observed for mutation of genes in normal strains. For example, normal strains produce all types of cyc1 mutants at a low rate of approximately 10-8 to 10-9. No evidence for multisite mutations was obtained upon analysis of numerous spontaneous ade1, ade2, met2 and met15 mutants isolated in a DEL1 strain. DEL1 segregates as a single Mendelian gene closely linked to the CYC1 locus. DEL1 appears to be both cis- and trans-dominant. The location of the DEL1 gene and the lack of effect on other genes suggest that the mutator acts only on a region adjacent to itself. PMID:231539

  1. Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma

    PubMed Central

    Plasilova, M.; Stoilov, I.; Sarfarazi, M.; Kadasi, L.; Ferakova, E.; Ferak, V.

    1999-01-01

    Primary congenital glaucoma (PCG) is an autosomal recessive eye disease that occurs at an unusually high frequency in the ethnic isolate of Roms (Gypsies) in Slovakia. Recently, we linked the disease in this population to the GLC3A locus on 2p21. At this locus, mutations in the cytochrome P4501B1 (CYP1B1) gene have been identified as a molecular basis for this condition. Here, we report the results of CYP1B1 mutation screening of 43 PCG patients from 26 Slovak Rom families. A homozygous G→A transition at nucleotide 1505 in the highly conserved region of exon 3 was detected in all families. This mutation results in the E387K substitution, which affects the conserved K helix region of the cytochrome P450 molecule. Determination of the CYP1B1 polymorphic background showed a common DNA haplotype in all patients, thus indicating that the E387K mutation in Roms has originated from a single ancestral mutational event. The Slovak Roms represent the first population in which PCG is found to result from a single mutation in the CYP1B1 gene, so that a founder effect is the most plausible explanation of its increased incidence. An ARMS-PCR assay has been developed for fast detection of this mutation, thus allowing direct DNA based prenatal diagnosis as well as gene carrier detection in this particular population. Screening of 158 healthy Roms identified 17 (10.8%) mutation carriers, indicating that the frequency of PCG in this population may be even higher than originally estimated.


Keywords: primary congenital glaucoma (PCG); cytochrome P4501B1; Roms (Gypsies); founder effect PMID:10227395

  2. Biallelic mutations in huntington disease: A new case with just one affected parent, review of the literature and terminology.

    PubMed

    Uhlmann, Wendy R; Peñaherrera, Maria S; Robinson, Wendy P; Milunsky, Jeff M; Nicholson, Jane M; Albin, Roger L

    2015-05-01

    Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin (HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD). The proband had biparental inheritance of HTT alleles (42/44 CAG repeats). Given the negative UPD results, the proband's unaffected mother either had a reduced penetrance allele that expanded into the full mutation range during transmission to our patient or an unknown full HTT mutation and died before symptom onset, unlikely given no family history of HD and asymptomatic at age 59. We made the novel observation in our literature review that most patients with biallelic HD did not have two full HTT mutations. Most had one HTT allele that was in the intermediate or reduced penetrance ranges or 40 CAG repeats, the lowest limit of the full mutation range. Although the number of patients is small, when an allele in these size ranges was present, generally the age of HD onset was in the 50s. If the second HTT allele had >45 repeats, then onset was typically 20s-30s. While similar ages of onset have been reported for patients with one or two HTT mutations, patients with biallelic mutations may have later onset if an expanded HTT allele has ≤40 CAG repeats. Finally, we propose that "biallelic mutations" or "compound heterozygosity" are more accurate descriptive terms than "homozygosity" when there are two non-identical expanded HTT alleles.

  3. Isolation of Mutations Affecting Neural Circuitry Required for Grooming Behavior in Drosophila Melanogaster

    PubMed Central

    Phillis, R. W.; Bramlage, A. T.; Wotus, C.; Whittaker, A.; Gramates, L. S.; Seppala, D.; Farahanchi, F.; Caruccio, P.; Murphey, R. K.

    1993-01-01

    We have developed a screen for the isolation of mutations that produce neural defects in adult Drosophila melanogaster. In this screen, we identify mutants as flies unable to remove a light coating of applied dust in a 2-hr period. We have recovered and characterized six mutations and have found that they produce coordination defects and some have reduced levels of reflex responsiveness to the stimulation of single tactile sensory bristles. The grooming defects produced by all six of the mutations are recessive, and each of the mutations has been genetically mapped. We have also used our assay to test the grooming ability of stocks containing mutations that produce known neural defects. PMID:8454205

  4. Identification of a novel mutation in the PAX9 gene in a family affected by oligodontia and other dental anomalies.

    PubMed

    Tallón-Walton, Victòria; Manzanares-Céspedes, Maria Cristina; Arte, Sirpa; Carvalho-Lobato, Patricia; Valdivia-Gandur, Ivan; Garcia-Susperregui, Antonio; Ventura, Francesc; Nieminen, Pekka

    2007-12-01

    The objective of the present work was to study the phenotype and the genotype of three generations of a family affected by oligodontia and other dental anomalies. These family members also presented systemic conditions such as hypercholesterolemia, hypothyroidism, diabetes mellitus, scoliosis, and congenital cardiovascular anomalies. Clinical evaluation, panoramic radiographs, and anamnestic data were used for dental analysis. DNA extraction was carried out from gum samples or buccal swabs. A mutation was identified in six subjects across three generations affected by oligodontia, as well as different phenotypical manifestations, both systemic and oral. The previously undescribed PAX9 mutation was observed in the paired box (exon 2); this was a heterozygote transition of C175 to T, implying the change of arginine 59 for a termination codon. These results strongly suggested that the identified mutation was the etiological cause of the oligodontia. However, in two family members affected by both hypodontia and peg-shaped upper lateral incisors, no mutations in the PAX9 and MSX1 genes were identified. This fact underscores the importance that other presently unknown genes and developmental factors have in tooth development and in the etiology of dental anomalies.

  5. Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

    PubMed

    Mistri, Mehul; Tamhankar, Parag M; Sheth, Frenny; Sanghavi, Daksha; Kondurkar, Pratima; Patil, Swapnil; Idicula-Thomas, Susan; Gupta, Sarita; Sheth, Jayesh

    2012-01-01

    Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

  6. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma

    PubMed Central

    Matlock, Matthew; Trani, Lee; Fronick, Catrina C.; Fulton, Robert S.; Kreisel, Friederike; Cashen, Amanda F.; Carson, Kenneth R.; Bartlett, Nancy L.

    2017-01-01

    Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment. PMID:28064239

  7. Cardiomyopathy Following Latrodectus Envenomation

    PubMed Central

    Levine, Michael; Canning, Josh; Chase, Robyn; Ruha, Anne-Michelle

    2010-01-01

    Latrodectus envenomations are common throughout the United States and the world. While many envenomations can result in catecholamine release with resultant hypertension and tachycardia, myocarditis is very rare. We describe a case of a 22-year-old male who sustained a Latrodectus envenomation complicated by cardiomyopathy. PMID:21293781

  8. Myocardial mechanics in cardiomyopathies.

    PubMed

    Modesto, Karen; Sengupta, Partho P

    2014-01-01

    Cardiomyopathies are a heterogeneous group of diseases that can be phenotypically recognized by specific patterns of ventricular morphology and function. The authors summarize recent clinical observations that mechanistically link the multidirectional components of left ventricular (LV) deformation with morphological phenotypes of cardiomyopathies for offering key insights into the transmural heterogeneity of myocardial function. Subendocardial dysfunction predominantly alters LV longitudinal shortening, lengthening and suction performance and contributes to the phenotypic patterns of heart failure (HF) with preserved ejection fraction (EF) seen with hypertrophic and restrictive patterns of cardiomyopathy. On the other hand, a more progressive transmural disease results in reduction of LV circumferential and twist mechanics leading to the phenotypic pattern of dilated cardiomyopathy and the clinical syndrome of HF with reduced (EF). A proper characterization of LV transmural mechanics, energetics, and space-time distributions of pressure and shear stress may allow recognition of early functional changes that can forecast progression or reversal of LV remodeling. Furthermore, the interactions between LV muscle and fluid mechanics hold the promise for offering newer mechanistic insights and tracking impact of novel therapies.

  9. Myocardial Expression Analysis of Osteopontin and Its Splice Variants in Patients Affected by End-Stage Idiopathic or Ischemic Dilated Cardiomyopathy

    PubMed Central

    Cabiati, Manuela; Svezia, Benedetta; Matteucci, Marco; Botta, Luca; Pucci, Angela; Rinaldi, Mauro; Caselli, Chiara; Lionetti, Vincenzo; Del Ry, Silvia

    2016-01-01

    Osteopontin (OPN) is a phosphoglycoprotein of cardiac extracellular matrix and it is still poorly defined whether its expression changes in failing heart of different origin. The full-length OPN-a and its isoforms (OPN-b, OPN-c) transcriptomic profile were evaluated in myocardium of patients with dilated or ischemic cardiomyopathy (DCM n = 8; LVEF% = 17.5±3; ICM n = 8; LVEF% = 19.5±5.2) and in auricle of valvular patients (VLP n = 5; LVEF%≥50), by Real-time PCR analysis. OPN-a and thrombin mRNA levels resulted significantly higher in DCM compared to ICM patients (DCM:31.3±7.4, ICM:2.7±1.1, p = 0.0002; DCM:19.1±4.9, ICM:5.4±2.2, p = 0.007, respectively). Although both genes’ mRNA levels increased in patients with LVEF<50% (DCM+ICM) with respect to VLP with LVEF>50%, a significant increase in OPN (p = 0.0004) and thrombin (p = 0.001) expression was observed only in DCM. In addition, a correlation between OPN-a and thrombin was found in patients with LVEF<50% (r = 0.6; p = 0.003). The mRNA pattern was confirmed by OPN-a cardiac protein concentration (VLP:1.127±0.26; DCM:1.29±0.22; ICM:1.00±0.077 ng/ml). The OPN splice variants expression were detectable only in ICM (OPN-b: 0.357±0.273; OPN-c: 0.091±0.033) and not in DCM patients. A significant correlation was observed between collagen type I, evaluated by immunohistochemistry analysis, and both OPN-a mRNA expression (r = 0.87, p = 0.002) and OPN protein concentrations (r = 0.77, p = 0.016). Concluding, OPN-a and thrombin mRNA resulted dependent on the origin of heart failure while OPN-b and OPN-c highlighted a different expression for DCM and ICM patients, suggesting their correlation with different clinical-pathophysiological setting. PMID:27479215

  10. Identification of polymerase gene mutations that affect viral replication in H5N1 influenza viruses isolated from pigeons.

    PubMed

    Elgendy, Emad Mohamed; Arai, Yasuha; Kawashita, Norihito; Daidoji, Tomo; Takagi, Tatsuya; Ibrahim, Madiha Salah; Nakaya, Takaaki; Watanabe, Yohei

    2017-01-01

    Highly pathogenic avian influenza virus H5N1 infects a wide range of host species, with a few cases of sporadic pigeon infections reported in the Middle East and Asia. However, the role of pigeons in the ecology and evolution of H5N1 viruses remains unclear. We previously reported two H5N1 virus strains, isolated from naturally infected pigeons in Egypt, that have several unique mutations in their viral polymerase genes. Here, we investigated the effect of these mutations on H5N1 polymerase activity and viral growth and identified three mutations that affected viral polymerase activity. The results showed that the PB1-V3D mutation significantly decreased polymerase activity and viral growth in both mammalian and avian cells. In contrast, the PB2-K627E and PA-K158R mutations had moderate effects: PB2-K627E decreased and PA-K158R increased polymerase activity. Structural homology modelling indicated that the PB1-V3D residue was located in the PB1 core region that interacts with PA, predicting that the PB1 mutation would produce a stronger interaction between PB1 and PA that results in decreased replication of pigeon-derived H5N1 viruses. Our results identified several unique mutations responsible for changes in polymerase activity in H5N1 virus strains isolated from infected pigeons, emphasizing the importance of avian influenza surveillance in pigeons and in studying the possible role of pigeon-derived H5N1 viruses in avian influenza virus evolution.

  11. Identification of a novel synonymous mutation in the human β -Ureidopropionase Gene UPB1 affecting pre-mRNA splicing.

    PubMed

    Meijer, J; Nakajima, Y; Zhang, C; Meinsma, R; Ito, T; Van Kuilenburg, A B P

    2013-01-01

    β-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and it catalyzes the conversion of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid to β-alanine and β-aminoisobutyric acid, respectively, and ammonia and CO2. To date, only 16 genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report the clinical, biochemical, and molecular analysis of a newly identified patient with β-ureidopropionase deficiency. Mutation analysis of the UPB1 gene showed that the patient was compound heterozygous for a novel synonymous mutation c.93C >T (p.Gly31Gly) in exon 1 and a previously described missense mutation c.977G >A (p.Arg326Gln) in exon 9. The in silico predicted effect of the synonymous mutation p.Gly31Gly on pre-mRNA splicing was investigated using a minigene approach. Wild-type and the mutated minigene constructs, containing the entire exon 1, intron 1, and exon 2 of UPB1, yielded different splicing products after expression in HEK293 cells. The c.93C >T (p.Gly31Gly) mutation resulted in altered pre-mRNA splicing of the UPB1 minigene construct and a deletion of the last 13 nucleotides of exon 1. This deletion (r.92_104delGCAAGGAACTCAG) results in a frame shift and the generation of a premature stop codon (p.Lys32SerfsX31). Using a minigene approach, we have thus identified the first synonymous mutation in the UPB1 gene, creating a cryptic splice-donor site affecting pre-mRNA splicing.

  12. Search for mutations affecting protein structure in children of atomic bomb survivors: preliminary report

    SciTech Connect

    Neel, J.V.; Satoh, C.; Hamilton, H.B.; Otake, M.; Goriki, K.; Kageoka, T.; Fujita, M.; Neriishi, S.; Asakawa J.

    1980-07-01

    A total of 289,868 locus tests, based on 28 different protein phenotypes and using one-dimensional electrophoresis to detect variant proteins, has yielded one probable mutation in the offspring of proximally exposed parents, who received an estimated average gonadal exposure of 31 to 39 rem in the atomic bombings of Hiroshima and Nagasaki. There were no mutations in 208,196 locus tests involving children of distally exposed parents, who had essentially no radiation exposure.

  13. Search for mutations affecting protein structure in children of atomic bomb survivors: preliminary report.

    PubMed

    Neel, J V; Satoh, C; Hamilton, H B; Otake, M; Goriki, K; Kageoka, T; Fujita, M; Neriishi, S; Asakawa, J

    1980-07-01

    A total of 289,868 locus tests, based on 28 different protein phenotypes and using one-dimensional electrophoresis to detect variant proteins, has yielded one probable mutation in the offspring of "proximally exposed" parents, who received an estimated average gonadal exposure of 31 to 39 rem in the atomic bombings of Hiroshima and Nagasaki. There were no mutations in 208,196 locus tests involving children of "distally exposed" parents, who had essentially no radiation exposure.

  14. Mutations in MCT8 in patients with Allan-Herndon-Dudley-syndrome affecting its cellular distribution.

    PubMed

    Kersseboom, Simone; Kremers, Gert-Jan; Friesema, Edith C H; Visser, W Edward; Klootwijk, Wim; Peeters, Robin P; Visser, Theo J

    2013-05-01

    Monocarboxylate transporter 8 (MCT8) is a thyroid hormone (TH)-specific transporter. Mutations in the MCT8 gene are associated with Allan-Herndon-Dudley Syndrome (AHDS), consisting of severe psychomotor retardation and disturbed TH parameters. To study the functional consequences of different MCT8 mutations in detail, we combined functional analysis in different cell types with live-cell imaging of the cellular distribution of seven mutations that we identified in patients with AHDS. We used two cell models to study the mutations in vitro: 1) transiently transfected COS1 and JEG3 cells, and 2) stably transfected Flp-in 293 cells expressing a MCT8-cyan fluorescent protein construct. All seven mutants were expressed at the protein level and showed a defect in T3 and T4 transport in uptake and metabolism studies. Three mutants (G282C, P537L, and G558D) had residual uptake activity in Flp-in 293 and COS1 cells, but not in JEG3 cells. Four mutants (G221R, P321L, D453V, P537L) were expressed at the plasma membrane. The mobility in the plasma membrane of P537L was similar to WT, but the mobility of P321L was altered. The other mutants studied (insV236, G282C, G558D) were predominantly localized in the endoplasmic reticulum. In essence, loss of function by MCT8 mutations can be divided in two groups: mutations that result in partial or complete loss of transport activity (G221R, P321L, D453V, P537L) and mutations that mainly disturb protein expression and trafficking (insV236, G282C, G558D). The cell type-dependent results suggest that MCT8 mutations in AHDS patients may have tissue-specific effects on TH transport probably caused by tissue-specific expression of yet unknown MCT8-interacting proteins.

  15. Genetics Home Reference: familial restrictive cardiomyopathy

    MedlinePlus

    ... Home Health Conditions familial restrictive cardiomyopathy familial restrictive cardiomyopathy Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Familial restrictive cardiomyopathy is a genetic form of heart disease. For ...

  16. Peripartum Cardiomyopathy From a Genetic Perspective.

    PubMed

    Kamiya, Chizuko A; Yoshimatsu, Jun; Ikeda, Tomoaki

    2016-07-25

    Peripartum cardiomyopathy (PPCM) is a rare, but life-threatening condition that occurs during the peripartum period in previously healthy women. Although its etiology remains unknown, potential risk factors include hypertensive disorders during pregnancy, such as preeclampsia, advanced maternal age, multiparity, multiple gestation, and African descent. Several cohort studies of PPCM revealed that the prevalence of these risk factors was quite similar. Clinically, approximately 40% of PPCM patients are complicated with hypertensive disorders during pregnancy. Because PPCM is a diagnosis of exclusion, heterogeneity is a common element in its pathogenesis. Recent genetic research has given us new aspects of the disease. PPCM and dilated cardiomyopathy (DCM) share genetic predisposition: 15% of PPCM patients were found to have genetic mutations that have been associated with DCM, and they showed a lower recovery rate. Other basic research using PPCM model mice suggests that predisposition genes related to both hypertensive and cardiac disorders via angiogenic imbalance may explain common elements of hypertensive disorders and PPCM. Furthermore, hypertensive disorders during pregnancy are now found to be a risk factor of not only PPCM, but also cardiomyopathy in the future. Understanding genetic variations allows us to stratify PPCM patients and to guide therapy. (Circ J 2016; 80: 1684-1688).

  17. Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase.

