RESUMEN
Heat-killed Lactobacillus plantarum L-137 (HK L-137) promotes immune function in animals. In healthy people, T-cell proliferation was shown to be enhanced by taking 10 mg HK L-137 daily for 12 weeks. However, the safety and efficacy of higher doses or longer treatments have not yet been investigated in humans. To investigate the high-dose and long-term use effects of HK L-137 on immune-related safety and on host intestinal bacterial flora, 15 healthy volunteers took a daily HK L-137 (50 mg) preparation for 4 weeks. An additional 29 participants who regularly visited a clinic for health care took HK L-137 (10 mg) daily for 12 months. Measures for anthropometrics, hematology, biochemistry, and urinalysis were taken at scheduled timepoints for all participants. Stool and blood samples were also collected and evaluated for microbes and short-chain fatty acids (SCFA); isolated T-cells were assessed for levels of proliferation induced by phytohemagglutinin in the long-term study. Adverse events or shifts in clinical measures from normal ranges due to the dietary intervention were not observed in the high-dose or long-term studies. Long-term intake also did not result in immune exhaustion due to any chronic immunostimulation; ex vivo T-cell proliferation was significantly greater at 12 months than at baseline (p < 0.01). In addition, the Firmicutes/Bacteroidetes ratio in stool samples was significantly lower at 12 months than at baseline (p < 0.05) due to the long-term intake of the HK L-137. Lastly, fecal SCFA concentrations were significantly greater (p < 0.05) at 6 months than at baseline. From these data, it can be concluded that the efficacy of HK L-137 is maintained with no overt adverse effects as a result of high-dose and/or long-term consumption.
Asunto(s)
Microbioma Gastrointestinal , Lactobacillus plantarum , Probióticos , Animales , Calor , HumanosRESUMEN
Although some studies have attempted to find useful prognostic factors in hypertrophic cardiomyopathy (HCM), those results are not fully helpful for use in actual clinical practice. Furthermore, several genetic abnormalities associated with HCM have been identified. However, the genotype-phenotype correlation in HCM remains to be elucidated. Here, we attempted to assess patients with different types of gene mutations causing HCM and investigate the prognosis. A total of 140 patients with HCM underwent a screening test for myofilament gene mutations by direct sequencing of eight sarcomeric genes. Patients with a single mutation in cardiac troponin T, cardiac troponin I, α-tropomyosin, and regulatory and essential light chains were excluded from the study because the number of cases was too small. The clinical presentations and outcomes of the remaining 127 patients with HCM, 31 ß-myosin heavy chain (MYH7) mutation carriers, 19 cardiac myosin-binding protein C (MYBPC3) mutation carriers, and 77 mutation non-carriers were analyzed retrospectively. MYBPC3 mutation carriers had a high frequency of ventricular arrhythmia and syncope. Kaplan-Meier curves revealed no significant difference in prognosis among the three groups, but a lack of family history of sudden death (SD) and a past history of syncope were significantly related to poor prognosis. An absence of family history of SD and past history of syncope are useful prognostic factors in patients with HCM. MYH7 and MYBPC3 mutations did not significantly influence prognosis compared to non-carriers. However, patients with the MYBPC3 mutation should be closely followed for the possibility of SD.
Asunto(s)
Miosinas Cardíacas/genética , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/mortalidad , Proteínas Portadoras/genética , Mutación , Cadenas Pesadas de Miosina/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Muerte Súbita Cardíaca/etiología , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Heterocigoto , Humanos , Japón , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Análisis de Regresión , Adulto JovenRESUMEN
Long QT syndrome (LQTS) can cause syncope, ventricular fibrillation, and death. Recently, several disease-causing mutations in ion channel genes have been identified, and compound mutations have also been detected. It is unclear whether children who are carriers of compound mutations exhibit a more severe phenotype than those with single mutations. Although predicting phenotypic severity is clinically important, the availability of prediction tools for LQTS is unknown. To determine whether the severity of the LQTS phenotype can be predicted by the presence of compound mutations in children is needed. We detected 97 single mutations (Group S) and 13 compound mutations (Group C) between 1998 and 2012, age at diagnosis ranging 0-19 years old (median age is 9.0) and 18.0 years of follow-up period. The phenotypes and Kaplan-Meier event-free rates of the two groups were compared for cardiac events. This study investigated phenotypic severity in relation to the location of mutations in the protein sequence, which was analyzed using two sequence homology-based tools. In results, compound mutations in children were associated with a high incidence of syncope within the first decade (Group S: 32 % vs. Group C: 61 %), requiring an ICD in the second decade (Group S: 3 % vs. Group C: 56 %). Mortality in these patients was high within 5 years of birth (23 %). Phenotypic prediction tools correctly predicted the phenotypic severity in both Groups S and C, especially by using their coupling method. The coupling prediction method is useful in the initial evaluation of phenotypes both with single and compound mutations of LQTS patients. However, it should be noted that the compound mutation makes more severe phenotype.