    PubMed

    Ramírez-Salinas, Gema L; García-Machorro, J; Quiliano, Miguel; Zimic, Mirko; Briz, Verónica; Rojas-Hernández, Saul; Correa-Basurto, J

    2015-11-01

    The goal of this study was to identify neuraminidase (NA) residue mutants from human influenza AH1N1 using sequences from 1918 to 2012. Multiple alignment studies of complete NA sequences (5732) were performed. Subsequently, the crystallographic structure of the 1918 influenza (PDB ID: 3BEQ-A) was used as a wild-type structure and three-dimensional (3-D) template for homology modeling of the mutated selected NA sequences. The 3-D mutated NAs were refined using molecular dynamics (MD) simulations (50 ns). The refined 3-D models were used to perform docking studies using oseltamivir. Multiple sequence alignment studies showed seven representative mutations (A232V, K262R, V263I, T264V, S367L, S369N, and S369K). MD simulations applied to 3-D NAs showed that each NA had different active-site shapes according to structural surface visualization and docking results. Moreover, Cartesian principal component analyses (cPCA) show structural differences among these NA structures caused by mutations. These theoretical results suggest that the selected mutations that are located outside of the active site of NA could affect oseltamivir recognition and could be associated with resistance to oseltamivir.

  18. A critical functional missense mutation (H173R) in the bovine PROP1 gene significantly affects growth traits in cattle.

    PubMed

    Pan, Chuanying; Wu, Chongyang; Jia, Wenchao; Xu, Yao; Lei, Chuzhao; Hu, Shenrong; Lan, Xianyong; Chen, Hong

    2013-12-01

    The PROP1 protein, encoded by the prophet of Pit-1 (PROP1) gene, exhibits both DNA-binding and transcriptional activation abilities. Its expression leads to the ontogenesis of growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and pituitary hormone. The missense mutation H173R in PROP1 may result in deficiencies of GH, PRL, TSH, and Pit-1, thereby affecting growth traits. The objective of this study was to characterize the H173R mutation within the PROP1 gene and examine its associations with growth traits in cattle. Accordingly, the H173R mutation was genotyped in 1207 cows belonging to five Chinese native breeds. Three genotypes were identified among the specimens, with genotype AA being the major one. Consequently, the "G" allele was the minor allele. Association testing revealed that the H173R mutation was significantly associated with body weight, average daily weight gain and physical parameters in the analyzed breeds. Interestingly, the cows with genotype AG and/or AA had superior growth traits compared with those expressing the GG genotype, in all tested breeds. These findings revealed that the "A" allele had positive effects on growth traits, which was consistent with the increasing binding ability and enhanced activation capacity associated with the bovine isoform PROP1-173H, representing the "A" allele. Therefore, the H173R mutation can be considered as a DNA marker for selecting individuals with superior growth traits, thereby contributing to research on breeding and genetics in the beef industry.

  19. Experimental models of inherited cardiomyopathy and its therapeutics

    PubMed Central

    Nonaka, Miki; Morimoto, Sachio

    2014-01-01

    Cardiomyopathy is a disease of myocardium categorized into three major forms, hypertrophic (HCM), dilated (DCM) and restrictive cardiomyopathy (RCM), which has recently been demonstrated to be a monogenic disease due to mutations in various proteins expressed in cardiomyocytes. Mutations in HCM and RCM typically increase the myofilament sensitivity to cytoplasmic Ca2+, leading to systolic hyperfunction and diastolic dysfunction. In contrast, mutations in DCM typically decrease the myofilament sensitivity to cytoplasmic Ca2+ and/or force generation/transmission, leading to systolic dysfunction. Creation of genetically-manipulated transgenic and knock-in animals expressing mutant proteins exogenously and endogenously, respectively, in their hearts provides valuable animal models to discover the molecular and cellular mechanisms for pathogenesis and promising therapeutic strategy in vivo. Recently, cardiomyocytes have been differentiated from patient’s induced pluripotent stem cells as a model of inherited cardiomyopathies in vitro. In this review, we provide overview of experimental models of cardiomyopathies with a focus on revealed molecular and cellular pathogenic mechanisms and potential therapeutics. PMID:25548614

  20. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study

    PubMed Central

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity. PMID:27147983

  1. Novel missense mutation in the GALNS gene in an affected patient with severe form of mucopolysaccharidosis type IVA.

    PubMed

    Seyedhassani, Seyed Mohammad; Hashemi-Gorji, Feyzollah; Yavari, Mahdieh; Mirfakhraie, Reza

    2015-10-23

    Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A, is an autosomal recessive disorder characterized by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes major skeletal and connective tissue abnormalities and affects multiple organ systems. In this study, one MPS IVA patient with a severe form from consanguine large Iranian family has been investigated. To find a mutation, all of the 14 exons and intron-exon junctions of GALNS gene were sequenced. Sequencing results were analyzed using bioinformatic analysis in order to predict probable pathogenic effect of the variant. One novel homozygous missense mutation in exon 5, c.542A>G (p.Y181C), was found in the proband. That was predicted as being probably pathogenic by bioinformatics analysis. Segregation and familial study confirmed this pathogenic mutation. In conclusion, we have identified the novel mutation responsible for MPS IVA in an Iranian patient to assist in the diagnosis, genetic counseling and prenatal diagnosis of the affected families.

  2. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

    PubMed

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

  3. An experimental approach to study the function of mitochondria in cardiomyopathy

    PubMed Central

    Chung, Youn Wook; Kang, Seok-Min

    2015-01-01

    Cardiomyopathy is an inherited or acquired disease of the myocardium, which can result in severe ventricular dysfunction. Mitochondrial dysfunction is involved in the pathological process of cardiomyopathy. Many dysfunctions in cardiac mitochondria are consequences of mutations in nuclear or mitochondrial DNA followed by alterations in transcriptional regulation, mitochondrial protein function, and mitochondrial dynamics and energetics, presenting with associated multisystem mitochondrial disorders. To ensure correct diagnosis and optimal management of mitochondrial dysfunction in cardiomyopathy caused by multiple pathogenesis, multidisciplinary approaches are required, and to integrate between clinical and basic sciences, ideal translational models are needed. In this review, we will focus on experimental models to provide insights into basic mitochondrial physiology and detailed underlying mechanisms of cardiomyopathy and current mitochondria-targeted therapies for cardiomyopathy. [BMB Reports 2015; 48(10): 541-548] PMID:26198095

  4. Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): A clue to the pathogenesis of oncocytic cardiomyopathy?

    SciTech Connect

    Bird, L.M.; Krous, H.F.; Eichenfield, L.F.; Swalwell, C.I.; Jones, M.C.

    1994-11-01

    A infant girl had red stellate skin lesions on the cheeks and neck, and mildly short palpebral fissures. Her skin abnormality was typical of microphthalmia with linear skin defects (MLS), a newly recognized syndrome consisting of congenital linear skin defects and ocular abnormalities in females monosomic for Xp22. She died suddenly and unexpectedly at age 4 months; the cause of death was ascribed to oncocytic cardiomyopathy. Oncocytic cardiomyopathy occurs only in young children, who present with refractory arrhythmias leading to cardiac arrest. The coexistence of two rare conditions, one of which is mapped to the X chromosome, and an excess of affected females with oncocytic cardiomyopathy is also X-linked, with Xp22 being a candidate region. Overlapping manifestations in the two conditions (ocular abnormalities in cases of oncocytic cardiomyopathy and arrhythmias in MLS) offer additional support for this hypothesis. 43 refs., 2 figs., 2 tabs.

  5. Development of Dilated Cardiomyopathy and Impaired Calcium Homeostasis with Cardiac-Specific Deletion of ESRRβ.

    PubMed

    Rowe, Glenn C; Asimaki, Angeliki; Graham, Evan L; Martin, Kimberly D; Margulies, Kenneth B; Das, Saumya; Saffitz, Jeffrey E; Arany, Zoltan

    2017-01-27

    Mechanisms underlying the development of Idiopathic Dilated Cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor beta (ESRRβ), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRβ (MHC-ERRB KO) develop dilated cardiomyopathy and sudden death at approximately 10 months of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRβ protein is absent from the nucleus of cardiomyocytes from patients with DCM, but not other forms of cardiomyopathy (ischemic, hypertrophic and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRβ is a critical component in the onset of dilated cardiomyopathy by affecting contractility and calcium balance.

  6. C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle

    PubMed Central

    Floriot, Sandrine; Vesque, Christine; Rodriguez, Sabrina; Bourgain-Guglielmetti, Florence; Karaiskou, Anthi; Gautier, Mathieu; Duchesne, Amandine; Barbey, Sarah; Fritz, Sébastien; Vasilescu, Alexandre; Bertaud, Maud; Moudjou, Mohammed; Halliez, Sophie; Cormier-Daire, Valérie; E.L. Hokayem, Joyce; Nigg, Erich A.; Manciaux, Luc; Guatteo, Raphaël; Cesbron, Nora; Toutirais, Geraldine; Eggen, André; Schneider-Maunoury, Sylvie; Boichard, Didier; Sobczak-Thépot, Joelle; Schibler, Laurent

    2015-01-01

    Caprine-like Generalized Hypoplasia Syndrome (SHGC) is an autosomal-recessive disorder in Montbéliarde cattle. Affected animals present a wide range of clinical features that include the following: delayed development with low birth weight, hind limb muscular hypoplasia, caprine-like thin head and partial coat depigmentation. Here we show that SHGC is caused by a truncating mutation in the CEP250 gene that encodes the centrosomal protein C-Nap1. This mutation results in centrosome splitting, which neither affects centriole ultrastructure and duplication in dividing cells nor centriole function in cilium assembly and mitotic spindle organization. Loss of C-Nap1-mediated centriole cohesion leads to an altered cell migration phenotype. This discovery extends the range of loci that constitute the spectrum of autosomal primary recessive microcephaly (MCPH) and Seckel-like syndromes. PMID:25902731

  7. Mutations in the passenger polypeptide can affect its partitioning between mitochondria and cytoplasm: mutations can impair the mitochondrial import of DsRed.

    PubMed

    Pastukh, Viktoriya; Shokolenko, Inna N; Wilson, Glenn L; Alexeyev, Mikhail F

    2008-06-01

    In this study, we report that the partitioning between mitochondria and cytoplasm of two variants, mCherry and DsRed Express (DRE), of the red fluorescent protein, DsRed, fused to one of the six matrix targeting sequences (MTSs) can be affected by both MTS and amino acid substitutions in DsRed. Of the six MTSs tested, MTSs from superoxide dismutase and DNA polymerase gamma failed to direct mCherry, but not DRE to mitochondria. By evaluating a series of chimeras between mCherry and DRE fused to the MTS of superoxide dismutase, we attribute the differences in the mitochondrial partitioning to differences in the primary amino acid sequence of the passenger polypeptide. The impairment of mitochondrial partitioning closely parallels the number of mCherry-specific mutations, and is not specific to mutations located in any particular region of the polypeptide. These observations suggest that both MTS and the passenger polypeptide affect the efficiency of mitochondrial import and provide a rationale for the observed diversity in the primary amino acid sequences of natural MTSs.

  8. The shiverer mutation affects the persistence of Theiler's virus in the central nervous system.

    PubMed Central

    Bihl, F; Pena-Rossi, C; Guénet, J L; Brahic, M; Bureau, J F

    1997-01-01

    Theiler's virus persists in the white matter of the spinal cord of genetically susceptible mice and causes primary demyelination. The virus persists in macrophages/microglial cells, but also in oligodendrocytes, the myelin-forming cells. Susceptibility/resistance to this chronic infection has been mapped to several loci including one tentatively located in the telomeric region of chromosome 18, close to the myelin basic protein locus (Mbp locus). To determine if the MBP gene influences viral persistence, we inoculated C3H mice bearing the shiverer mutation, a 20-kb deletion in the gene. Whereas control C3H mice were of intermediate susceptibility, C3H mice heterozygous for the mutation were very susceptible, and those homozygous for the mutation were completely resistant. This resistance was not immune mediated. Furthermore, C3H/101H mice homozygous for a point mutation in the gene coding for the proteolipid protein of myelin, the rumpshaker mutation, were resistant. These results strongly support the view that oligodendrocytes are a necessary viral target for the establishment of a persistent infection by Theiler's virus. PMID:9188567

  9. Two desmin gene mutations associated with myofibrillar myopathies in Polish families.

    PubMed

    Fichna, Jakub Piotr; Karolczak, Justyna; Potulska-Chromik, Anna; Miszta, Przemyslaw; Berdynski, Mariusz; Sikorska, Agata; Filipek, Slawomir; Redowicz, Maria Jolanta; Kaminska, Anna; Zekanowski, Cezary

    2014-01-01

    Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, α-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization.

  10. Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

    PubMed Central

    Marques, Mayra de A.; de Oliveira, Guilherme A. P.

    2016-01-01

    Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM) was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the “disease of the sarcomere.” The most common macroscopic phenotypes are left ventricle and interventricular septal thickening, but because the clinical profile of this disease is quite heterogeneous, these phenotypes are not suitable for an accurate diagnosis. The development of genomic approaches for clinical investigation allows for diagnostic progress and understanding at the molecular level. Meanwhile, the lack of accurate in vivo models to better comprehend the cellular events triggered by this pathology has become a challenge. Notwithstanding, the imbalance of Ca2+ concentrations, altered signaling pathways, induction of apoptotic factors, and heart remodeling leading to abnormal anatomy have already been reported. Of note, a misbalance of signaling biomolecules, such as kinases and tumor suppressors (e.g., Akt and p53), seems to participate in apoptotic and fibrotic events. In HCM, structural and cellular information about defective sarcomeric proteins and their altered interactome is emerging but still represents a bottleneck for developing new concepts in basic research and for future therapeutic interventions. This review focuses on the structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins and how structural biology can aid in the discovery of new platforms for therapeutics. We highlight the

  11. Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy.

    PubMed

    Roma-Rodrigues, Catarina; Fernandes, Alexandra R

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems.

  12. Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy

    PubMed Central

    Li Mura, Ilena Egle Astrid; Bauce, Barbara; Nava, Andrea; Fanciulli, Manuela; Vazza, Giovanni; Mazzotti, Elisa; Rigato, Ilaria; De Bortoli, Marzia; Beffagna, Giorgia; Lorenzon, Alessandra; Calore, Martina; Dazzo, Emanuela; Nobile, Carlo; Luisa Mostacciuolo, Maria; Corrado, Domenico; Basso, Cristina; Daliento, Luciano; Thiene, Gaetano; Rampazzo, Alessandra

    2013-01-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high−density SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes. PMID:23486541

  13. A novel locus for autosomal-dominant dilated cardiomyopathy maps to chromosome 7q22.3-31.1.

    PubMed

    Schönberger, Jost; Kühler, Leif; Martins, Elisabete; Lindner, Tom H; Silva-Cardoso, Jose; Zimmer, Michael

    2005-12-01

    Inherited dilated cardiomyopathy (DCM) is a genetically and phenotypically very heterogeneous disease. DCM is caused by mutations in multiple genes encoding proteins that are involved in force generation, force transmission, energy production and several signalling pathways. Thus, the pathophysiology of heart failure is complex and not yet fully understood. Familial forms of DCM let the way to identify new key proteins by positional cloning and to study respective pathomechanisms that are critical for normal cardiac function, but may not have been correlated with heart disease before. Here we report a three-generation pedigree including 16 individuals affected by dilated cardiomyopathy without additional phenotypes. The pedigree is consistent with autosomal-dominant inheritance and age-related penetrance. A genome-wide linkage analysis excluded linkage to all known DCM genes and loci, whereas several close markers on chromosome 7q22.3-31.1 segregated with the disease (maximum logarithm of odds score, 4.20 at D7S471 and D7S501). The disease causing mutation lies in a 9.73 Mb interval between markers D7S2545 and D7S2554 that contains no known cytoskeletal genes. Coding exons of the candidate genes LAMB1, LAMB4 and PIK3CG were screened but no mutations were identified.

  14. [Tachycardia-induced cardiomyopathy].

    PubMed

    Povolný, Jan

    2015-01-01

    Cardiomyopathy is a heterogeneous group of diseases of heart muscle accompanied with impaired cardiac function. Tachycardia-induced cardiomyopathy (TIC) is caused by prolonged tachycardia leading to dilatation and systolic dysfunction with clinical manifestation of heart failure. This state is reversible after normalization of heart rate. The diagnosis is usually made retrospectively after normalization of heart rate and recovery of left ventricular function (LVF). More than 100 years after the first documented case (described in 1913 in a young patient with atrial fibrillation and symptoms of heart failure [25]) is still limited knowledge of pathophysiological mechanisms. The most common arrhythmias responsible for the TIC include atrial fibrillation [1,2], atrial flutter [3], incessant supraventricular tachycardia [4], ventricular tachycardia (VT) [5] and frequent ventricular extrasystoles (VES) [6]. TIC detection and therapeutic intervention is crucial considering potential reversibility of tachycardia. Current options of treatment involve drug therapy and surgical or catheter ablation.

  15. Inflammatory dilated cardiomyopathy (DCMI).

    PubMed

    Maisch, Bernhard; Richter, Anette; Sandmöller, Andrea; Portig, Irene; Pankuweit, Sabine

    2005-09-01

    Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm(2)), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations. Within the German heart failure net it is the authors' working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors' primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.A pivotal role for

  16. Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane

    NASA Astrophysics Data System (ADS)

    Zhang, Mingzhen; Zheng, Jie; Nussinov, Ruth; Ma, Buyong

    2016-09-01

    Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy measurements and provide structural details in line with the DEER data. Comparison with the latest experimental results revealed that our models agree well with both Bax and Bak pores, pointed to a converged structural arrangement for Bax and Bak pore formation. Using multi-scale molecular dynamics simulations, we probed mutational effects on Bax transformation from monomer → dimer → membrane pore formation at atomic resolution. We observe that two cancer-related mutations, G40E and S118I, allosterically destabilize the monomer and stabilize an off-pathway swapped dimer, preventing productive pore formation. This observation suggests a mechanism whereby the mutations may work mainly by over-stabilizing the monomer → dimer transformation toward an unproductive off-pathway swapped-dimer state. Our observations point to misfolded Bax states, shedding light on the molecular mechanism of Bax mutation-elicited cancer. Most importantly, the structure of the Bax pore facilitates future study of releases cytochrome C in atomic detail.

  17. Characterization of novel Brown midrib 6 mutations affecting lignin biosynthesis in sorghum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The presence of lignin reduces the quality of lignocellulosic biomass for forage materials and feedstock for biofuels. In C4 grasses, the brown midrib phenotype has been linked to mutations to genes in the monolignol biosynthesis pathway. For example, the Bmr6 gene in sorghum (Sorghum bicolor) has b...