Asunto(s)
Síndrome de QT Prolongado , Mutación , Adolescente , Arritmias Cardíacas , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Canal de Potasio KCNQ1 , Fenotipo , Homología de Secuencia , Adulto JovenRESUMEN
BACKGROUND: A high incidence of cardiovascular (CV) risk factors has been reported in adults with Williams-Beuren syndrome (WS). However, the prevalence of these factors in children and adolescents with WS is unknown. Therefore, the purpose of this study was to evaluate the prevalence of CV risk factors in these patients. METHODS: Thirty-two WS patients aged <18 years were enrolled in the study. Oxidized low-density lipoprotein levels (n = 32), oral glucose tolerance test results (n = 20), plasma renin and aldosterone levels (n = 31), 24-h ambulatory blood pressure (ABP; n = 24), carotid artery intima-media thickness (IMT; n = 15), and brachial artery flow-mediated dilatation (FMD; n = 15) were measured and analyzed. RESULTS: The lipid profile revealed hypercholesterolemia in 22% and elevated oxidized low-density lipoprotein levels in 94% of the patients. Glucose metabolism abnormalities were found in 70% of the patients. Insulin resistance was observed in 40% of the patients. High plasma renin and aldosterone levels were detected in 45 and 39% of the patients, respectively. A mean systolic blood pressure above the 90th percentile was noted in 29% of patients. High IMT (>0.65 mm) and low FMD (<9%) were detected in 80 and 73% of patients, respectively. CONCLUSION: In patients with WS, CV risk factors are frequently present from childhood. In children with WS, screening tests for the early detection of CV risk factors and long-term follow-up are required to determine whether long-term exposure to these factors increases the risk for CV events in adulthood.
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Enfermedades Cardiovasculares/epidemiología , Síndrome de Williams/complicaciones , Adolescente , Aldosterona/sangre , Presión Sanguínea/fisiología , Monitoreo Ambulatorio de la Presión Arterial , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Grosor Intima-Media Carotídeo , Niño , Preescolar , Elastina/sangre , Femenino , Humanos , Lactante , Japón/epidemiología , Lipoproteínas LDL/sangre , Masculino , Prevalencia , Factores de Riesgo , Síndrome de Williams/fisiopatologíaRESUMEN
Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.
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Cardiomiopatía Dilatada/genética , Mutación , Proteínas Proto-Oncogénicas c-raf/genética , Adulto , Edad de Inicio , Anciano , Secuencia de Aminoácidos , Animales , Cardiomiopatía Dilatada/etnología , Estudios de Casos y Controles , Estudios de Cohortes , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Células HEK293 , Humanos , India , Japón , Masculino , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenotipo , Prevalencia , Homología de Secuencia de Aminoácido , Sirolimus/química , Pez CebraRESUMEN
We purified an Erk1/2-activating component in Agaricus blazei and identified it as brefeldin A (BFA). The extract of A. blazei mycelia (ABE) previously showed an estrogenic gene-expression profile and positive effects in patients with cardiovascular symptoms. Here, we demonstrate that BFA has estrogenic activity in reporter gene assays and stimulates an estrogen-receptor pathway revealed by activation of Erk1/2, although BFA had no growth-stimulating activity in breast cancer MCF-7 cells. The presence of estrogenic activity without any explicit growth-stimulating effect is unique to BFA, and such components are termed here "silent estrogens". To test this hypothesis, we examined the target-gene transcription and signaling pathways induced by BFA. Furthermore, BFA was found in the mycelium but not fruiting body of A. blazei, suggesting the potential use of ABE for therapeutics and its supplementary use in traditional medicines and functional foods.
Asunto(s)
Agaricus/efectos de los fármacos , Brefeldino A/farmacología , Estrógenos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Agaricus/química , Secuencia de Bases , Western Blotting , Cromatografía Líquida de Alta Presión , Cartilla de ADN , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: The genetic basis of most congenital heart defects (CHDs), especially non-syndromic and non-familial conditions, remains largely unknown. METHODS AND RESULTS: DNA samples were collected from immortalized cell lines and original genomes of 256 non-syndromic, non-familial patients with cardiac outflow tract (OFT) defects. Genes encoding NKX2.5, GATA4, GATA6, MEF2C, and ISL1, essential for heart development, were analyzed using PCR-based bidirectional sequencing. The transcriptional activity of proteins with identified sequence variations was analyzed using a luciferase assay. A novel sequence variant (A103V in MEF2C) was identified, in addition to 4 unreported non-synonymous sequence variants in 3 known causative genes (A6V in NKX2.5, T330R and S339R in GATA4, and E142K in GATA6) in 5 individuals. None of these was found in 500 controls without CHDs. In vitro functional assay showed that all proteins with identified sequence variations exhibited significant changes in transcriptional activity and/or synergistic activity with other transcription factors. Furthermore, overexpression of the A103V MEF2C variant in a fish system disturbed early cardiac development. CONCLUSIONS: New mutations in the transcription factors NKX2.5, GATA4, GATA6, and MEF2C that affect their protein function were identified in 2.3% (6/256) of patients with OFT defects. Our results provide the first demonstration of MEF2C mutation and suggest that disturbances in the regulatory circuits involving these cardiac transcription factors may cause a subset of non-syndromic and non-familial CHDs.
Asunto(s)
Cardiopatías Congénitas/genética , Mutación , Miocardio/metabolismo , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Células COS , Estudios de Casos y Controles , Chlorocebus aethiops , Análisis Mutacional de ADN , Factor de Transcripción GATA4/genética , Factor de Transcripción GATA6/genética , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Predisposición Genética a la Enfermedad , Células HeLa , Corazón/embriología , Cardiopatías Congénitas/embriología , Cardiopatías Congénitas/metabolismo , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/genética , Humanos , Japón , Proteínas de Dominio MADS/genética , Factores de Transcripción MEF2 , Datos de Secuencia Molecular , Factores Reguladores Miogénicos/genética , Oryzias , Fenotipo , Reacción en Cadena de la Polimerasa , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
Noonan syndrome (NS) is the most common non-chromosomal syndrome seen in children and is characterized by short stature, dysmorphic facial features, chest deformity, a wide range of congenital heart defects and developmental delay of variable degree. Mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathways cause about 70% of NS cases with a KRAS mutation present in about 2%. In a cohort of 65 clinically confirmed NS patients of Japanese origin, we screened for mutations in the RAS genes by direct sequencing. We found a novel mutation in KRAS with an amino acid substitution of asparagine to serine at codon 116 (N116S). We analyzed the biological activity of this mutant by ectopic expression of wild-type or mutant KRAS. NS-associated KRAS mutation resulted in Erk activation and active Ras-GTP levels, and exhibited mild cell proliferation. In addition, kras-targeted morpholino knocked-down zebrafish embryos caused heart and craniofacial malformations, while the expression of mutated kras resulted in maldevelopment of the heart. Our findings implicate that N116S change in KRAS is a hyperactive mutation which is a causative agent of NS through maldevelopment of the heart.