  18. The glabra1 mutation affects cuticle formation and plant responses to microbes.

    PubMed

    Xia, Ye; Yu, Keshun; Navarre, Duroy; Seebold, Kenneth; Kachroo, Aardra; Kachroo, Pradeep

    2010-10-01

    Systemic acquired resistance (SAR) is a form of defense that provides resistance against a broad spectrum of pathogens in plants. Previous work indicates a role for plastidial glycerolipid biosynthesis in SAR. Specifically, mutations in FATTY ACID DESATURASE7 (FAD7), which lead to reduced trienoic fatty acid levels and compromised plastidial lipid biosynthesis, have been associated with defective SAR. We show that the defective SAR in Arabidopsis (Arabidopsis thaliana) fad7-1 plants is not associated with a mutation in FAD7 but rather with a second-site mutation in GLABRA1 (GL1), a gene well known for its role in trichome formation. The compromised SAR in gl1 plants is associated with impairment in their cuticles. Furthermore, mutations in two other components of trichome development, GL3 and TRANSPARENT TESTA GLABRA1, also impaired cuticle development and SAR. This suggests an overlap in the biochemical pathways leading to cuticle and trichome development. Interestingly, exogenous application of gibberellic acid (GA) not only enhanced SAR in wild-type plants but also restored SAR in gl1 plants. In contrast to GA, the defense phytohoromes salicylic acid and jasmonic acid were unable to restore SAR in gl1 plants. GA application increased levels of cuticular components but not trichome formation on gl1 plants, thus implicating cuticle, but not trichomes, as an important component of SAR. Our findings question the prudence of using mutant backgrounds for genetic screens and underscore a need to reevaluate phenotypes previously studied in the gl1 background.

  19. Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane

    PubMed Central

    Zhang, Mingzhen; Zheng, Jie; Nussinov, Ruth; Ma, Buyong

    2016-01-01

    Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy measurements and provide structural details in line with the DEER data. Comparison with the latest experimental results revealed that our models agree well with both Bax and Bak pores, pointed to a converged structural arrangement for Bax and Bak pore formation. Using multi-scale molecular dynamics simulations, we probed mutational effects on Bax transformation from monomer → dimer → membrane pore formation at atomic resolution. We observe that two cancer-related mutations, G40E and S118I, allosterically destabilize the monomer and stabilize an off-pathway swapped dimer, preventing productive pore formation. This observation suggests a mechanism whereby the mutations may work mainly by over-stabilizing the monomer → dimer transformation toward an unproductive off-pathway swapped-dimer state. Our observations point to misfolded Bax states, shedding light on the molecular mechanism of Bax mutation-elicited cancer. Most importantly, the structure of the Bax pore facilitates future study of releases cytochrome C in atomic detail. PMID:27630059

  20. Structural analysis of tissues affected by cytochrome C oxidase deficiency due to mutations in the SCO2 gene.

    PubMed

    Vesela, Katerina; Hulkova, Helena; Hansikova, Hana; Zeman, Jiri; Elleder, Milan

    2008-01-01

    Structural and histochemical studies carried out in a series of seven cases (from five families) with isolated cytochrome c oxidase (COX) deficiency caused by mutations in the SCO2 gene (1, 2) disclosed changes concentrated in the nervous system, skeletal muscle and myocardium. In five patients homozygous for the E140K mutation, the phenotype was predominantly neuromuscular and the average life span ranged between 9 and 15 months. In two cases, the course was more rapid (death at 7 and 11 weeks of life) and featured marked cardiac hypertrophy (3- and 4-fold increase in heart weight). This predominantly cardiomyopathic phenotype was associated with compound heterozygosity (E140K with another nonsense mutation) in the SCO2 gene. Polioencephalopathy with neurodegeneration and neuronal drop out was present in all cases with evidence that retinal neurons might be seriously affected too. Involvement of spinal motoneurons together with cytochrome c oxidase deficiency in muscle represents a "double hit" for the skeletal muscle. The mitochondrial population was not found to be significantly increased or structurally altered, with the exception of two compound heterozygotes in which the cardiac mitochondria were increased in number and size. Our report extends knowledge of the pathology of COX deficiency caused by mutations in the SCO2 gene.

  1. Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport.

    PubMed Central

    Tripodi, G; Valtorta, F; Torielli, L; Chieregatti, E; Salardi, S; Trusolino, L; Menegon, A; Ferrari, P; Marchisio, P C; Bianchi, G

    1996-01-01

    The adducin heterodimer is a protein affecting the assembly of the actin-based cytoskeleton. Point mutations in rat adducin alpha (F316Y) and beta (Q529R) subunits are involved in a form of rat primary hypertension (MHS) associated with faster kidney tubular ion transport. A role for adducin in human primary hypertension has also been suggested. By studying the interaction of actin with purified normal and mutated adducin in a cell-free system and the actin assembly in rat kidney epithelial cells (NRK-52E) transfected with mutated rat adducin cDNA, we show that the adducin isoforms differentially modulate: (a) actin assembly both in a cell-free system and within transfected cells; (b) topography of alpha V integrin together with focal contact proteins; and (c) Na-K pump activity at V(max) (faster with the mutated isoforms, 1281 +/- 90 vs 841 +/- 30 nmol K/h.mg pt., P < 0.0001). This co-modulation suggests a role for adducin in the constitutive capacity of the epithelia both to transport ions and to expose adhesion molecules. These findings may also lead to the understanding of the relation between adducin polymorphism and blood pressure and to the development of new approaches to the study of hypertension-associated organ damage. PMID:8675693

  2. Down Syndrome with Complete Atrioventricular Septal Defect, Hypertrophic Cardiomyopathy, and Pulmonary Vein Stenosis.

    PubMed

    Mahadevaiah, Guruprasad; Gupta, Manoj; Ashwath, Ravi

    2015-10-01

    The prevalence of congenital heart disease in infants with Down syndrome is 40%, compared with 0.3% in children who have normal chromosomes. Atrioventricular and ventricular septal defects are often associated with chromosomal aberrations, such as in trisomy 21, whereas hypertrophic cardiomyopathy is chiefly thought to be secondary to specific gene mutations. We found only one reported case of congenital hypertrophic cardiomyopathy and atrioventricular septal defect in an infant with Down syndrome. Here, we report atrioventricular septal defect, hypertrophic cardiomyopathy, and pulmonary vein stenosis in a neonate with Down syndrome-an apparently unique combination. In addition, we discuss the relevant medical literature.

  3. Congenital hypothyroidism mutations affect common folding and trafficking in the α/β-hydrolase fold proteins.

    PubMed

    De Jaco, Antonella; Dubi, Noga; Camp, Shelley; Taylor, Palmer

    2012-12-01

    The α/β-hydrolase fold superfamily of proteins is composed of structurally related members that, despite great diversity in their catalytic, recognition, adhesion and chaperone functions, share a common fold governed by homologous residues and conserved disulfide bridges. Non-synonymous single nucleotide polymorphisms within the α/β-hydrolase fold domain in various family members have been found for congenital endocrine, metabolic and nervous system disorders. By examining the amino acid sequence from the various proteins, mutations were found to be prevalent in conserved residues within the α/β-hydrolase fold of the homologous proteins. This is the case for the thyroglobulin mutations linked to congenital hypothyroidism. To address whether correct folding of the common domain is required for protein export, we inserted the thyroglobulin mutations at homologous positions in two correlated but simpler α/β-hydrolase fold proteins known to be exported to the cell surface: neuroligin3 and acetylcholinesterase. Here we show that these mutations in the cholinesterase homologous region alter the folding properties of the α/β-hydrolase fold domain, which are reflected in defects in protein trafficking, folding and function, and ultimately result in retention of the partially processed proteins in the endoplasmic reticulum. Accordingly, mutations at conserved residues may be transferred amongst homologous proteins to produce common processing defects despite disparate functions, protein complexity and tissue-specific expression of the homologous proteins. More importantly, a similar assembly of the α/β-hydrolase fold domain tertiary structure among homologous members of the superfamily is required for correct trafficking of the proteins to their final destination.

  4. Decade in review--cardiomyopathies: Cardiomyopathy on the move.

    PubMed

    Yacoub, Magdi H

    2014-11-01

    Since Wallace Brigden first used the term 'cardiomyopathy' in 1952, this group of diseases has continued to attract the interest of clinicians, researchers, and importantly, patients. The past decade has seen a substantial accumulation of knowledge relating to various cardiomyopathies, which has partially lifted the mystery surrounding this topic.

  5. Mutations in Nonconserved Domains of Ty3 Integrase Affect Multiple Stages of the Ty3 Life Cycle

    PubMed Central

    Nymark-McMahon, M. Henrietta; Sandmeyer, Suzanne B.

    1999-01-01

    Ty3, a retroviruslike element of Saccharomyces cerevisiae, transposes into positions immediately upstream of RNA polymerase III-transcribed genes. The Ty3 integrase (IN) protein is required for integration of the replicated, extrachromosomal Ty3 DNA. In retroviral IN, a conserved core region is sufficient for strand transfer activity. In this study, charged-to-alanine scanning mutagenesis was used to investigate the roles of the nonconserved amino- and carboxyl-terminal regions of Ty3 IN. Each of the 20 IN mutants was defective for transposition, but no mutant was grossly defective for capsid maturation. All mutations affecting steady-state levels of mature IN protein resulted in reduced levels of replicated DNA, even when polymerase activity was not grossly defective as measured by exogenous reverse transcriptase activity assay. Thus, IN could contribute to nonpolymerase functions required for DNA production in vivo or to the stability of the DNA product. Several mutations in the carboxyl-terminal domain resulted in relatively low levels of processed 3′ ends of the replicated DNA, suggesting that this domain may be important for binding of IN to the long terminal repeat. Another class of mutants produced wild-type amounts of DNA with correctly processed 3′ ends. This class could include mutants affected in nuclear entry and target association. Collectively, these mutations demonstrate that in vivo, within the preintegration complex, IN performs a central role in coordinating multiple late stages of the retrotransposition life cycle. PMID:9847351

  6. Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells.

    PubMed

    Kim, Euysoo; Hyrc, Krzysztof L; Speck, Judith; Salles, Felipe T; Lundberg, Yunxia W; Goldberg, Mark P; Kachar, Bechara; Warchol, Mark E; Ornitz, David M

    2011-03-01

    Otopetrin 1 (Otop1) encodes a protein that is essential for the development of otoconia. Otoconia are the extracellular calcium carbonate containing crystals that are important for vestibular mechanosensory transduction of linear motion and gravity. There are two mutant alleles of Otop1 in mice, titled (tlt) and mergulhador (mlh), which result in non-syndromic otoconia agenesis and a consequent balance defect. Biochemically, Otop1 has been shown to modulate purinergic control of intracellular calcium in vestibular supporting cells, which could be one of the mechanisms by which Otop1 participates in the mineralization of otoconia. To understand how tlt and mlh mutations affect the biochemical function of Otop1, we examined the purinergic response of COS7 cells expressing mutant Otop1 proteins, and dissociated sensory epithelial cells from tlt and mlh mice. We also examined the subcellular localization of Otop1 in whole sensory epithelia from tlt and mlh mice. Here we show that tlt and mlh mutations uncouple Otop1 from inhibition of P2Y receptor function. Although the in vitro biochemical function of the Otop1 mutant proteins is normal, in vivo they behave as null alleles. We show that in supporting cells the apical membrane localization of the mutant Otop1 proteins is lost. These data suggest that the tlt and mlh mutations primarily affect the localization of Otop1, which interferes with its ability to interact with other proteins that are important for its cellular and biochemical function.

  7. Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics

    PubMed Central

    Kawada, Ichiro; Hasina, Rifat; Lennon, Frances E; Bindokas, Vytautas P; Usatyuk, Peter; Tan, Yi-Hung C; Krishnaswamy, Soundararajan; Arif, Qudsia; Carey, George; Hseu, Robyn D; Robinson, Matthew; Tretiakova, Maria; Brand, Toni M; Iida, Mari; Ferguson, Mark K; Wheeler, Deric L; Husain, Aliya N; Natarajan, Viswanathan; Vokes, Everett E; Singleton, Patrick A; Salgia, Ravi

    2013-01-01

    Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HEK-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets. PMID:23792636

  8. A new Gsdma3 mutation affecting anagen phase of first hair cycle

    SciTech Connect

    Tanaka, Shigekazu; Tamura, Masaru; Aoki, Aya; Fujii, Tomoaki; Komiyama, Hiromitsu; Sagai, Tomoko; Shiroishi, Toshihiko . E-mail: tshirois@lab.nig.ac.jp

    2007-08-10

    Recombination-induced mutation 3 (Rim3) is a spontaneous mouse mutation that exhibits dominant phenotype of hyperkeratosis and hair loss. Fine linkage analysis of Rim3 and sequencing revealed a novel single point mutation, G1124A leading to Ala348Thr, in Gsdma3 in chromosome 11. Transgenesis with BAC DNA harboring the Rim3-type Gsdma3 recaptured the Rim3 phenotype, providing direct evidence that Gsdma3 is the causative gene of Rim3. We examined the spatial expression of Gsdma3 and characterized the Rim3 phenotype in detail. Gsdma3 is expressed in differentiated epidermal cells in the skin, but not in the proliferating epidermal cells. Histological analysis of Rim3 mutant showed hyperplasia of the epidermal cells in the upper hair follicles and abnormal anagen phase at the first hair cycle. Furthermore, immunohistochemical analysis revealed hyperproliferation and misdifferentiation of the upper follicular epidermis in Rim3 mutant. These results suggest that Gsdma3 is involved in the proliferation and differentiation of epidermal stem cells.

  9. Mutations in Durum Wheat SBEII Genes affect Grain Yield Components, Quality, and Fermentation Responses in Rats.

    PubMed

    Hazard, Brittany; Zhang, Xiaoqin; Naemeh, Mahmoudreza; Hamilton, M Kristina; Rust, Bret; Raybould, Helen E; Newman, John W; Martin, Roy; Dubcovsky, Jorge

    2015-01-01

    Increased amylose in wheat (Triticum ssp.) starch is associated with increased resistant starch, a fermentable dietary fiber. Fermentation of resistant starch in the large intestine produces short-chain fatty acids that are associated with human health benefits. Since wheat foods are an important component of the human diet, increases in amylose and resistant starch in wheat grains have the potential to deliver health benefits to a large number of people. In three replicated field trials we found that mutations in starch branching enzyme II genes (SBEIIa and SBEIIb) in both A and B genomes (SBEIIa/b-AB) of durum wheat [T. turgidum L. subsp. durum (Desf.) Husn.] resulted in large increases of amylose and resistant starch content. The presence of these four mutations was also associated with an average 5% reduction in kernel weight (P = 0.0007) and 15% reduction in grain yield (P = 0.06) compared to the wild type. Complete milling and pasta quality analysis showed that the mutant lines have an acceptable quality with positive effects on pasta firmness and negative effects on semolina extraction and pasta color. Positive fermentation responses were detected in rats (Rattus spp.) fed with diets incorporating mutant wheat flour. This study quantifies benefits and limitations associated with the deployment of the SBEIIa/b-AB mutations in durum wheat and provides the information required to develop realistic strategies to deploy durum wheat varieties with increased levels of amylose and resistant starch.

  10. Myotonia congenita-associated mutations in chloride channel-1 affect zebrafish body wave swimming kinematics.

    PubMed

    Cheng, Wei; Tian, Jing; Burgunder, Jean-Marc; Hunziker, Walter; Eng, How-Lung

    2014-01-01

    Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1). Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita.

  11. Mutations in Durum Wheat SBEII Genes affect Grain Yield Components, Quality, and Fermentation Responses in Rats

    PubMed Central

    Hazard, Brittany; Zhang, Xiaoqin; Naemeh, Mahmoudreza; Hamilton, M. Kristina; Rust, Bret; Raybould, Helen E.; Newman, John W.; Martin, Roy; Dubcovsky, Jorge

    2016-01-01

    Increased amylose in wheat (Triticum ssp.) starch is associated with increased resistant starch, a fermentable dietary fiber. Fermentation of resistant starch in the large intestine produces short-chain fatty acids that are associated with human health benefits. Since wheat foods are an important component of the human diet, increases in amylose and resistant starch in wheat grains have the potential to deliver health benefits to a large number of people. In three replicated field trials we found that mutations in starch branching enzyme II genes (SBEIIa and SBEIIb) in both A and B genomes (SBEIIa/b-AB) of durum wheat [T. turgidum L. subsp. durum (Desf.) Husn.] resulted in large increases of amylose and resistant starch content. The presence of these four mutations was also associated with an average 5% reduction in kernel weight (P = 0.0007) and 15% reduction in grain yield (P = 0.06) compared to the wild type. Complete milling and pasta quality analysis showed that the mutant lines have an acceptable quality with positive effects on pasta firmness and negative effects on semolina extraction and pasta color. Positive fermentation responses were detected in rats (Rattus spp.) fed with diets incorporating mutant wheat flour. This study quantifies benefits and limitations associated with the deployment of the SBEIIa/b-AB mutations in durum wheat and provides the information required to develop realistic strategies to deploy durum wheat varieties with increased levels of amylose and resistant starch. PMID:27134286

  12. Mutations in two regions upstream of the A gamma globin gene canonical promoter affect gene expression.

    PubMed Central

    Lloyd, J A; Lee, R F; Lingrel, J B

    1989-01-01

    Two regions upstream of the human fetal (A gamma) globin gene, which interact with protein factors from K562 and HeLa nuclear extracts, have functional significance in gene expression. One binding site (site I) is at a position -290 to -267 bp upstream of the transcription initiation site, the other (site II) is at -182 to -168 bp. Site II includes the octamer sequence (ATGCAAAT) found in an immunoglobulin enhancer and the histone H2b gene promoter. A point mutation (T----C) at -175, within the octamer sequence, is characteristic of a naturally occurring HPFH (hereditary persistence of fetal hemoglobin), and decreases factor binding to an oligonucleotide containing the octamer motif. Expression assays using a A gamma globin promoter-CAT (chloramphenicol acetyl transferase) fusion gene show that the point mutation at -175 increases expression in erythroid, but not non-erythroid cells when compared to a wild-type construct. This correlates with the actual effect of the HPFH mutation in humans. This higher expression may result from a mechanism more complex than reduced binding of a negative regulator. A site I clustered-base substitution gives gamma-CAT activity well below wild-type, suggesting that this factor is a positive regulator. Images PMID:2472607

  13. Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation

    PubMed Central

    Klerk, CPW; Smorenburg, SM; Spek, CA; Van Noorden, CJF

    2007-01-01

    Abstract Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model. PMID:17635646

  14. Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2.

    PubMed

    Yoshizawa-Ogasawara, Atsuko; Abe, Kiyomi; Ogikubo, Sayaka; Narumi, Satoshi; Hasegawa, Tomonobu; Satoh, Mari

    2016-03-01

    Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%-9%, p<0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (-0.7%±0.6%, p<0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%±0.9%, p<0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.