Asunto(s)
Genes ras , Mutación , Síndrome de Noonan/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Estudios de Cohortes , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Hibridación in Situ , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Homología de Secuencia de Aminoácido , Pez CebraRESUMEN
Agaricus blazei (A. blazei) Murrill mycelia-dikaryon has attracted the attention of scientists and clinicians worldwide owing to its potential for the treatment of cancer. However, little is known about its effect on other pathologies. This study sought to extend the potential medical usefulness of A. blazei for preventing vascular damage and to unravel its mechanism of action. The A. blazei extract showed estrogen-like activity in both gene expression profiling and a luciferase assay. Indeed, the extract inhibited oxidized low-density lipoprotein-stimulated activation of Erk1/2, Akt and p38 in HUVECs and macrophage-derived TIB-67 cells. Moreover, the extract enhanced transcription of the glutathione peroxidase 3 (GPX3), α-synuclein (SNCA) and endothelial nitrogen-oxide synthase (eNOS) genes. Furthermore, atherosclerotic lesions in rabbits were reduced by intake of A. blazei powder. Therefore, A. blazei may be useful for preventing atherosclerosis via dual roles in cell signaling, suppression of macrophage development and the recovery of endothelial cells from vascular damage.
Asunto(s)
Agaricus/química , Estrógenos/metabolismo , Micelio/química , Transducción de Señal , Agaricus/citología , Agaricus/metabolismo , Animales , Fusión Artificial Génica , Aterosclerosis/patología , Aterosclerosis/prevención & control , Línea Celular , Células Endoteliales/efectos de los fármacos , Estrógenos/aislamiento & purificación , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Luciferasas/análisis , Luciferasas/genética , Macrófagos/efectos de los fármacos , ConejosRESUMEN
The human ether-a-go-go-related gene (hERG) protein is a cardiac potassium channel. Mutations in hERG can result in reductions in membrane channel current, cardiac repolarization, prolongation of QT intervals, and lethal arrhythmia. In the last decade, it has been found that some mutants of hERG involved in long QT syndrome exhibit intracellular protein trafficking defects, while other mutants sort to the membrane but cannot form functional channels. Due to the close relationship between intracellular trafficking and functional protein expression, we aimed to measure differences in protein behavior/motion between wild-type and mutant hERG by directly analyzing the fluorescence fluctuations of green fluorescent protein-labeled proteins using fluorescence correlation spectroscopy (FCS). Our data imply that FCS can be applied as a new diagnostic tool to assess whether the defect in a particular mutant channel protein involves aberrant intracellular trafficking.
Asunto(s)
Sustitución de Aminoácidos/fisiología , Canales de Potasio Éter-A-Go-Go/metabolismo , Transporte de Proteínas/fisiología , Espectrometría de Fluorescencia/métodos , Membrana Celular/metabolismo , Citosol/metabolismo , Difusión , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/genética , Glicosilación , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , TransfecciónRESUMEN
Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.
Asunto(s)
Muerte Súbita Cardíaca , Ventrículos Cardíacos/patología , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Tropomiosina/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Pueblo Asiatico/genética , Niño , Proteínas Asociadas a la Distrofina/genética , Electrocardiografía , Femenino , Genotipo , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , No Compactación Aislada del Miocardio Ventricular/patología , Proteínas con Dominio LIM , Masculino , Persona de Mediana Edad , Neuropéptidos/genética , Linaje , Polimorfismo de Nucleótido Simple , Ultrasonografía , Adulto JovenRESUMEN
BACKGROUND: Gastric atrophy caused by Helicobacter pylori (H. pylori) infection is a risk factor for gastric cancer. We aimed to evaluate the relationship between gastric cancer risk and tumor markers in the general population. MATERIALS AND METHODS: A total of 688 volunteers were examined to test their serum pepsinogen (PG) levels and anti-H. pylori antibodies, in addition to a total of 22 serum tumor markers. The participants were classified into four groups according to their anti-H. pylori antibody and serum PG serological status. Accordingly, groups A and D were negative, whereas groups B and C were positive for anti-H. pylori antibodies; and groups A and B were normal, whereas groups C and D were abnormal for serum PG levels. All the blood examination results were statistically evaluated using Student's t-test among these groups. RESULTS: There were 424, 202, 50, and 12 individuals in groups A, B, C, and D, respectively. Because of the small number of participants in groups C and D, we combined these two groups. Compared to the normal group (A), a statistically significant higher in adenosine deaminase level was found in group C+D (p=0.01). CONCLUSION: This result supports a previous study indicating that adenosine deaminase is involved in the regulatory system of chronic atrophic gastritis and gastric cancer risk.
Asunto(s)
Adenosina Desaminasa/sangre , Neoplasias Gástricas/enzimología , Adenosina Desaminasa/fisiología , Adulto , Anciano , Enfermedad Crónica , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/etiología , Humanos , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Factores de Riesgo , Neoplasias Gástricas/etiologíaRESUMEN
BACKGROUND: Carbohydrate antigen 15-3 (CA15-3), Kerbs von den Lungen (KL-6) and breast cancer antigen 225 (BCA225) are widely used tumor markers for breast and lung cancer respectively. PATIENTS AND METHODS: We analyzed 460 Japanese volunteers for 99 items on blood examination including 27 serum tumor markers. Correlations between 27 tumor markers and the other items were statistically analyzed. RESULTS: Positive correlations were identified between CA15-3 vs. KL-6, CA15-3 vs. BCA225, and KL-6 vs. BCA225, with correlation coefficients of 0.84, 0.86, and 0.79, respectively. CONCLUSION: This is the first report to show a positive correlation among these markers in the general population. All of these are recognized as belonging to the mucin family, and this might be the reason for the positive correlation.
Asunto(s)
Glicoproteínas/sangre , Mucina-1/sangre , Biomarcadores de Tumor/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Congenital heart diseases (CHD) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. Although an improved understanding of the genetic causes of CHD would provide insight into the underlying pathobiology, the genetic etiology of most CHD remains unknown. Here we show that mutations in the gene encoding the transcription factor GATA6 cause CHD characteristic of a severe form of cardiac outflow tract (OFT) defect, namely persistent truncus arteriosus (PTA). Two different GATA6 mutations were identified by systematic genetic analysis using DNA from patients with PTA. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggests that, in the developing heart, the expression of SEMA3C in the OFT/subpulmonary myocardium and PLXNA2 in the cardiac neural crest contributing to the OFT is dependent on GATA transcription factors. Together, our data implicate mutations in GATA6 as genetic causes of CHD involving OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling.
Asunto(s)
Factor de Transcripción GATA6/genética , Cardiopatías Congénitas/genética , Proteínas del Tejido Nervioso/genética , Receptores de Superficie Celular/genética , Semaforinas/metabolismo , Animales , Secuencia de Bases , Femenino , Factor de Transcripción GATA6/fisiología , Corazón/fisiología , Humanos , Masculino , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/genética , Semaforinas/fisiología , Transducción de SeñalRESUMEN
BACKGROUND: Mutations of the bone morphogenetic protein receptor II gene (BMPR2), and 1 mutation of the activin receptor-like kinase 1 gene (ALK1) have been reported in patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: A genomic study of ALK1 and BMPR2 was conducted in 21 PAH probands under 16 years of age to study the relationship between the clinical features of the patients and these genes. In all 4 familial aggregates of PAH, 3 ALK1 or 1 BMPR2 mutations were identified. Among 17 probands aged between 4 and 14 years with idiopathic PAH, 2 ALK1 mutations (2/17: 11.8%) and 3 BMPR2 mutations (3/17: 17.6%; 5 mutations in total: 5/17: 29.4%) were found. CONCLUSION: Each proband with the ALK1 mutation developed PAH, as did the probands with the BMPR2 mutation. Hence, it is proposed that ALK1 plays as notable a role as BMPR2 in the etiology of PAH. Furthermore, asymptomatic carriers with the ALK1 mutation within the serine - threonine kinase domain are at risk of developing PAH and hereditary hemorrhagic telangiectasia, so close follow-up is recommended for those individuals.
Asunto(s)
Receptores de Activinas Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Hipertensión Pulmonar/genética , Mutación , Adolescente , Determinación de la Edad por el Esqueleto , Niño , Preescolar , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Genómica/métodos , Humanos , Masculino , Linaje , Proteínas Serina-Treonina Quinasas/genética , Arteria Pulmonar/fisiopatología , Telangiectasia Hemorrágica Hereditaria/genéticaRESUMEN
Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause approximately 60% of cases of Noonan syndrome. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome-associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.