  15. Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies

    PubMed Central

    Frisso, Giulia; Detta, Nicola; Coppola, Pamela; Mazzaccara, Cristina; Pricolo, Maria Rosaria; D’Onofrio, Antonio; Limongelli, Giuseppe; Calabrò, Raffaele; Salvatore, Francesco

    2016-01-01

    Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families. PMID:27834932

  16. Role of neuropeptides in cardiomyopathies.

    PubMed

    Dvorakova, Magdalena Chottova; Kruzliak, Peter; Rabkin, Simon W

    2014-11-01

    The role of neuropeptides in cardiomyopathy-associated heart failure has been garnering more attention. Several neuropeptides--Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP) and their receptors have been studied in the various types of cardiomyopathies. The data indicate associations with the strength of the association varying depending on the kind of neuropeptide and the nature of the cardiomyopathy--diabetic, ischemic, inflammatory, stress-induced or restrictive cardiomyopathy. Several neuropeptides appear to alter regulation of genes involved in heart failure. Demonstration of an association is an essential first step in proving causality or establishing a role for a factor in a disease. Understanding the complexity of neuropeptide function should be helpful in establishing new or optimal therapeutic strategies for the treatment of heart failure in cardiomyopathies.

  17. A novel COL11A1 mutation affecting splicing in a patient with Stickler syndrome

    PubMed Central

    Kohmoto, Tomohiro; Naruto, Takuya; Kobayashi, Haruka; Watanabe, Miki; Okamoto, Nana; Masuda, Kiyoshi; Imoto, Issei; Okamoto, Nobuhiko

    2015-01-01

    Stickler syndrome is a clinically and genetically heterogeneous collagenopathy characterized by ocular, auditory, skeletal and orofacial abnormalities, commonly occurring as an autosomal dominant trait. We conducted target resequencing to analyze candidate genes associated with known clinical phenotypes from a 4-year-old girl with Stickler syndrome. We detected a novel heterozygous intronic mutation (NM_001854.3:c.3168+5G>A) in COL11A1 that may impair splicing, which was suggested by in silico prediction and a minigene assay. PMID:27081549

  18. A novel COL11A1 mutation affecting splicing in a patient with Stickler syndrome.

    PubMed

    Kohmoto, Tomohiro; Naruto, Takuya; Kobayashi, Haruka; Watanabe, Miki; Okamoto, Nana; Masuda, Kiyoshi; Imoto, Issei; Okamoto, Nobuhiko

    2015-01-01

    Stickler syndrome is a clinically and genetically heterogeneous collagenopathy characterized by ocular, auditory, skeletal and orofacial abnormalities, commonly occurring as an autosomal dominant trait. We conducted target resequencing to analyze candidate genes associated with known clinical phenotypes from a 4-year-old girl with Stickler syndrome. We detected a novel heterozygous intronic mutation (NM_001854.3:c.3168+5G>A) in COL11A1 that may impair splicing, which was suggested by in silico prediction and a minigene assay.

  19. Mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle

    SciTech Connect

    Argaw, Takele; Wilson, Carolyn A.

    2015-01-15

    Previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the PERV-C envelope (RQKK to RPKK) resulted in non-infectious vectors. Here, we show that RPKK results in a non-infectious vector when placed in not only a PERV envelope, but also the envelope of a related gammaretrovirus, FeLV-B. The amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. Rather, the mutations result in the formation of hyperglycosylated glycoprotein and a reduction in the reverse transcribed minus strand synthesis and undetectable 2-LTR circular DNA in cells exposed to vectors with these mutated envelopes. Our findings suggest novel functions associated with the cleavage signal sequence that may affect trafficking through the glycosylation machinery of the cell. Further, the glycosylation status of the envelope appears to impact post-binding events of the viral life cycle, either membrane fusion, internalization, or reverse transcription. - Highlights: • Env cleavage signal impacts infectivity of gammaretroviruses. • Non-infectious mutants have hyper-glycosylated envelope that bind target cells. • Non-infectious mutants have defects in the formation of the double-stranded DNA. • Env cleavage motif has functions beyond cleavage of the env precursor.

  20. Skeletal muscle sodium channel is affected by an epileptogenic beta1 subunit mutation.

    PubMed

    Moran, O; Conti, F

    2001-03-23

    The syndrome of generalized epilepsy with febrile seizures plus type 1 (GEFS+) has been associated to the gene SCN1B coding for the sodium channel beta1 subunit (Wallace, R. H. et al. (1998) Nature Genetics 19, 366-370). In patients, a mutation of the cysteine 121 to trpyptophane (C121W) would cause a lack of modulatory activity of the beta1 subunit on sodium channels expressed in the brain, rendering neurons hyperexcitable. We have confirmed that the normal beta1-modulation of type-IIA adult brain alpha subunits (BIIA) expressed in frog oocytes is defective in C121W. We observed that the mixture of wild-type and mutant beta1 subunits is less effective than wild-type alone, suggesting that the mutant beta1 subunit does bind the alpha subunit. However, we also observed a similar lack of modulation by C121W of the in adult skeletal muscle alpha subunit (SkM1). This finding is in contrast with the simple idea that the mutational effect observed in the oocyte expression system is the principal physiopathological correlate of GEFS+, because no skeletal muscle symptoms have been reported in GEFS+ patients. We conclude that the manifestation of the pathological phenotype is conditioned by the presence of susceptibility genes and/or that the frog oocyte expression system is inadequate for the study of the mutant beta1 subunit physiopathology.

  1. pigk Mutation underlies macho behavior and affects Rohon-Beard cell excitability

    PubMed Central

    Carmean, V.; Yonkers, M. A.; Tellez, M. B.; Willer, J. R.; Willer, G. B.; Gregg, R. G.; Geisler, R.; Neuhauss, S. C.

    2015-01-01

    The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons. PMID:26133798

  2. pigk Mutation underlies macho behavior and affects Rohon-Beard cell excitability.

    PubMed

    Carmean, V; Yonkers, M A; Tellez, M B; Willer, J R; Willer, G B; Gregg, R G; Geisler, R; Neuhauss, S C; Ribera, A B

    2015-08-01

    The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons.

  3. A mutation in protein phosphatase 2A regulatory subunit A affects auxin transport in Arabidopsis

    NASA Technical Reports Server (NTRS)

    Garbers, C.; DeLong, A.; Deruere, J.; Bernasconi, P.; Soll, D.; Evans, M. L. (Principal Investigator)

    1996-01-01

    The phytohormone auxin controls processes such as cell elongation, root hair development and root branching. Tropisms, growth curvatures triggered by gravity, light and touch, are also auxin-mediated responses. Auxin is synthesized in the shoot apex and transported through the stem, but the molecular mechanism of auxin transport is not well understood. Naphthylphthalamic acid (NPA) and other inhibitors of auxin transport block tropic curvature responses and inhibit root and shoot elongation. We have isolated a novel Arabidopsis thaliana mutant designated roots curl in NPA (rcn1). Mutant seedlings exhibit altered responses to NPA in root curling and hypocotyl elongation. Auxin efflux in mutant seedlings displays increased sensitivity to NPA. The rcn1 mutation was transferred-DNA (T-DNA) tagged and sequences flanking the T-DNA insert were cloned. Analysis of the RCN1 cDNA reveals that the T-DNA insertion disrupts a gene for the regulatory A subunit of protein phosphatase 2A (PP2A-A). The RCN1 gene rescues the rcn1 mutant phenotype and also complements the temperature-sensitive phenotype of the Saccharomyces cerevisiae PP2A-A mutation, tpd3-1. These data implicate protein phosphatase 2A in the regulation of auxin transport in Arabidopsis.

  4. A mutation in protein phosphatase 2A regulatory subunit A affects auxin transport in Arabidopsis.

    PubMed Central

    Garbers, C; DeLong, A; Deruére, J; Bernasconi, P; Söll, D

    1996-01-01

    The phytohormone auxin controls processes such as cell elongation, root hair development and root branching. Tropisms, growth curvatures triggered by gravity, light and touch, are also auxin-mediated responses. Auxin is synthesized in the shoot apex and transported through the stem, but the molecular mechanism of auxin transport is not well understood. Naphthylphthalamic acid (NPA) and other inhibitors of auxin transport block tropic curvature responses and inhibit root and shoot elongation. We have isolated a novel Arabidopsis thaliana mutant designated roots curl in NPA (rcn1). Mutant seedlings exhibit altered responses to NPA in root curling and hypocotyl elongation. Auxin efflux in mutant seedlings displays increased sensitivity to NPA. The rcn1 mutation was transferred-DNA (T-DNA) tagged and sequences flanking the T-DNA insert were cloned. Analysis of the RCN1 cDNA reveals that the T-DNA insertion disrupts a gene for the regulatory A subunit of protein phosphatase 2A (PP2A-A). The RCN1 gene rescues the rcn1 mutant phenotype and also complements the temperature-sensitive phenotype of the Saccharomyces cerevisiae PP2A-A mutation, tpd3-1. These data implicate protein phosphatase 2A in the regulation of auxin transport in Arabidopsis. Images PMID:8641277

  5. Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot?

    PubMed Central

    Moraes, C T; Ciacci, F; Bonilla, E; Jansen, C; Hirano, M; Rao, N; Lovelace, R E; Rowland, L P; Schon, E A; DiMauro, S

    1993-01-01

    We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease. Images PMID:8254046

  6. Mutations of Arabidopsis TBL32 and TBL33 Affect Xylan Acetylation and Secondary Wall Deposition

    PubMed Central

    Yuan, Youxi; Teng, Quincy; Zhong, Ruiqin; Haghighat, Marziyeh; Richardson, Elizabeth A.; Ye, Zheng-Hua

    2016-01-01

    Xylan is a major acetylated polymer in plant lignocellulosic biomass and it can be mono- and di-acetylated at O-2 and O-3 as well as mono-acetylated at O-3 of xylosyl residues that is substituted with glucuronic acid (GlcA) at O-2. Based on the finding that ESK1, an Arabidopsis thaliana DUF231 protein, specifically mediates xylan 2-O- and 3-O-monoacetylation, we previously proposed that different acetyltransferase activities are required for regiospecific acetyl substitutions of xylan. Here, we demonstrate the functional roles of TBL32 and TBL33, two ESK1 close homologs, in acetyl substitutions of xylan. Simultaneous mutations of TBL32 and TBL33 resulted in a significant reduction in xylan acetyl content and endoxylanase digestion of the mutant xylan released GlcA-substituted xylooligomers without acetyl groups. Structural analysis of xylan revealed that the tbl32 tbl33 mutant had a nearly complete loss of 3-O-acetylated, 2-O-GlcA-substituted xylosyl residues. A reduction in 3-O-monoacetylated and 2,3-di-O-acetylated xylosyl residues was also observed. Simultaneous mutations of TBL32, TBL33 and ESK1 resulted in a severe reduction in xylan acetyl level down to 15% of that of the wild type, and concomitantly, severely collapsed vessels and stunted plant growth. In particular, the S2 layer of secondary walls in xylem vessels of tbl33 esk1 and tbl32 tbl33 esk1 exhibited an altered structure, indicating abnormal assembly of secondary wall polymers. These results demonstrate that TBL32 and TBL33 play an important role in xylan acetylation and normal deposition of secondary walls. PMID:26745802

  7. Mutations of Arabidopsis TBL32 and TBL33 affect xylan acetylation and secondary wall deposition

    DOE PAGES

    Yuan, Youxi; Teng, Quincy; Zhong, Ruiqin; ...

    2016-01-08

    Xylan is a major acetylated polymer in plant lignocellulosic biomass and it can be monoand di-acetylated at O-2 and O-3 as well as mono-acetylated at O-3 of xylosyl residues that is substituted with glucuronic acid (GlcA) at O-2. Based on the finding that ESK1, an Arabidopsis thaliana DUF231 protein, specifically mediates xylan 2-O- and 3-O-monoacetylation, we previously proposed that different acetyltransferase activities are required for regiospecific acetyl substitutions of xylan. Here, we demonstrate the functional roles of TBL32 and TBL33, two ESK1 close homologs, in acetyl substitutions of xylan. Simultaneous mutations of TBL32 and TBL33 resulted in a significant reductionmore » in xylan acetyl content and endoxylanase digestion of the mutant xylan released GlcA-substituted xylooligomers without acetyl groups. Structural analysis of xylan revealed that the tbl32 tbl33 mutant had a nearly complete loss of 3-O-acetylated, 2-O-GlcA-substituted xylosyl residues. A reduction in 3-Omonoacetylated and 2,3-di-O-acetylated xylosyl residues was also observed. Simultaneous mutations of TBL32, TBL33 and ESK1 resulted in a severe reduction in xylan acetyl level down to 15% of that of the wild type, and concomitantly, severely collapsed vessels and stunted plant growth. In particular, the S2 layer of secondary walls in xylem vessels of tbl33 esk1 and tbl32 tbl33 esk1 exhibited an altered structure, indicating abnormal assembly of secondary wall polymers. Furthermore, these results demonstrate that TBL32 and TBL33 play an important role in xylan acetylation and normal deposition of secondary walls.« less

  8. Takotsubo cardiomyopathy (Broken heart syndrome).

    PubMed

    Javed, Aqib; Chitkara, Kamal; Mahmood, Arslan; Kainat, Aleesha

    2015-11-01

    Takotsubo cardiomyopathy is an acute reversible cardiomyopathy characterised by transient regional left ventricular (LV) motion abnormalities. It is diagnosed on a coronary angiography and left ventriculography. We report the case of a 50-year-old lady who presented with sudden onset of chest pain, with no history of cardiac disease and no risk factors. Remarkably though, she had lost her husband the previous night. Coronary and LV angiography was done which revealed findings typical of takotsubo cardiomyopathy. We report this case for its rarity. Informed consent was taken from the patient before undertaking and reporting this study.

  9. Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

    PubMed Central

    Franaszczyk, Maria; Chmielewski, Przemyslaw; Truszkowska, Grazyna; Stawinski, Piotr; Michalak, Ewa; Rydzanicz, Malgorzata; Sobieszczanska-Malek, Malgorzata; Pollak, Agnieszka; Szczygieł, Justyna; Kosinska, Joanna; Parulski, Adam; Stoklosa, Tomasz; Tarnowska, Agnieszka; Machnicki, Marcin M.; Foss-Nieradko, Bogna; Szperl, Malgorzata; Sioma, Agnieszka; Kusmierczyk, Mariusz; Grzybowski, Jacek; Zielinski, Tomasz; Ploski, Rafal

    2017-01-01

    TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance. PMID:28045975

  10. Experimental and molecular dynamics studies showed that CBP KIX mutation affects the stability of CBP:c-Myb complex.

    PubMed

    Odoux, Anne; Jindal, Darren; Tamas, Tamara C; Lim, Benjamin W H; Pollard, Drake; Xu, Wu

    2016-06-01

    The coactivators CBP (CREBBP) and its paralog p300 (EP300), two conserved multi-domain proteins in eukaryotic organisms, regulate gene expression in part by binding DNA-binding transcription factors. It was previously reported that the CBP/p300 KIX domain mutant (Y650A, A654Q, and Y658A) altered both c-Myb-dependent gene activation and repression, and that mice with these three point mutations had reduced numbers of platelets, B cells, T cells, and red blood cells. Here, our transient transfection assays demonstrated that mouse embryonic fibroblast cells containing the same mutations in the KIX domain and without a wild-type allele of either CBP or p300, showed decreased c-Myb-mediated transcription. Dr. Wright's group solved a 3-D structure of the mouse CBP:c-Myb complex using NMR. To take advantage of the experimental structure and function data and improved theoretical calculation methods, we performed MD simulations of CBP KIX, CBP KIX with the mutations, and c-Myb, as well as binding energy analysis for both the wild-type and mutant complexes. The binding between CBP and c-Myb is mainly mediated by a shallow hydrophobic groove in the center where the side-chain of Leu302 of c-Myb plays an essential role and two salt bridges at the two ends. We found that the KIX mutations slightly decreased stability of the CBP:c-Myb complex as demonstrated by higher binding energy calculated using either MM/PBSA or MM/GBSA methods. More specifically, the KIX mutations affected the two salt bridges between CBP and c-Myb (CBP-R646 and c-Myb-E306; CBP-E665 and c-Myb-R294). Our studies also revealed differing dynamics of the hydrogen bonds between CBP-R646 and c-Myb-E306 and between CBP-E665 and c-Myb-R294 caused by the CBP KIX mutations. In the wild-type CBP:c-Myb complex, both of the hydrogen bonds stayed relatively stable. In contrast, in the mutant CBP:c-Myb complex, hydrogen bonds between R646 and E306 showed an increasing trend followed by a decreasing trend, and hydrogen

  11. Genetics of hypertrophic and dilated cardiomyopathy.

    PubMed

    Friedrich, Felix W; Carrier, Lucie

    2012-10-01

    Cardiomyopathies are categorized as extrinsic, being caused by external factors, such as hypertension, ischemia, inflammation, valvular dysfunction, or as intrinsic, which correspond to myocardial diseases without identifiable external causes. These so called primary cardiomyopathies can be categorized in four main forms: hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy. Cardiomyopathies are diagnosed by clinical expression, echocardiography, electrocardiography, non-invasive imaging, and sometimes by cardiac catheterization to rule out external causes as ischemia. The two main forms of primary cardiomyopathies are the hypertrophic and dilated cardiomyopathies. Most of hypertrophic cardiomyopathy and 20-50% of dilated cardiomyopathy are familial showing a wide genetic and phenotypic heterogeneity. This review presents the current knowledge on the causative genes, molecular mechanisms and the genotype � phenotype relations of hypertrophic and dilated cardiomyopathies.

  12. A Premature Stop Codon in MYO18B is Associated with Severe Nemaline Myopathy with Cardiomyopathy

    PubMed Central

    Malfatti, Edoardo; Böhm, Johann; Lacène, Emmanuelle; Beuvin, Maud; Guy Brochier; Romero, Norma B.; Laporte, Jocelyn

    2015-01-01

    Abstract Background: Nemaline myopathies (NM) are rare and severe muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Although ten genes have been implicated in the etiology of NM, an important number of patients remain without a molecular diagnosis. Objective: Here we describe the clinical and histopathological features of a sporadic case presenting with severe NM and cardiomyopathy. Using exome sequencing, we aimed to identify the causative gene. Results: We identified a homozygous nonsense mutation in the last exon of MYO18B, leading to a truncated protein lacking the most C-terminal part. MYO18B codes for an unconventional myosin protein and it is mainly expressed in skeletal and cardiac muscles, two tissues severely affected in the patient. We showed that the mutation does not impact on mRNA stability. Immunostaining and Western blot confirmed the absence of the full-length protein. Conclusion: We propose MYO18B as a novel gene associated with nemaline myopathy and cardiomyopathy. PMID:27858739

  13. Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

    PubMed

    Li, Monica X; Hwang, Peter M

    2015-10-25

    In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

  14. Structure and Function of Cardiac Troponin C (TNNC1): Implications for Heart Failure, Cardiomyopathies, and Troponin Modulating Drugs

    PubMed Central

    Li, Monica X.; Hwang, Peter M.