Asunto(s)
Mutación Missense , Síndrome de Noonan/genética , Proteínas Proto-Oncogénicas c-raf/genética , Animales , Línea Celular , Línea Celular Transformada , Femenino , Corazón/embriología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miocardio/metabolismo , Estructura Terciaria de Proteína , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Proto-Oncogénicas c-raf/química , Proteínas Proto-Oncogénicas c-raf/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.
Asunto(s)
Proteínas de Unión al ADN/genética , Defectos del Tabique Interatrial/genética , Proteínas de Homeodominio/genética , Mutación , Factores de Transcripción/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Factor de Transcripción GATA4 , Defectos del Tabique Interatrial/patología , Proteína Homeótica Nkx-2.5 , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Literatura de Revisión como AsuntoRESUMEN
The phenotypic expression of cardiomyopathy is greatly influenced by extrinsic factors other than intrinsic genetic defects, such as environmental stress. Exercise is assumed to be an important extrinsic factor, since sudden death is sometimes seen during exercise in young patients with hypertrophic cardiomyopathy (HCM). However, the long-term effects of mild exercise on phenotypic expression in cardiomyopathy remain unclear. To evaluate the effects of exercise performed during infancy or adolescence in cardiomyopathic patients, cardiomyopathic Syrian hamsters (BIO14.6) were subjected to swimming. BIO14.6 and age-matched congenic normal hamsters (CN) as controls were divided into three groups: sedentary (Sed), and trained during infancy (Inf) and during adolescence (Ado). Histological and biochemical analysis of 41-week-old hamsters revealed that (1) the relative level of beta-myosin heavy chain mRNA was significantly lower in the Inf group than in the Sed and Ado groups of BIO14.6. The level in the Inf group of BIO14.6 was compatible with that in the age-matched Sed group of the CN strain; (2) in BIO14.6, degenerative mitochondrial change in the cardiomyocytes was not seen in the Inf group while it was common in the Sed and Ado groups; (3) calcineurin phosphatase activity in the swimming group in 10-week-old CN was significantly higher than that of the age-matched sedentary group, and was as much as that of the swimming and sedentary groups in 10- and 41-week-old BIO14.6.
Asunto(s)
Cardiomiopatía Hipertrófica/metabolismo , Ventrículos Cardíacos/fisiopatología , Condicionamiento Físico Animal/fisiología , Natación , Factores de Edad , Animales , Peso Corporal , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Tamaño de la Célula , Cricetinae , Modelos Animales de Enfermedad , Ventrículos Cardíacos/química , Técnicas In Vitro , Mesocricetus , Miocardio/química , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Cadenas Pesadas de Miosina/genética , Tamaño de los Órganos , Monoéster Fosfórico Hidrolasas/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , Natación/fisiología , Factores de Tiempo , Función Ventricular , Miosinas Ventriculares/genéticaRESUMEN
Diabetes was reported to be associated with a mitochondrial (mt) DNA mutation at 3243 and variants at 1310, 1438, 3290, 3316, 3394, 12,026, 15,927, and 16,189. Among these mtDNA abnormalities, those at 3243, 3316, 15,927, and 16,189 were also suggested to cause cardiomyopathies. We investigated the prevalence of such mtDNA abnormalities in 68 diabetic patients with LV hypertrophy (LVH), 100 without LVH, and 100 controls. Among the 9 mtDNA abnormalities, those at 3243, 3316, and 15,927 tended to be more prevalent in diabetic patients with LVH than in those without LVH (1%, 1%, and 4% vs. 0%, 0%, and 0%). Notably, the variant at 16,189 was more prevalent in diabetic patients with LVH than without LVH (46% vs. 24%, [Formula: see text] ). The odds ratio for LVH was 3.0 (95% CI, 1.5-6.1) for the 16,189 variant. A common mtDNA variant at 16,189 was found to be associated with LVH in diabetic patients.