    2015-01-01

    In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure. PMID:26232335

  15. Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era.

    PubMed

    Teekakirikul, Polakit; Kelly, Melissa A; Rehm, Heidi L; Lakdawala, Neal K; Funke, Birgit H

    2013-03-01

    Inherited cardiomyopathies include hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, and restrictive cardiomyopathy. These diseases have a substantial genetic component and predispose to sudden cardiac death, which provides a high incentive to identify and sequence disease genes in affected individuals to identify pathogenic variants. Clinical genetic testing, which is now widely available, can be a powerful tool for identifying presymptomatic individuals. However, locus and allelic heterogeneity are the rule, as are clinical variability and reduced penetrance of disease in carriers of pathogenic variants. These factors, combined with genetic and phenotypic overlap between different cardiomyopathies, have made clinical genetic testing a lengthy and costly process. Next-generation sequencing technologies have removed many limitations such that comprehensive testing is now feasible, shortening diagnostic odysseys for clinically complex cases. Remaining challenges include the incomplete understanding of the spectrum of benign and pathogenic variants in the cardiomyopathy genes, which is a source of inconclusive results. This review provides an overview of inherited cardiomyopathies with a focus on their genetic etiology and diagnostic testing in the postgenomic era.

  16. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore.

    PubMed

    Zhang, Zhifen; Park, Minyoung; Tam, John; Auger, Anick; Beilhartz, Greg L; Lacy, D Borden; Melnyk, Roman A

    2014-03-11

    Disease associated with Clostridium difficile infection is caused by the actions of the homologous toxins TcdA and TcdB on colonic epithelial cells. Binding to target cells triggers toxin internalization into acidified vesicles, whereupon cryptic segments from within the 1,050-aa translocation domain unfurl and insert into the bounding membrane, creating a transmembrane passageway to the cytosol. Our current understanding of the mechanisms underlying pore formation and the subsequent translocation of the upstream cytotoxic domain to the cytosol is limited by the lack of information available regarding the identity and architecture of the transmembrane pore. Here, through systematic perturbation of conserved sites within predicted membrane-insertion elements of the translocation domain, we uncovered highly sensitive residues--clustered between amino acids 1,035 and 1,107--that when individually mutated, reduced cellular toxicity by as much as >1,000-fold. We demonstrate that defective variants are defined by impaired pore formation in planar lipid bilayers and biological membranes, resulting in an inability to intoxicate cells through either apoptotic or necrotic pathways. These findings along with the unexpected similarities uncovered between the pore-forming "hotspots" of TcdB and the well-characterized α-helical diphtheria toxin translocation domain provide insights into the structure and mechanism of formation of the translocation pore for this important class of pathogenic toxins.

  17. Mutations Affecting Donor Preference during Mating Type Interconversion in Saccharomyces Cerevisiae

    PubMed Central

    Weiler, K. S.; Szeto, L.; Broach, J. R.

    1995-01-01

    Homothallic strains of Saccharomyces cerevisiae can convert mating type from a to α or α to a as often as every generation, by replacing genetic information specifying one mating type at the expressor locus, MAT, with information specifying the opposite mating type. The cryptic mating type information that is copied and inserted at MAT is contained in either of two loci, HML or HMR. The particular locus selected as donor during mating type interconversion is regulated by the allele expressed at MAT. MATa cells usually select HML, and MATα cells usually select HMR, a process referred to as donor preference. To identify factors required for donor preference, we isolated and characterized a number of mutants that frequently selected the nonpreferred donor locus during mating type interconversion. Many of these mutants were found to harbor chromosome rearrangements or mutations at MAT or HML that interfered with the switching process. However, one mutant carried a recessive allele of CHL1, a gene previously shown to be required for efficient chromosome segregation during mitosis. Homothallic strains of yeast containing a null allele of CHL1 exhibited almost random selection of the donor locus in a MATa background but were normal in their ability to select HMR in a MATα background. Our results indicate that Chl1p participates in the process of donor selection and are consistent with a model in which Chl1p helps establish an intrinsic bias in donor preference. PMID:7789755

  18. Characterization and genetic mapping of a mutation affecting apurinic endonuclease activity in Staphylococcus aureus.

    PubMed Central

    Tam, J E; Pattee, P A

    1986-01-01

    Protoplast fusion between the Rec- mutant RN981 (L. Wyman, R. V. Goering, and R. P. Novick, Genetics 76:681-702, 1974) of Staphylococcus aureus NCTC 8325 and a Rec+ NCTC 8325 derivative yielded Rec+ recombinants that exhibited the increased sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine characteristic of RN981. Transformation analyses identified a specific mutation, designated ngr-374, that was responsible not only for N-methyl-N'-nitro-N-nitrosoguanidine sensitivity, but also sensitivity to methyl methanesulfonate, ethyl methanesulfonate, nitrous acid, and UV irradiation. However, ngr-374-carrying recombinants showed no significant increase in their sensitivity to mitomycin C or 4-nitroquinoline 1-oxide and were unaffected in recombination proficiency. In vitro assays showed that ngr-374-carrying strains had lower apurinic/apyrimidinic endonuclease activities than the wild type. The chromosomal locus occupied by ngr-374 was shown to exist in the gene order omega(Chr::Tn551)40-ngr-374-thrB106. PMID:2430940

  19. Lethal Factor Active-Site Mutations Affect Catalytic Activity In Vitro

    PubMed Central

    Hammond, S. E.; Hanna, P. C.

    1998-01-01

    The lethal factor (LF) protein of Bacillus anthracis lethal toxin contains the thermolysin-like active-site and zinc-binding consensus motif HEXXH (K. R. Klimpel, N. Arora, and S. H. Leppla, Mol. Microbiol. 13:1093–1100, 1994). LF is hypothesized to act as a Zn2+ metalloprotease in the cytoplasm of macrophages, but no proteolytic activities have been previously shown on any target substrate. Here, synthetic peptides are hydrolyzed by LF in vitro. Mass spectroscopy and peptide sequencing of isolated cleavage products separated by reverse-phase high-pressure liquid chromatography indicate that LF seems to prefer proline-containing substrates. Substitution mutations within the consensus active-site residues completely abolish all in vitro catalytic functions, as does addition of 1,10-phenanthroline, EDTA, and certain amino acid hydroxamates, including the novel zinc metalloprotease inhibitor ZINCOV. In contrast, the protease inhibitors bestatin and lysine CMK, previously shown to block LF activity on macrophages, did not block LF activity in vitro. These data provide the first direct evidence that LF may act as an endopeptidase. PMID:9573135

  20. Point mutation of H3/H4 histones affects acetic acid tolerance in Saccharomyces cerevisiae.

    PubMed

    Liu, Xiangyong; Zhang, Xiaohua; Zhang, Zhaojie

    2014-10-10

    The molecular mechanism of acetic acid tolerance in yeast remains unclear despite of its importance for efficient cellulosic ethanol production. In this study, we examined the effects of histone H3/H4 point mutations on yeast acetic acid tolerance by comprehensively screening a histone H3/H4 mutant library. A total of 24 histone H3/H4 mutants (six acetic acid resistant and 18 sensitive) were identified. Compared to the wild-type strain, the histone acetic acid-resistant mutants exhibited improved ethanol fermentation performance under acetic acid stress. Genome-wide transcriptome analysis revealed that changes in the gene expression in the acetic acid-resistant mutants H3 K37A and H4 K16Q were mainly related to energy production, antioxidative stress. Our results provide novel insights into yeast acetic acid tolerance on the basis of histone, and suggest a novel approach to improve ethanol production by altering the histone H3/H4 sequences.

  1. Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy.

    PubMed

    Ikon, Nikita; Ryan, Robert O

    2017-02-01

    The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy.

  2. Takotsubo cardiomyopathy following subarachnoid haemorrhage.

    PubMed

    Maekawa, Hidetsugu; Hadeishi, Hiromu

    2014-08-01

    A 67-year-old woman was admitted with aneurysmal subarachnoid haemorrhage and a 12-lead ECG showed ST segment elevation. Transthoracic echocardiography confirmed akinesis of the left ventricular mid-apical segment, with an ejection fraction of 26%, features characteristic of takotsubo cardiomyopathy. Five days later, we identified thrombus in the apex of the left ventricle. Sixteen days after onset, the thrombus had disappeared and wall motion improved (ejection fraction 58%) without evidence of cardioembolism. Takotsubo cardiomyopathy is a cause of cardiac dysfunction after stroke, including SAH. It is characterised by transiently depressed contractile function of the left mid and apical ventricle, without obstructive coronary artery disease. Clinicians should suspect takotsubo cardiomyopathy in patients with subarachnoid haemorrhage who have an ECG abnormality. Echocardiography is needed to detect the distinctive regional wall motion abnormality. Despite its severity in the acute phase, takotsubo cardiomyopathy is self-limiting and its management is conservative.

  3. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

    PubMed

    Gripp, Karen W; Lin, Angela E; Stabley, Deborah L; Nicholson, Linda; Scott, Charles I; Doyle, Daniel; Aoki, Yoko; Matsubara, Yoichi; Zackai, Elaine H; Lapunzina, Pablo; Gonzalez-Meneses, Antonio; Holbrook, Jennifer; Agresta, Cynthia A; Gonzalez, Iris L; Sol-Church, Katia

    2006-01-01

    Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

  4. Molecular biology of doxorubicin-induced cardiomyopathy

    PubMed Central

    Umlauf, J; Horký, M

    2002-01-01

    The anthracycline doxorubicin is an antineoplastic agent, eliciting chronic cardiac toxicity. It occurs in patients after prolonged administration of doxorubicin, leading to congestive heart failure. The pathogenesis of the doxorubicin-induced car-diomyopathy is not well understood. The present article summarizes the unique effect of doxorubicin on cardiac-specific gene expression. In addition to binding to DNA, doxorubicin directly affects the function of a variety of proteins. Free radical generation, damage to mitochondria and active cell death are also critical in the development of doxorubicin-induced cardiac toxicity. Agents providing effective cardioprotection are also reviewed. PMID:19644577

  5. Methamphetamine-Associated Cardiomyopathy

    PubMed Central

    Won, Sekon; Hong, Robert A.; Shohet, Ralph V.; Seto, Todd B.; Parikh, Nisha I.

    2015-01-01

    Methamphetamine and related compounds are now the second most commonly used illicit substance worldwide, after cannabis. Reports of methamphetamine-associated cardiomyopathy (MAC) are increasing, but MAC has not been well reviewed. This analysis of MAC will provide an overview of the pharmacology of methamphetamine, historical perspective and epidemiology, a review of case and clinical studies, and a summary of the proposed mechanisms for MAC. Clinically, many questions remain, including the appropriate therapeutic interventions for MAC, the incidence and prevalence of cardiac pathology in methamphetamine users, risk factors for developing MAC, and prognosis of these patients. In conclusion, recognition of the significance of MAC among physicians and other medical caregivers is important given the growing use of methamphetamine and related stimulants worldwide. PMID:24037954

  6. Mutations that affect phosphorylation of the adenovirus DNA-binding protein alter its ability to enhance its own synthesis.

    PubMed Central

    Morin, N; Delsert, C; Klessig, D F

    1989-01-01

    The multifunctional adenovirus single-strand DNA-binding protein (DBP) is highly phosphorylated. Its phosphorylation sites are located in the amino-terminal domain of the protein, and its DNA- and RNA-binding activity resides in the carboxy-terminal half of the polypeptide. We have substituted cysteine or alanine for up to 10 of these potential phosphorylation sites by using oligonucleotide-directed mutagenesis. Alteration of one or a few of these sites had little effect on the viability of virus containing the mutated DBP. However, when eight or more sites were altered, viral growth decreased significantly. This suggests that the overall phosphorylation state of the protein was more important than whether any particular site was modified. The reduction in growth correlated with both depressed DNA replication and expression of late genes. This reduction was probably the result of lower DBP accumulation in mutant-infected cells. Interestingly, although the stability of the mutated DBP was not affected, DBP synthesis and the level of its mRNA were depressed 5- to 10-fold for the underphosphorylated protein. These results suggest that DBP enhances its own expression and imply that phosphorylation of the DBP may be important for this function. Similarities to several eucaryotic transcriptional activators, which are composed of negatively charged activating domains and separate binding domains, are discussed. Images PMID:2585602

  7. Mutation increasing β-carotene concentrations does not adversely affect concentrations of essential mineral elements in pepper fruit

    PubMed Central

    Thompson, Jacqueline A.; Penchev, Emil A.; Nielen, Stephan

    2017-01-01

    Vitamin and mineral deficiencies are prevalent in human populations throughout the world. Vitamin A deficiency affects hundreds of millions of pre-school age children in low income countries. Fruits of pepper (Capsicum annuum L.) can be a major dietary source of precursors to Vitamin A biosynthesis, such as β-carotene. Recently, pepper breeding programs have introduced the orange-fruited (of) trait of the mutant variety Oranzheva kapiya, which is associated with high fruit β-carotene concentrations, to the mutant variety Albena. In this manuscript, concentrations of β-carotene and mineral elements (magnesium, phosphorus, sulphur, potassium, zinc, calcium, manganese, iron and copper) were compared in fruit from P31, a red-fruited genotype derived from the variety Albena, and M38, a genotype developed by transferring the orange-fruited mutation (of) into Albena. It was observed that fruit from M38 plants had greater β-carotene concentration at both commercial and botanical maturity (4.9 and 52.7 mg / kg fresh weight, respectively) than fruit from P31 plants (2.3 and 30.1 mg / kg fresh weight, respectively). The mutation producing high β-carotene concentrations in pepper fruits had no detrimental effect on the concentrations of mineral elements required for human nutrition. PMID:28207797

  8. Mutation increasing β-carotene concentrations does not adversely affect concentrations of essential mineral elements in pepper fruit.

    PubMed

    Tomlekova, Nasya B; White, Philip J; Thompson, Jacqueline A; Penchev, Emil A; Nielen, Stephan

    2017-01-01

    Vitamin and mineral deficiencies are prevalent in human populations throughout the world. Vitamin A deficiency affects hundreds of millions of pre-school age children in low income countries. Fruits of pepper (Capsicum annuum L.) can be a major dietary source of precursors to Vitamin A biosynthesis, such as β-carotene. Recently, pepper breeding programs have introduced the orange-fruited (of) trait of the mutant variety Oranzheva kapiya, which is associated with high fruit β-carotene concentrations, to the mutant variety Albena. In this manuscript, concentrations of β-carotene and mineral elements (magnesium, phosphorus, sulphur, potassium, zinc, calcium, manganese, iron and copper) were compared in fruit from P31, a red-fruited genotype derived from the variety Albena, and M38, a genotype developed by transferring the orange-fruited mutation (of) into Albena. It was observed that fruit from M38 plants had greater β-carotene concentration at both commercial and botanical maturity (4.9 and 52.7 mg / kg fresh weight, respectively) than fruit from P31 plants (2.3 and 30.1 mg / kg fresh weight, respectively). The mutation producing high β-carotene concentrations in pepper fruits had no detrimental effect on the concentrations of mineral elements required for human nutrition.

  9. Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

    DOE PAGES

    Golbus, Jessica R.; Puckelwartz, Megan J.; Dellefave-Castillo, Lisa; ...

    2014-09-01

    Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused onmore » 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. We conclude that these pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.« less

  10. Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

    SciTech Connect

    Golbus, Jessica R.; Puckelwartz, Megan J.; Dellefave-Castillo, Lisa; Fahrenbach, John P.; Nelakuditi, Viswateja; Pesce, Lorenzo L.; Pytel, Peter; McNally, Elizabeth M.

    2014-09-01

    Background—Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results—Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. We conclude that these pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.

  11. Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation

    PubMed Central

    Han, Yongmei; Ripley, Barry; Serada, Satoshi; Naka, Tetsuji; Fujimoto, Minoru

    2016-01-01

    Background & Aim Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS. Methods Mice with mutant SOD1 (G93A) transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG) mice were assessed by real time PCR. Mice were then crossed with IL-6(-/-) mice to generate SOD1TG/IL-6(-/-) mice. SOD1 TG/IL-6(-/-) mice (n = 17) were compared with SOD1 TG/IL-6(+/-) mice (n = 18), SOD1 TG/IL-6(+/+) mice (n = 11), WT mice (n = 15), IL-6(+/-) mice (n = 5) and IL-6(-/-) mice (n = 8), with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups. Results Levels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/-) mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days), similarly to SOD1 TG /IL-6(+/+) mice (164.31±12.16 days). Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/-) mice and SOD1 TG /IL-6 (+/+) mice. Conclusion These results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations. PMID:27070121

  12. Mutations that affect structure and assembly of light-harvesting proteins in the cyanobacterium Synechocystis sp. strain 6701

    SciTech Connect

    Anderson, L.K.; Rayner, M.C.; Eiserling, F.A.

    1987-01-01

    The unicellular cyanobacterium Synechocystis sp. strain 6701 was mutagenized with UV irradiation and screened for pigment changes that indicated genetic lesions involving the light-harvesting proteins of the phycobilisome. A previous examination of the pigment mutant UV16 showed an assembly defect in the phycocyanin component of the phycobilisome. Mutagenesis of UV16 produced an additional double mutant, UV16-40, with decreased phycoerythrin content. Phycocyanin and phycoerythrin were isolated from UV16-40 and compared with normal biliproteins. The results suggested that the UV16 mutation affected the alpha subunit of phycocyanin, while the phycoerythrin beta subunit from UV16-40 had lost one of its three chromophores. Characterization of the unassembled phycobilisome components in these mutants suggests that these strains will be useful for probing in vivo the regulated expression and assembly of phycobilisomes.

  13. Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia

    SciTech Connect

    Shimron-Abarbanell, D.; Harms, H.; Erdmann, J.; Propping, P.; Noethen, M.M.

    1996-04-09

    Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT{sub 1F}) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T{r_arrow}A transversion in the third position of codon 261 (encoding isoleucine), a silent C{r_arrow}T transition in the third position of codon 176 (encoding histidine), and a C{r_arrow}T transition in position -78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT{sub 1F} receptor is not commonly involved in the etiology of these diseases. 12 refs., 1 fig., 2 tabs.

  14. BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age

    PubMed Central

    Bergthorsson, J; Ejlertsen, B; Olsen, J; Borg, A; Nielsen, K; Barkardottir, R; Klausen, S; Mouridsen, H; Winther, K; Fenger, K; Niebuhr, A; Harboe, T; Niebuhr, E

    2001-01-01

    INTRODUCTION—A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general.
OBJECTIVES—To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer.
SUBJECTS—From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease.
METHODS—DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry.
RESULTS—Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers.
CONCLUSIONS—A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast

  15. A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies

    PubMed Central

    Gigli, Marta; Begay, Rene L.; Morea, Gaetano; Graw, Sharon L.; Sinagra, Gianfranco; Taylor, Matthew R. G.; Granzier, Henk; Mestroni, Luisa

    2016-01-01

    Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current

  16. An affective disorder in zebrafish with mutation of the glucocorticoid receptor.

    PubMed

    Ziv, L; Muto, A; Schoonheim, P J; Meijsing, S H; Strasser, D; Ingraham, H A; Schaaf, M J M; Yamamoto, K R; Baier, H

    2013-06-01

    Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium ('novel tank'), mutant fish become immobile ('freeze'), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants.

  17. The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy

    SciTech Connect

    Li, Xiaochuan; Suphamungmee, Worawit; Janco, Miro; Geeves, Michael A.; Marston, Steven B.; Fischer, Stefan; Lehman, William

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Well-known tropomyosin mutants, D175N and E180G are linked to cardiomyopathies. Black-Right-Pointing-Pointer The structural mechanics of D175N and E180G tropomyosins have been investigated. Black-Right-Pointing-Pointer D175N and E180G mutations increase both local and global tropomyosin flexibility. Black-Right-Pointing-Pointer In muscle, this increased flexibility will enhance myosin interactions on actin. Black-Right-Pointing-Pointer Extra myosin interaction can alter cardiac Ca{sup 2+}-switching, leading to dysfunction. -- Abstract: Point mutations targeting muscle thin filament proteins are the cause of a number of cardiomyopathies. In many cases, biological effects of the mutations are well-documented, whereas their structural and mechanical impact on filament assembly and regulatory function is lacking. In order to elucidate molecular defects leading to cardiac dysfunction, we have examined the structural mechanics of two tropomyosin mutants, E180G and D175N, which are associated with hypertrophic cardiomyopathy (HCM). Tropomyosin is an {alpha}-helical coiled-coil dimer which polymerizes end-to-end to create an elongated superhelix that wraps around F-actin filaments of muscle and non-muscle cells, thus modulating the binding of other actin-binding proteins. Here, we study how flexibility changes in the E180G and D175N mutants might affect tropomyosin binding and regulatory motion on F-actin. Electron microscopy and Molecular Dynamics simulations show that E180G and D175N mutations cause an increase in bending flexibility of tropomyosin both locally and globally. This excess flexibility is likely to increase accessibility of the myosin-binding sites on F-actin, thus destabilizing the low-Ca{sup 2+} relaxed-state of cardiac muscle. The resulting imbalance in the on-off switching mechanism of the mutants will shift the regulatory equilibrium towards Ca{sup 2+}-activation of cardiac muscle, as is observed in affected

  18. Interacting genes that affect microtubule function in Drosophila melanogaster: Two classes of mutation revert the failure to complement between hay sup nc2 and mutations in tubulin genes

    SciTech Connect

    Regan, C.L.; Fuller, M.T. )

    1990-05-01

    The recessive male sterile mutation hay{sup nc2} of Drosophila melanogaster fails to complement certain {beta}{sub 2}-tubulin and {alpha}-tubulin mutations, suggesting that the haywire product plays a role in microtubule function, perhaps as a structural component of microtubules. The genetic interaction appears to require the presence of the aberrant product encoded by hay{sup nc2}, which may act as a structural poison. Based on this observation, the authors have isolated ten new mutations with EMS that revert the failure to complement between hay{sup nc2} and B2t{sup n}. The revertants tested behaved as intragenic mutations of hay in recombination tests, and feel into two phenotypic classes, suggesting two functional domains of the hay gene product. Some revertants were hemizygous viable and less severe than hay{sup nc2} in their recessive phenotype. These mutations might revert the poison by restoring the aberrant product encoded by the hay{sup nc2} allele to more wild-type function. Most of the revertants were recessive lethal mutations, indicating that the hay gene product is essential for viability. These more extreme mutations could revert the poison by destroying the ability of the aberrant haywire{sup nc2} product to interact structurally with microtubules. Flies heterozygous for the original hay{sup nc2} allele and an extreme revertant show defects in both the structure and the function of the male meiotic spindle.

  19. Interacting Genes That Affect Microtubule Function in Drosophila Melanogaster: Two Classes of Mutation Revert the Failure to Complement between Hay(nc2) and Mutations in Tubulin Genes

    PubMed Central

    Regan, C. L.; Fuller, M. T.

    1990-01-01

    The recessive male sterile mutation hay(nc2) of Drosophila melanogaster fails to complement certain β(2)-tubulin and α-tubulin mutations, suggesting that the haywire product plays a role in microtubule function, perhaps as a structural component of microtubules. The genetic interaction appears to require the presence of the aberrant product encoded by hay(nc2), which may act as a structural poison. Based on this observation, we have isolated ten new mutations that revert the failure to complement between hay(nc2) and B2t(n). The revertants tested behaved as intragenic mutations of hay in recombination tests, and fell into two phenotypic classes, suggesting two functional domains of the hay gene product. Some revertants were hemizygous viable and less severe than hay(nc2) in their recessive phenotype. These mutations might revert the poison by restoring the aberrant product encoded by the hay(nc2) allele to more wild-type function. Most of the revertants were recessive lethal mutations, indicating that the hay gene product is essential for viability. These more extreme mutations could revert the poison by destroying the ability of the aberrant haywire(nc2) product to interact structurally with microtubules. Flies heterozygous for the original hay(nc2) allele and an extreme revertant show defects in both the structure and the function of the male meiotic spindle. PMID:2111265

  20. Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.

    PubMed

    Zampieri, Stefania; Montalvo, Annalisa; Blanco, Mariana; Zanin, Irene; Amartino, Hernan; Vlahovicek, Kristian; Szlago, Marina; Schenone, Andrea; Pittis, Gabriela; Bembi, Bruno; Dardis, Andrea

    2012-05-15

    Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.

  1. Characterization of a disease-associated mutation affecting a putative splicing regulatory element in intron 6b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

    PubMed

    Faà, Valeria; Incani, Federica; Meloni, Alessandra; Corda, Denise; Masala, Maddalena; Baffico, A Maria; Seia, Manuela; Cao, Antonio; Rosatelli, M Cristina

    2009-10-30

    Cystic fibrosis (CF) is a common recessive disorder caused by >1600 mutations in the CF transmembrane conductance regulator (CFTR) gene. About 13% of CFTR mutations are classified as "splicing mutations," but for almost 40% of these, their role in affecting the pre-mRNA splicing of the gene is not yet defined. In this work, we describe a new splicing mutation detected in three unrelated Italian CF patients. By DNA analyses and mRNA studies, we identified the c.1002-1110_1113delTAAG mutation localized in intron 6b of the CFTR gene. At the mRNA level, this mutation creates an aberrant inclusion of a sequence of 101 nucleotides between exons 6b and 7. This sequence corresponds to a portion of intron 6b and resembles a cryptic exon because it is characterized by an upstream ag and a downstream gt sequence, which are most probably recognized as 5'- and 3'-splice sites by the spliceosome. Through functional analysis of this splicing defect, we show that this mutation abolishes the interaction of the splicing regulatory protein heterogeneous nuclear ribonucleoprotein A2/B1 with an intronic splicing regulatory element and creates a new recognition motif for the SRp75 splicing factor, causing activation of the cryptic exon. Our results show that the c.1002-1110_1113delTAAG mutation creates a new intronic splicing regulatory element in intron 6b of the CFTR gene exclusively recognized by SRp75.

  2. Genetics Home Reference: arrhythmogenic right ventricular cardiomyopathy

    MedlinePlus

    ... Genetics Home Health Conditions ARVC arrhythmogenic right ventricular cardiomyopathy Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Arrhythmogenic right ventricular cardiomyopathy ( ARVC ) is a form of heart disease that ...

  3. NF1 mutation rather than individual genetic variability is the main determinant of the NF1-transcriptional profile of mutations affecting splicing.

    PubMed

    Pros, Eva; Larriba, Sara; López, Eva; Ravella, Anna; Gili, M Lluïsa; Kruyer, Helena; Valls, Joan; Serra, Eduard; Lázaro, Conxi

    2006-11-01

    A significant number of neurofibromatosis type 1 (NF1) mutations result in exon skipping. The majority of these mutations do not occur in the canonical splice sites and can produce different aberrant transcripts whose proportions have not been well studied. It has been hypothesized that differences in the mutation-determined NF1-transcriptional profile could partially explain disease variability among patients bearing the same NF1 splice defect. In order to gain insight into these aspects, we analyzed the proportion of the different transcripts generated by nine NF1-splicing mutations in 30 patients. We assessed the influence of the mutation in the NF1-related transcriptional profiles and investigated the existence of individual differences in a global manner. We analyzed potential differences in tissue-specific transcriptional profiles and evaluated the influence of sample processing and mRNA nonsense-mediated decay (NMD). Small transcriptional differences were found in neurofibromas and neurofibroma-derived Schwann cells (SC) compared to blood. We also detected a higher cell culture-dependent NMD. We observed that mutation per se explains 93.5% of the profile variability among mutations studied. However, despite the importance of mutation in determining the proportion of NF1 transcripts generated, we found certain variability among patients with the same mutation. From our results, it seems that genetic factors influencing RNA processing play a minor role in determining the NF1-transcriptional profile. Nevertheless neurofibromin studies would clarify whether these small differences translate into significant functional changes that could explain the great clinical expressivity observed in the disease or any of the disease-related traits.

  4. X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings.

    PubMed

    Bissar-Tadmouri, Nesrine; Donahue, Whithey L; Al-Gazali, Lihadh; Nelson, Stanley F; Bayrak-Toydemir, Pinar; Kantarci, Sibel

    2014-01-01

    X-linked intellectual disability (XLID) is a heterogeneous condition associated with mutations in >100 genes, accounting for over 10% of all cases of intellectual impairment. The majority of XLID cases show nonsyndromic forms (NSXLID), in which intellectual disability is the sole clinically consistent manifestation. Here we performed X chromosome exome (X-exome) sequencing to identify the causative mutation in an NSXLID family with four affected male siblings and five unaffected female siblings. The X-exome sequencing at 88× coverage in one affected male sibling revealed a novel missense mutation (p.Tyr1074Cys) in the asparagine-linked glycosylation 13 homolog (ALG13) gene. Segregation analysis by Sanger sequencing showed that the all affected siblings were hemizygous and the mother was heterozygous for the mutation. Recently, a de novo missense mutation in ALG13 has been reported in a patient with X-linked congenital disorders of glycosylation type I. Our study reports the first case of NSXLID caused by a mutation in ALG13 involved in protein N-glycosylation.

  5. Cerebral embolic stroke after disappearing takotsubo cardiomyopathy.

    PubMed

    Matsuzono, Kosuke; Ikeda, Yoshio; Deguchi, Shoko; Yamashita, Toru; Kurata, Tomoko; Deguchi, Kentaro; Abe, Koji

    2013-11-01

    Takotsubo cardiomyopathy can induce cerebral embolic stroke because of intracardiac thrombosis, but the timing of cardiogenic embolism relating to takotsubo cardiomyopathy has not been well described. We evaluated a 71-year-old woman with takotsubo cardiomyopathy, who developed cardiogenic cerebral embolism after recovery of cardiac wall motion. Nevertheless, we treated her with anticoagulation therapy. The present clinical observation suggests that attention should be paid to the timing when takotsubo cardiomyopathy resolves against risk of cardiogenic cerebral embolism.

  6. Dilated cardiomyopathy: the complexity of a diverse genetic architecture.

    PubMed

    Hershberger, Ray E; Hedges, Dale J; Morales, Ana

    2013-09-01

    Remarkable progress has been made in understanding the genetic basis of dilated cardiomyopathy (DCM). Rare variants in >30 genes, some also involved in other cardiomyopathies, muscular dystrophy, or syndromic disease, perturb a diverse set of important myocardial proteins to produce a final DCM phenotype. Large, publicly available datasets have provided the opportunity to evaluate previously identified DCM-causing mutations, and to examine the population frequency of sequence variants similar to those that have been observed to cause DCM. The frequency of these variants, whether associated with dilated or hypertrophic cardiomyopathy, is greater than estimates of disease prevalence. This mismatch might be explained by one or more of the following possibilities: that the penetrance of DCM-causing mutations is lower than previously thought, that some variants are noncausal, that DCM prevalence is higher than previously estimated, or that other more-complex genomics underlie DCM. Reassessment of our assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted. Much about the genomic basis of DCM remains to be investigated, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.

  7. The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease.

    PubMed

    Delmar, Mario; McKenna, William J

    2010-09-17

    Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Mechanical continuity is provided by desmosomes and adherens junctions, while gap junctions provide a pathway for passage of ions and small molecules between cells. These complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Recognition that some forms of arrhythmogenic cardiomyopathy are caused by mutations in desmosomal protein genes has galvanized interest in the biology of the desmosome and its interactions with other junctional molecules. This review presents the cellular and molecular biology of the desmosome, current knowledge on the relation of desmosomal mutations and disease phenotypes, and an overview of the molecular pathophysiology of arrhythmogenic right ventricular cardiomyopathy. Clinical experience and results from cellular and animal models provide insights into the intercalated disc as a functional unit and into the basic substrates that underlie pathogenesis and arrhythmogenesis of arrhythmogenic right ventricular cardiomyopathy.

  8. Arrhythmogenic right ventricular cardiomyopathy, clinical manifestations, and diagnosis.

    PubMed

    Haugaa, Kristina H; Haland, Trine F; Leren, Ida S; Saberniak, Jørg; Edvardsen, Thor

    2016-07-01

    This review aims to give an update on the pathogenesis, clinical manifestations, and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic right ventricular cardiomyopathy is mainly an autosomal dominant inherited disease linked to mutations in genes encoding desmosomes or desmosome-related proteins. Classic symptoms include palpitations, cardiac syncope, and aborted cardiac arrest due to ventricular arrhythmias. Heart failure may develop in later stages. Diagnosis is based on the presence of major and minor criteria from the Task Force Criteria revised in 2010 (TFC 2010), which includes evaluation of findings from six different diagnostic categories. Based on this, patients are classified as having possible, borderline, or definite ARVC. Imaging is important in ARVC diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting structural and functional abnormalities, but importantly these findings may occur after electrical alterations and ventricular arrhythmias. Electrocardiograms (ECGs) and signal-averaged ECGs are analysed for depolarization and repolarization abnormalities, including T-wave inversions as the most common ECG alteration. Ventricular arrhythmias are common in ARVC and are considered a major diagnostic criterion if originating from the RV inferior wall or apex. Family history of ARVC and detection of an ARVC-related mutation are included in the TFC 2010 and emphasize the importance of family screening. Electrophysiological studies are not included in the diagnostic criteria, but may be important for differential diagnosis including RV outflow tract tachycardia. Further differential diagnoses include sarcoidosis, congenital abnormalities, myocarditis, pulmonary hypertension, dilated cardiomyopathy, and athletic cardiac adaptation, which may mimic ARVC.

  9. Takotsubo cardiomyopathy, a new concept of cardiomyopathy: clinical features and pathophysiology.

    PubMed

    Yoshikawa, Tsutomu

    2015-03-01

    Takotsubo cardiomyopathy, a new concept of cardiomyopathy, is characterized by transient cardiac dysfunction, commonly triggered by physical or emotional stress. Differential diagnosis is important, since takotsubo cardiomyopathy presents similar images to those shown in acute coronary syndrome, with ST-segment elevation, T-wave inversion, QT-prolongation, and others on electrocardiogram. Typically, apical involvement with hypercontraction of basal left ventricle (apical type) is predominant, but atypical types involving basal, mid-ventricular, and right ventricular myocardium are also described. In-hospital death occurs at similar level with patients with acute coronary syndrome, but it is significantly affected by underlying diseases. This disease presents diverse cardiac complications in acute phase, such as life-threatening ventricular arrhythmias, pump failure, cardiac rupture, and systemic embolism. The pathogenic mechanism of this disease is still unclear but sympathetic hyperactivity, as well as coronary vasospasm, microcirculatory disorder, and estrogen deficiency, have been considered as one of the most likely pathogenic mechanism. Long-term prognosis is also largely unknown. Issues such as establishment of acute phase treatment, prediction of cardiac complications, and prophylactic measures against recurrence need to be further explored.

  10. The MOGE(S) classification of cardiomyopathy for clinicians.

    PubMed

    Arbustini, Eloisa; Narula, Navneet; Tavazzi, Luigi; Serio, Alessandra; Grasso, Maurizia; Favalli, Valentina; Bellazzi, Riccardo; Tajik, Jamil A; Bonow, Robert O; Bonow, Robert D; Fuster, Valentin; Narula, Jagat

    2014-07-22

    Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X-linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and involvement of organs other than the heart, as well as the genotype and the mode of inheritance. The recently proposed MOGE(S) nosology system embodies all of these characteristics, and describes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association functional class. The proposed nomenclature is supported by a web-assisted application and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing. It is expected that such a nomenclature would help group cardiomyopathies on their etiological basis, describe complex genetics, and create collaborative registries.

  11. Mutation of AREA affects growth, sporulation, nitrogen regulation, and pathogenicity in Colletotrichum gloeosporioides.

    PubMed

    Bi, Fangcheng; Ment, Dana; Luria, Neta; Meng, Xiangchun; Prusky, Dov

    2017-02-01

    The GATA transcription factor AreA is a global nitrogen regulator that restricts the utilization of complex and poor nitrogen sources in the presence of good nitrogen sources in microorganisms. In this study, we report the biological function of an AreA homolog (the CgareA gene) in the fruit postharvest pathogen Colletotrichum gloeosporioides. Targeted gene deletion mutants of areA exhibited significant reductions in vegetative growth, increases in conidia production, and slight decreases in conidial germination rates. Quantitative RT-PCR (qRT-PCR) analysis revealed that the expression of AreA was highly induced under nitrogen-limiting conditions. Moreover, compared to wild-type and complemented strains, nitrogen metabolism-related genes were misregulated in ΔareA mutant strains. Pathogenicity assays indicated that the virulence of ΔareA mutant strains were affected by the nitrogen content, but not the carbon content, of fruit hosts. Taken together, our results indicate that CgareA plays a critical role in fungal development, conidia production, regulation of nitrogen metabolism and virulence in Colletotrichum gloeosporioides.

  12. Diagnostic approaches for diabetic cardiomyopathy and myocardial fibrosis

    PubMed Central

    Maya, Lisandro; Villarreal, Francisco J.

    2009-01-01

    In diabetes mellitus, alterations in cardiac structure/function in the absence of ischemic heart disease, hypertension or other cardiac pathologies is termed diabetic cardiomyopathy. In the United States, the prevalence of diabetes mellitus continues to rise and the disease currently affects about 8% of the general population. Hence, it is imperative the use of appropriate diagnostic strategies for diabetic cardiomyopathy, which may help correctly identify the disease at early stages and implement suitable corrective therapies. Currently, there is no single diagnostic method for the identification of diabetic cardiomyopathy. Diabetic cardiomyopathy is known to induce changes in cardiac structure such as, myocardial hypertrophy, fibrosis and fat droplet deposition. Early changes in cardiac function are typically manifested as abnormal diastolic function that with time leads to loss of contractile function. Echocardiography based methods currently stands as the preferred diagnostic approach for diabetic cardiomyopathy, due to its wide availability and economical use. In addition to conventional techniques, magnetic resonance imaging and spectroscopy along with contrast agents are now leading new approaches in the diagnosis of myocardial fibrosis, and cardiac and hepatic metabolic changes. These strategies can be complemented with serum biomarkers so they can offer a clear picture as to diabetes-induced changes in cardiac structure/function even at very early stages of the disease. This review article intends to provide a summary of experimental and routine tools currently available to diagnose diabetic cardiomyopathy induced changes in cardiac structure/function. These tools can be reliably used in either experimental models of diabetes or for clinical applications. PMID:19595694

  13. PSORIASIS AND CARDIOMYOPATHY: AN INTRIGUING ASSOCIATION

    PubMed Central

    Prakash, Anupam; Deepshikha

    2010-01-01

    A 25-year-old male symptomatic of heart disease for four months presented with biventricular failure. Echocardiography revealed dilated cardiomyopathy. He had skin lesions for 10 years which were clinically and histopathologically identified as psoriasis. Association of cardiomyopathy with psoriasis is uncommon and intriguing. The link between dilated cardiomyopathy and psoriasis on a common inflammatory background is discussed. PMID:21063523

  14. Takotsubo cardiomyopathy triggered by alcohol withdrawal.

    PubMed

    Alexandre, Joakim; Benouda, Leila; Champ-Rigot, Laure; Labombarda, Fabien

    2011-07-01

    Takotsubo cardiomyopathy is a reversible cardiomyopathy frequently precipitated by a sudden emotional or physical stress. The exact physiopathology is still debated and may involve catecholamine-induced myocardial stunning. Alcohol withdrawal is associated with an hyperadrenergic state and may be a period at risk of cardiac events. We report a 56-year-old man with Takotsubo cardiomyopathy triggered by alcohol withdrawal.

  15. Biventricular Takotsubo cardiomyopathy in Graves hyperthyroidism.

    PubMed

    Perkins, Matthew J; Schachter, David T

    2014-03-01

    Graves hyperthyroidism is commonly seen in clinical practice and Takotsubo stress cardiomyopathy is an increasingly recognized cardiac complication of physical or emotional stress. We report the rare case of a patient with Graves hyperthyroidism that was complicated by severe biventricular takotsubo cardiomyopathy, which was demonstrated on heart catheterization. After appropriate pharmacologic treatment of her hyperthyroidism, she had complete resolution of her cardiomyopathy.

  16. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

    PubMed Central

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary‐Alice; Atkin, Joan; Babovic‐Vuksanovic, Dusica; Barnett, Christopher P.; Crenshaw, Melissa; Bartholomew, Dennis W.; Basel, Lina; Bellus, Gary; Ben‐Shachar, Shay; Bialer, Martin G.; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L.; Destree, Anne; Duat‐Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M.; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W.; Hernández‐Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano‐Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K.; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin‐Parton, Patricia; Pedro, Helio; Pivnick, Eniko K.; Powell, Cynthia M.; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P.; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C.; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric

    2015-01-01

    ABSTRACT Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients. PMID:26178382

  17. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

    PubMed

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary-Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P; Crenshaw, Melissa; Bartholomew, Dennis W; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano-Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K; Powell, Cynthia M; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine

    2015-11-01

    Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

  18. Peripartum cardiomyopathy and dilated cardiomyopathy: different at heart

    PubMed Central

    Bollen, Ilse A. E.; Van Deel, Elza D.; Kuster, Diederik W. D.; Van Der Velden, Jolanda

    2015-01-01

    Peripartum cardiomyopathy (PPCM) is a severe cardiac disease occurring in the last month of pregnancy or in the first 5 months after delivery and shows many similar clinical characteristics as dilated cardiomyopathy (DCM) such as ventricle dilation and systolic dysfunction. While PPCM was believed to be DCM triggered by pregnancy, more and more studies show important differences between these diseases. While it is likely they share part of their pathogenesis such as increased oxidative stress and an impaired microvasculature, discrepancies seen in disease progression and outcome indicate there must be differences in pathogenesis as well. In this review, we compared studies in DCM and PPCM to search for overlapping and deviating disease etiology, pathogenesis and outcome in order to understand why these cardiomyopathies share similar clinical features but have different underlying pathologies. PMID:25642195

  19. Current insights into LMNA cardiomyopathies: Existing models and missing LINCs.

    PubMed

    Brayson, Daniel; Shanahan, Catherine M

    2017-01-02

    The nuclear lamina is a critical structural domain for the maintenance of genomic stability and whole-cell mechanics. Mutations in the LMNA gene, which encodes nuclear A-type lamins lead to the disruption of these key cellular functions, resulting in a number of devastating diseases known as laminopathies. Cardiomyopathy is a common laminopathy and is highly penetrant with poor prognosis. To date, cell mechanical instability and dysregulation of gene expression have been proposed as the main mechanisms driving cardiac dysfunction, and indeed discoveries in these areas have provided some promising leads in terms of therapeutics. However, important questions remain unanswered regarding the role of lamin A dysfunction in the heart, including a potential role for the toxicity of lamin A precursors in LMNA cardiomyopathy, which has yet to be rigorously investigated.

  20. Current insights into LMNA cardiomyopathies: Existing models and missing LINCs

    PubMed Central

    Brayson, Daniel; Shanahan, Catherine M.

    2017-01-01

    ABSTRACT The nuclear lamina is a critical structural domain for the maintenance of genomic stability and whole-cell mechanics. Mutations in the LMNA gene, which encodes nuclear A-type lamins lead to the disruption of these key cellular functions, resulting in a number of devastating diseases known as laminopathies. Cardiomyopathy is a common laminopathy and is highly penetrant with poor prognosis. To date, cell mechanical instability and dysregulation of gene expression have been proposed as the main mechanisms driving cardiac dysfunction, and indeed discoveries in these areas have provided some promising leads in terms of therapeutics. However, important questions remain unanswered regarding the role of lamin A dysfunction in the heart, including a potential role for the toxicity of lamin A precursors in LMNA cardiomyopathy, which has yet to be rigorously investigated. PMID:28125396

  1. Culture Volume and Vessel Affect Long-Term Survival, Mutation Frequency, and Oxidative Stress of Escherichia coli

    PubMed Central

    Kram, Karin E.

    2014-01-01

    Bacteria such as Escherichia coli are frequently studied during exponential- and stationary-phase growth. However, many strains can survive in long-term stationary phase (LTSP), without the addition of nutrients, from days to several years. During LTSP, cells experience a variety of stressors, including reactive oxidative species, nutrient depletion, and metabolic toxin buildup, that lead to physiological responses and changes in genetic stability. In this study, we monitored survival during LTSP, as well as reporters of genetic and physiological change, to determine how the physical environment affects E. coli during long-term batch culture. We demonstrate differences in yield during LTSP in cells incubated in LB medium in test tubes versus Erlenmeyer flasks, as well as growth in different volumes of medium. We determined that these differences are only partially due to differences in oxygen levels by incubating the cells in different volumes of media under anaerobic conditions. Since we hypothesized that differences in long-term survival are the result of changes in physiological outputs during the late log and early stationary phases, we monitored alkalization, mutation frequency, oxidative stress response, and glycation. Although initial cell yields are essentially equivalent under each condition tested, physiological responses vary greatly in response to culture environment. Incubation in lower-volume cultures leads to higher oxyR expression but lower mutation frequency and glycation levels, whereas incubation in high-volume cultures has the opposite effect. We show here that even under commonly used experimental conditions that are frequently treated as equivalent, the stresses experienced by cells can differ greatly, suggesting that culture vessel and incubation conditions should be carefully considered in the planning or analysis of experiments. PMID:24375138

  2. DHPLC Screening of ATM Gene in Italian Patients Affected by Ataxia-Telangiectasia: Fourteen Novel ATM Mutations

    PubMed Central

    Magliozzi, Monia; Piane, Maria; Torrente, Isabella; Sinibaldi, Lorenzo; Rizzo, Giovanni; Savio, Camilla; Lulli, Patrizia; De Luca, Alessandro; Dallapiccola, Bruno; Chessa, Luciana

    2006-01-01

    The gene for ataxia-telangiectasia (A-T:MIM:#208900), ATM, spans about 150~kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100% of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86% detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients. PMID:17124347

  3. Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome

    PubMed Central

    2013-01-01

    Background Whereas mutations affecting the helical domain of type I procollagen classically cause Osteogenesis Imperfecta (OI), helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed OI/Ehlers-Danlos syndrome (EDS)-phenotype. Methods We performed biochemical and molecular analysis of type I (pro-) collagen in a cohort of seven patients referred with a clinical diagnosis of EDS and showing only subtle signs of OI. Transmission electron microscopy of the dermis was available for one patient. Results All of these patients harboured a COL1A1 / COL1A2 mutation residing within the most N-terminal part of the type I collagen helix. These mutations affect the rate of type I collagen N-propeptide cleavage and disturb normal collagen fibrillogenesis. Importantly, patients with this type of mutation do not show a typical OI phenotype but mainly present as EDS patients displaying severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, easy bruising, and sometimes signs of arterial fragility. In addition, they show subtle signs of OI including blue sclerae, relatively short stature and osteopenia or fractures. Conclusion Recognition of this distinct phenotype is important for accurate genetic counselling, clinical management and surveillance, particularly in relation to the potential risk for vascular rupture associated with these mutations. Because these patients present clinical overlap with other EDS subtypes, biochemical collagen analysis is necessary to establish the correct diagnosis. PMID:23692737

  4. Whole-Genome Sequencing and iPLEX MassARRAY Genotyping Map an EMS-Induced Mutation Affecting Cell Competition in Drosophila melanogaster

    PubMed Central

    Lee, Chang-Hyun; Rimesso, Gerard; Reynolds, David M.; Cai, Jinlu; Baker, Nicholas E.

    2016-01-01

    Cell competition, the conditional loss of viable genotypes only when surrounded by other cells, is a phenomenon observed in certain genetic mosaic conditions. We conducted a chemical mutagenesis and screen to recover new mutations that affect cell competition between wild-type and RpS3 heterozygous cells. Mutations were identified by whole-genome sequencing, making use of software tools that greatly facilitate the distinction between newly induced mutations and other sources of apparent sequence polymorphism, thereby reducing false-positive and false-negative identification rates. In addition, we utilized iPLEX MassARRAY for genotyping recombinant chromosomes. These approaches permitted the mapping of a new mutation affecting cell competition when only a single allele existed, with a phenotype assessed only in genetic mosaics, without the benefit of complementation with existing mutations, deletions, or duplications. These techniques expand the utility of chemical mutagenesis and whole-genome sequencing for mutant identification. We discuss mutations in the Atm and Xrp1 genes identified in this screen. PMID:27574103

  5. A Naturally Occurring Mutation of the Opsin Gene (T4R) in Dogs Affects Glycosylation and Stability of the G Protein-coupled Receptor*

    PubMed Central

    Zhu, Li; Jang, Geeng-Fu; Jastrzebska, Beata; Filipek, Sławomir; Pearce-Kelling, Susan E.; Aguirre, Gustavo D.; Stenkamp, Ronald E.; Acland, Gregory M.; Palczewski, Krzysztof

    2005-01-01

    Rho (rhodopsin; opsin plus 11-cis-retinal) is a prototypical G protein-coupled receptor responsible for the capture of a photon in retinal photoreceptor cells. A large number of mutations in the opsin gene associated with autosomal dominant retinitis pigmentosa have been identified. The naturally occurring T4R opsin mutation in the English mastiff dog leads to a progressive retinal degeneration that closely resembles human retinitis pigmentosa caused by the T4K mutation in the opsin gene. Using genetic approaches and biochemical assays, we explored the properties of the T4R mutant protein. Employing immunoaffinity-purified Rho from affected RHOT4R/T4R dog retina, we found that the mutation abolished glycosylation at Asn2, whereas glycosylation at Asn15 was unaffected, and the mutant opsin localized normally to the rod outer segments. Moreover, we found that T4R Rho* lost its chromophore faster as measured by the decay of meta-rhodopsin II and that it was less resistant to heat denaturation. Detergent-solubilized T4R opsin regenerated poorly and interacted abnormally with the G protein transducin (Gt). Structurally, the mutation affected mainly the “plug” at the intradiscal (extracellular) side of Rho, which is possibly responsible for protecting the chromophore from the access of bulk water. The T4R mutation may represent a novel molecular mechanism of degeneration where the unliganded form of the mutant opsin exerts a detrimental effect by losing its structural integrity. PMID:15459196

  6. A naturally occurring mutation of the opsin gene (T4R) in dogs affects glycosylation and stability of the G protein-coupled receptor.

    PubMed

    Zhu, Li; Jang, Geeng-Fu; Jastrzebska, Beata; Filipek, Slawomir; Pearce-Kelling, Susan E; Aguirre, Gustavo D; Stenkamp, Ronald E; Acland, Gregory M; Palczewski, Krzysztof

    2004-12-17

    Rho (rhodopsin; opsin plus 11-cis-retinal) is a prototypical G protein-coupled receptor responsible for the capture of a photon in retinal photoreceptor cells. A large number of mutations in the opsin gene associated with autosomal dominant retinitis pigmentosa have been identified. The naturally occurring T4R opsin mutation in the English mastiff dog leads to a progressive retinal degeneration that closely resembles human retinitis pigmentosa caused by the T4K mutation in the opsin gene. Using genetic approaches and biochemical assays, we explored the properties of the T4R mutant protein. Employing immunoaffinity-purified Rho from affected RHO(T4R/T4R) dog retina, we found that the mutation abolished glycosylation at Asn(2), whereas glycosylation at Asn(15) was unaffected, and the mutant opsin localized normally to the rod outer segments. Moreover, we found that T4R Rho(*) lost its chromophore faster as measured by the decay of meta-rhodopsin II and that it was less resistant to heat denaturation. Detergent-solubilized T4R opsin regenerated poorly and interacted abnormally with the G protein transducin (G(t)). Structurally, the mutation affected mainly the "plug" at the intradiscal (extracellular) side of Rho, which is possibly responsible for protecting the chromophore from the access of bulk water. The T4R mutation may represent a novel molecular mechanism of degeneration where the unliganded form of the mutant opsin exerts a detrimental effect by losing its structural integrity.

  7. G364R mutation of MCM4 detected in human skin cancer cells affects DNA helicase activity of MCM4/6/7 complex.

    PubMed

    Ishimi, Yukio; Irie, Daiki

    2015-06-01

    A number of gene mutations are detected in cells derived from human cancer tissues, but roles of these mutations in cancer cell development are largely unknown. We examined G364R mutation of MCM4 detected in human skin cancer cells. Formation of MCM4/6/7 complex is not affected by the mutation. Consistent with this notion, the binding to MCM6 is comparable between the mutant MCM4 and wild-type MCM4. Nuclear localization of this mutant MCM4 expressed in HeLa cells supports this conclusion. Purified MCM4/6/7 complex containing the G364R MCM4 exhibited similar levels of single-stranded DNA binding and ATPase activities to the complex containing wild-type MCM4. However, the mutant complex showed only 30-50% of DNA helicase activity of the wild-type complex. When G364R MCM4 was expressed in HeLa cells, it was fractionated into nuclease-sensitive chromatin fraction, similar to wild-type MCM4. These results suggest that this mutation does not affect assembly of MCM2-7 complex on replication origins but it interferes some step at function of MCM2-7 helicase. Thus, this mutation may contribute to cancer cell development by disturbing DNA replication.

  8. Exclusion of PAX9 and MSX1 mutation in six families affected by tooth agenesis. A genetic study and literature review

    PubMed Central

    Manzanares-Céspedes, Maria C.; Carvalho-Lobato, Patricia; Valdivia-Gandur, Ivan; Arte, Sirpa; Nieminen, Pekka

    2014-01-01

    Objectives: In the present study, it is described the phenotypical analysis and the mutational screening, for genes PAX9 and MSX1, of six families affected by severe forms of tooth agenesis associated with other dental anomalies and systemic entities. Study Design: Six families affected by severe tooth agenesis associated with other dental anomalies and systemic entities were included. Oral exploration, radiological examination, medical antecedents consideration and mutational screening for PAX9 and MSX1 were carried out. Results: No mutations were discovered despite the fact that numerous teeth were missing. An important phenotypical variability was observed within the probands, not being possible to establish a parallelism with the patterns associated to previously described PAX9 and MSX1 mutations. Conclusions: These results bring us to conclude that probably other genes can determine phenotypical patterns of dental agenesis in the families studied, different than the ones described in the mutations of PAX9 and MSX1. Moreover, epigenetic factors can be involved, as those that can reduce gene dosage and other post-transcriptional modulation agents, causing dental agenesis associated or not with systemic anomalies. Key words:Maxillofacial development, tooth agenesis, PAX9 gene, MSX1 gene, gene mutation. PMID:24316698

  9. Nomenclature and systems of classification for cardiomyopathy in children.

    PubMed

    Konta, Laura; Franklin, Rodney C G; Kaski, Juan P

    2015-08-01

    There has been a progressive evolution in systems of classification for cardiomyopathy, driven by advances in imaging modalities, disease recognition, and genetics, following initial clinical descriptions in the 1960s. A pathophysiological classification emerged and was endorsed by World Health Organisation Task Forces in 1980 and 1995: dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular cardiomyopathies; subdivided into idiopathic and disease-specific cardiomyopathies. Genetic advances have increasingly linked "idiopathic" phenotypes to specific mutations, although most linkages exhibit highly variable or little genotype-phenotype correlation, confounded by age-dependent changes and varying penetrance. The following two dominant classification systems are currently in use, with advocates in both continents. First, American Heart Association (2006): "A heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually exhibit inappropriate ventricular hypertrophy or dilatation due to a variety of causes that frequently are genetic". These are subdivided to those predominantly involving the heart - primary - due to genetic mutation, including ion channelopathies, acquired disease, or mixed; and those with systemic involvement in other organ systems - secondary. Second, European Society of Cardiology (2008): "A myocardial disorder in which heart muscle is structurally and functionally abnormal… sufficient to cause the observed myocardial abnormality", with subdivision to familial and non-familial, excluding ion channelopathies, and split to specific disease subtypes and idiopathic. Further differences exist in the definitions for hypertrophic cardiomyopathy; however, whichever high-level classification is used, the clinical reality remains phenotype driven. Clinical evaluation and diagnostic imaging dominate initial patient contact, revealing diagnostic red flags that determine further

  10. Discoveries in peripartum cardiomyopathy.

    PubMed

    Fett, James D; Markham, David W

    2015-07-01

    The past decade has seen remarkable gains for outcomes in peripartum cardiomyopathy (PPCM), one of the leading causes of maternal mortality and morbidity in the USA and many other countries, including the high-incidence areas of Haiti and South Africa. This review article emphasizes the importance of continuing the process of increasing awareness of PPCM and presents details of this evolving picture, including important discoveries that point the way to full recovery for almost all PPCM subjects. In addition, new interventions will be highlighted, which may facilitate recovery. Numerous studies have demonstrated that when the diagnosis of PPCM is made with LVEF > 0.30, the probability is that recovery to LVEF ≥ 0.50 will occur in the overwhelming majority of subjects. PPCM patients diagnosed with severely depressed systolic function (LVEF < 0.30) and a remodeled left ventricle with greater dilatation (LVEDd ≥ 60mm) are least likely to reach the outcome recovery goals. These are the patients with the greatest need for newer interventional strategies.

  11. An update on peripartum cardiomyopathy.

    PubMed

    Dalzell, Jonathan R; Jackson, Colette E; Gardner, Roy S

    2011-09-01

    Peripartum cardiomyopathy is a rare but potentially devastating complication of pregnancy. Although the definition of this condition has recently been revised by the Heart Failure Association of the European Society of Cardiology, the pathogenesis of peripartum cardiomyopathy is not well understood and relatively little is known about its incidence and prevalence. Hence, peripartum cardiomyopathy is often under-recognized in the clinical setting. A heightened awareness of this condition and its current management options is therefore warranted throughout primary and secondary care. The identification of the putative role of prolactin in the development and progression of this condition has been recently discovered, with preclinical work suggesting beneficial effects of prolactin antagonism. In this article, we review the literature regarding this condition including these recent advances.

  12. Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing

    PubMed Central

    Kostareva, Anna; Kiselev, Artem; Gudkova, Alexandra; Frishman, Goar; Ruepp, Andreas; Frishman, Dmitrij; Smolina, Natalia; Tarnovskaya, Svetlana; Nilsson, Daniel; Zlotina, Anna; Khodyuchenko, Tatiana; Vershinina, Tatiana; Pervunina, Tatiana; Klyushina, Alexandra; Kozlenok, Andrey; Sjoberg, Gunnar; Golovljova, Irina; Sejersen, Thomas; Shlyakhto, Eugeniy

    2016-01-01

    Background Cardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis. Patients and Methods We used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM. Pathogenicity of genetic variants was classified according to American College of Medical Genetics and Genomics classification. Results Pathogenic and likely-pathogenic variants were detected in 13 of 24 patients resulting in an overall genotype-positive rate of 54%. Half of the genotype-positive patients carried a combination of pathogenic, likely-pathogenic variants and variants of unknown significance. The most frequent combination included mutations in sarcomeric and cytoskeletal genes (38%). A bioinformatics approach underlined the mechanotransducing protein networks important for RCM pathogenesis. Conclusions Multiple gene mutations were detected in half of the RCM cases, with a combination of sarcomeric and cytoskeletal gene mutations being the most common. Mutations of genes encoding sarcomeric, cytoskeletal, and Z-line-associated proteins appear to have a predominant role in the development of RCM. PMID:27662471

  13. Use of advanced recombinant lines to study the impact and potential of mutations affecting starch synthesis in barley☆

    PubMed Central

    Howard, Thomas P.; Fahy, Brendan; Leigh, Fiona; Howell, Phil; Powell, Wayne; Greenland, Andy; Trafford, Kay; Smith, Alison M.

    2014-01-01

    The effects on barley starch and grain properties of four starch synthesis mutations were studied during the introgression of the mutations from diverse backgrounds into an elite variety. The lys5f (ADPglucose transporter), wax (granule-bound starch synthase), isa1 (debranching enzyme isoamylase 1) and sex6 (starch synthase IIa) mutations were introgressed into NFC Tipple to give mutant and wild-type BC2F4 families with different genomic contributions of the donor parent. Comparison of starch and grain properties between the donor parents, the BC2F4 families and NFC Tipple allowed the effects of the mutations to be distinguished from genetic background effects. The wax and sex6 mutations had marked effects on starch properties regardless of genetic background. The sex6 mutation conditioned low grain weight and starch content, but the wax mutation did not. The lys5 mutation conditioned low grain weight and starch content, but exceptionally high β-glucan contents. The isa1 mutation promotes synthesis of soluble α-glucan (phytoglycogen). Its introgression into NFC Tipple increased grain weight and total α-glucan content relative to the donor parent, but reduced the ratio of phytoglycogen to starch. This study shows that introgression of mutations into a common, commercial background provides new insights that could not be gained from the donor parent. PMID:24748716

  14. Use of advanced recombinant lines to study the impact and potential of mutations affecting starch synthesis in barley.

    PubMed

    Howard, Thomas P; Fahy, Brendan; Leigh, Fiona; Howell, Phil; Powell, Wayne; Greenland, Andy; Trafford, Kay; Smith, Alison M

    2014-03-01

    The effects on barley starch and grain properties of four starch synthesis mutations were studied during the introgression of the mutations from diverse backgrounds into an elite variety. The lys5f (ADPglucose transporter), wax (granule-bound starch synthase), isa1 (debranching enzyme isoamylase 1) and sex6 (starch synthase IIa) mutations were introgressed into NFC Tipple to give mutant and wild-type BC2F4 families with different genomic contributions of the donor parent. Comparison of starch and grain properties between the donor parents, the BC2F4 families and NFC Tipple allowed the effects of the mutations to be distinguished from genetic background effects. The wax and sex6 mutations had marked effects on starch properties regardless of genetic background. The sex6 mutation conditioned low grain weight and starch content, but the wax mutation did not. The lys5 mutation conditioned low grain weight and starch content, but exceptionally high β-glucan contents. The isa1 mutation promotes synthesis of soluble α-glucan (phytoglycogen). Its introgression into NFC Tipple increased grain weight and total α-glucan content relative to the donor parent, but reduced the ratio of phytoglycogen to starch. This study shows that introgression of mutations into a common, commercial background provides new insights that could not be gained from the donor parent.

  15. Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies.

    PubMed

    Gupte, Tejas M; Haque, Farah; Gangadharan, Binnu; Sunitha, Margaret S; Mukherjee, Souhrid; Anandhan, Swetha; Rani, Deepa Selvi; Mukundan, Namita; Jambekar, Amruta; Thangaraj, Kumarasamy; Sowdhamini, Ramanathan; Sommese, Ruth F; Nag, Suman; Spudich, James A; Mercer, John A

    2015-03-13

    The most frequent known causes of primary cardiomyopathies are mutations in the genes encoding sarcomeric proteins. Among those are 30 single-residue mutations in TPM1, the gene encoding α-tropomyosin. We examined seven mutant tropomyosins, E62Q, D84N, I172T, L185R, S215L, D230N, and M281T, that were chosen based on their clinical severity and locations along the molecule. The goal of our study was to determine how the biochemical characteristics of each of these mutant proteins are altered, which in turn could provide a structural rationale for treatment of the cardiomyopathies they produce. Measurements of Ca(2+) sensitivity of human β-cardiac myosin ATPase activity are consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca(2+) activation, and dilated cardiomyopathies are hyposensitive. We also report correlations between ATPase activity at maximum Ca(2+) concentrations and conformational changes in TnC measured using a fluorescent probe, which provide evidence that different substitutions perturb the structure of the regulatory complex in different ways. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally, we examined a computationally designed mutant, E181K, that is hypersensitive, confirming predictions derived from in silico structural analysis.

  16. Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies*

    PubMed Central

    Gupte, Tejas M.; Haque, Farah; Gangadharan, Binnu; Sunitha, Margaret S.; Mukherjee, Souhrid; Anandhan, Swetha; Rani, Deepa Selvi; Mukundan, Namita; Jambekar, Amruta; Thangaraj, Kumarasamy; Sowdhamini, Ramanathan; Sommese, Ruth F.; Nag, Suman; Spudich, James A.; Mercer, John A.

    2015-01-01

    The most frequent known causes of primary cardiomyopathies are mutations in the genes encoding sarcomeric proteins. Among those are 30 single-residue mutations in TPM1, the gene encoding α-tropomyosin. We examined seven mutant tropomyosins, E62Q, D84N, I172T, L185R, S215L, D230N, and M281T, that were chosen based on their clinical severity and locations along the molecule. The goal of our study was to determine how the biochemical characteristics of each of these mutant proteins are altered, which in turn could provide a structural rationale for treatment of the cardiomyopathies they produce. Measurements of Ca2+ sensitivity of human β-cardiac myosin ATPase activity are consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca2+ activation, and dilated cardiomyopathies are hyposensitive. We also report correlations between ATPase activity at maximum Ca2+ concentrations and conformational changes in TnC measured using a fluorescent probe, which provide evidence that different substitutions perturb the structure of the regulatory complex in different ways. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally, we examined a computationally designed mutant, E181K, that is hypersensitive, confirming predictions derived from in silico structural analysis. PMID:25548289

  17. Peripartum cardiomyopathy: a contemporary review.

    PubMed

    Shah, Tina; Ather, Sameer; Bavishi, Chirag; Bambhroliya, Arvind; Ma, Tony; Bozkurt, Biykem

    2013-01-01

    Peripartum cardiomyopathy is a rare and potentially fatal disease. Though approximately half of the patients recover, the clinical course is highly variable and some patients develop refractory heart failure and persistent left ventricular systolic dysfunction. It is diagnosed when women present with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. Etiology remains unclear, and treatment is similar to other cardiomyopathies and includes evidence-based standard heart failure management strategies. Experimental strategies such as intravenous immunoglobulin and bromocriptine await further clinical validation.

  18. Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy

    PubMed Central

    Frade, Amanda Farage; Teixeira, Priscila Camilo; Ianni, Barbara Maria; Pissetti, Cristina Wide; Saba, Bruno; Wang, Lin Hui Tzu; Kuramoto, Andréia; Nogueira, Luciana Gabriel; Buck, Paula; Dias, Fabrício; Giniaux, Helene; Llored, Agnes; Alves, Sthefanny; Schmidt, Andre; Donadi, Eduardo; Marin-Neto, José Antonio; Hirata, Mario; Sampaio, Marcelo; Fragata, Abílio; Bocchi, Edimar Alcides; Stolf, Antonio Noedir; Fiorelli, Alfredo Inacio; Santos, Ronaldo Honorato Barros; Rodrigues, Virmondes; Pereira, Alexandre Costa; Kalil, Jorge; Cunha-Neto, Edecio; Chevillard, Christophe

    2013-01-01

    Aims Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis. Methods and Results We conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5’ region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful. Conclusions Genetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions. PMID:24367596

  19. Molecular characterization of a mutation affecting abscisic acid biosynthesis and consequently stomatal responses to humidity in an agriculturally important species

    PubMed Central

    McAdam, Scott A. M.; Sussmilch, Frances C.; Brodribb, Timothy J.; Ross, John J.

    2015-01-01

    Mutants deficient in the phytohormone abscisic acid (ABA) have been instrumental in determining not only the biosynthetic pathway for this hormone, but also its physiological role in land plants. The wilty mutant of Pisum sativum is one of the classical, well-studied ABA-deficient mutants; however, this mutant remains uncharacterized at a molecular level. Using a candidate gene approach, we show that the wilty mutation affects the xanthoxin dehydrogenase step in ABA biosynthesis. To date, this step has only been represented by mutants in the ABA2 gene of Arabidopsis thaliana. Functional ABA biosynthesis appears to be critical for normal stomatal responses to changes in humidity in angiosperms, with wilty mutant plants having no increase in foliar ABA levels in response to a doubling in vapour pressure deficit, and no closure of stomata. Phylogenetic analysis of the ABA2 gene family from diverse land plants indicates that an ABA-biosynthesis-specific short-chain dehydrogenase (ABA2) evolved in the earliest angiosperms. The relatively recent origin of specificity in this step has important implications for both the evolution of ABA biosynthesis and action in land plants. PMID:26216469

  20. Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

    PubMed Central

    Kubli, Dieter A.

    2015-01-01

    Abstract Significance: Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Recent Advances: Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Critical Issues: Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed “mitophagy,” is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. Future Directions: This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically. Antioxid. Redox Signal. 22, 1527–1544. PMID:25808102

  1. Mendelian bases of myopathies, cardiomyopathies, and neuromyopathies

    PubMed Central

    Piluso, G; Aurino, S; Cacciottolo, M; Del Vecchio Blanco, F; Lancioni, A; Rotundo, IL; Torella, A; Nigro, V

    2010-01-01

    Summary A second genetic revolution is approaching thanks to next-generation DNA sequencing technologies. In the next few years, the 1,000$-genome sequencing promises to reveal every individual variation of DNA. There is, however, a major problem: the identification of thousands of nucleotide changes per individual with uncertain pathological meaning. This is also an ethical issue. In the middle, there is today the possibility to address the sequencing analysis of genetically heterogeneous disorders to selected groups of genes with defined mutation types. This will be cost-effective and safer. We assembled an easy-to manage overview of most Mendelian genes involved in myopathies, cardiomyopathies, and neuromyopathies. This was entirely put together using a number of open access web resources that are listed below. During this effort we realized that there are unexpected countless sources of data, but the confusion is huge. In some cases, we got lost in the validation of disease genes and in the difficulty to discriminate between polymorphisms and disease-causing alleles. In the table are the annotated genes, their associated disorders, genomic, mRNA and coding sizes. We also counted the number of pathological alleles so far reported and the percentage of single nucleotide mutations. PMID:22029103

  2. The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific.

    PubMed

    Raule, Nicola; Sevini, Federica; Li, Shengting; Barbieri, Annalaura; Tallaro, Federica; Lomartire, Laura; Vianello, Dario; Montesanto, Alberto; Moilanen, Jukka S; Bezrukov, Vladyslav; Blanché, Hélène; Hervonen, Antti; Christensen, Kaare; Deiana, Luca; Gonos, Efstathios S; Kirkwood, Tom B L; Kristensen, Peter; Leon, Alberta; Pelicci, Pier Giuseppe; Poulain, Michel; Rea, Irene M; Remacle, Josè; Robine, Jean Marie; Schreiber, Stefan; Sikora, Ewa; Eline Slagboom, Peternella; Spazzafumo, Liana; Antonietta Stazi, Maria; Toussaint, Olivier; Vaupel, James W; Rose, Giuseppina; Majamaa, Kari; Perola, Markus; Johnson, Thomas E; Bolund, Lars; Yang, Huanming; Passarino, Giuseppe; Franceschi, Claudio

    2014-06-01

    To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

  3. Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation.

    PubMed

    Asselta, Rosanna; Robusto, Michela; Platé, Manuela; Santoro, Cristina; Peyvandi, Flora; Duga, Stefano

    2015-07-01

    Fibrinogen is a hexameric glycoprotein consisting of two sets of three polypeptides (the Aα, Bβ, and γ chains, encoded by the three genes FGA, FGB, and FGG). It is involved in the final phase of the coagulation process, being the precursor of the fibrin monomers necessary for the formation of the hemostatic plug. Rare inherited fibrinogen disorders can manifest as quantitative deficiencies, qualitative defects, or both. In particular, dysfibrinogenemia and hypo-dysfibrinogenemia are characterized by reduced functional activity associated with normal or reduced antigen levels, and are usually determined by heterozygous mutations affecting any of the three fibrinogen genes. In this study, we investigated the genetic basis of dys- and hypo-dysfibrinogenemia in seven unrelated patients. Mutational screening disclosed six different variants, two of which novel (FGB-p.Asp185Asn and FGG-p.Asn230Lys). The molecular characterization of the FGG-p.Asn230Lys mutation, performed by transient expression experiments of the recombinant mutant protein, demonstrated that it induces an almost complete impairment in fibrinogen secretion, according to a molecular mechanism often associated with quantitative fibrinogen disorders. Conversely, the FGB-p.Asp185Asn variant was demonstrated to be a gain-of-glycosylation mutation leading to a hyperglycosylation of the Bβ chain, not affecting fibrinogen assembly and secretion. To our knowledge, this is the second gain-of-glycosylation mutation involving the FGB gene.

  4. A pedigree-based genetic appraisal of Boxer ARVC and the role of the Striatin mutation.

    PubMed

    Cattanach, B M; Dukes-McEwan, J; Wotton, P R; Stephenson, H M; Hamilton, R M

    2015-05-09

    The objective of this paper was to investigate by pedigree-based genetic means the origins and inheritance of arrhythmogenic right ventricular cardiomyopathy (ARVC) in UK Boxers and assess the role of the proposed causal mutation in the gene, Striatin (STRN). All ARVC cases traced back to a small number of imported American dogs deriving from the group of Boxers studied by Harpster (1983) to define the disease, strongly suggesting that the disease is the same in the two countries. Dogs with and without the STRN mutation were found in both ARVC affected and normal Boxers showing that the mutation is not responsible for the disease. Evidence was found that the STRN mutation is, however, genetically linked with the gene responsible on the same chromosome. The linkage implies that the two genes can separate by meiotic recombination such that both ARVC-affected and ARVC-unaffected lines of dogs may carry either the STRN mutation or its wild-type allele. These have been found. Homozygotes for the STRN mutation tended to be severely affected at early ages, suggesting that there is an interaction between the known effects of the STRN mutation on the cardiomyocyte and ARVC.

  5. A pedigree-based genetic appraisal of Boxer ARVC and the role of the Striatin mutation

    PubMed Central

    Cattanach, B. M.; Dukes-McEwan, J.; Wotton, P. R.; Stephenson, H. M.; Hamilton, R. M.

    2015-01-01

    The objective of this paper was to investigate by pedigree-based genetic means the origins and inheritance of arrhythmogenic right ventricular cardiomyopathy (ARVC) in UK Boxers and assess the role of the proposed causal mutation in the gene, Striatin (STRN). All ARVC cases traced back to a small number of imported American dogs deriving from the group of Boxers studied by Harpster (1983) to define the disease, strongly suggesting that the disease is the same in the two countries. Dogs with and without the STRN mutation were found in both ARVC affected and normal Boxers showing that the