Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2-related disorders.

The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS-MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain-containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.

The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort.

BACKGROUND AND AIMS: Apoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed. METHODS AND RESULTS: The study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression. The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05-1.99) and female (OR = 2.22, 95%CI = 1.58-3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression). CONCLUSION: A common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.

IL17RA in early-onset coronary artery disease: Total leukocyte transcript analysis and promoter polymorphism (rs4819554) association.

BACKGROUND AND AIMS: The interleukin-17 (IL-17) pathway would play an important role in the pathogenesis of atherosclerosis and coronary-artery disease (CAD). The IL-17 inflammatory mediators are expressed by Th17 cells, a group of CD4 + leukocytes that infiltrate the vascular milieu and are pivotal in the origin, progression, stability and rupture of the atherosclerotic lesion. Cigarette smoke compounds stimulated the expression of IL-17 and IL-17-receptors. In atherogenic mice models the deficiency of IL-17RA resulted in a reduction of the atherosclerotic lesion size and leukocyte infiltrate. We hypothesised that common the IL-17RA transcript might be differential expressed in the leukocytes from CAD patients and healthy individuals. METHODS: The relative amount of the IL-17RA to ACTB transcript was determined in total leukocytes of 55 patients and 50 controls, all smokers. We genotyped the IL-17RA rs48195554 promoter polymorphisms in 390 healthy controls and 450 early-onset CAD patients. RESULTS: Patients showed significantly higher mean IL-17RA normalised transcript value than controls (p < 0.001). For the IL-17RA rs48195554 promoter polymorphisms, IL-17RA G-carriers showed higher transcript values. However, allele and genotype frequencies did not differ between patients and controls and we thus excluded a significant association with CAD. CONCLUSIONS: The higher levels of the IL-17RA transcript among CAD-patients was in agreement with a role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis.

New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomeric proteins. Its variable phenotype suggests the existence of modifier genes. Myocyte enhancer factor (MEF) 2C could be important in this process given its role as transcriptional regulator of several cardiac genes. Any variant affecting MEF2C expression and/or function may impact on hypertrophic cardiomyopathy clinical manifestations. In this candidate gene approach, we screened 209 Caucasian hypertrophic cardiomyopathy patients and 313 healthy controls for genetic variants in MEF2C gene by single-strand conformation polymorphism analysis and direct sequencing. Functional analyses were performed with transient transfections of luciferase reporter constructions. Three new variants in non-coding exon 1 were found both in patients and controls with similar frequencies. One-way ANOVA analyses showed a greater left ventricular outflow tract obstruction (p = 0.011) in patients with 10C+10C genotype of the c.-450C(8_10) variant. Moreover, one patient was heterozygous for two rare variants simultaneously. This patient presented thicker left ventricular wall than her relatives carrying the same sarcomeric mutation. In vitro assays additionally showed a slightly increased transcriptional activity for both rare MEF2C alleles. In conclusion, our data suggest that 15 bp-deletion and C-insertion in the 5'UTR region of MEF2C could affect hypertrophic cardiomyopathy, potentially by affecting expression of MEF2C and therefore, the expression of their target cardiac proteins that are implicated in the hypertrophic process.

Association of the Genetic Variation in the Long Non-Coding RNA FENDRR with the Risk of Developing Hypertrophic Cardiomyopathy.

Background: In around 40−60% of Hypertrophic Cardiomyopathy (HCM) cases pathogenic variants are not identified. Our aim was to evaluate the possible association of lncRNAs with the risk of developing HCM. Methods: We sequenced 10 lncRNAs coding genes that have been associated with cardiovascular disease in a discovery cohort (238 HCM patients and 212 controls) by NGS, and genotyped rs74035787 G>A and rs1424019 A>G polymorphism in a validation cohort (962 HCM patients and 923 controls). Finally, we sequenced the FENDRR promoter by Sanger sequencing. Results: We observed by NGS that FENDRR rs39527, rs39529 and rs40384 polymorphisms were significantly associated with HCM in our cohort (p = 0.0284; OR: 0.24, 95%CI: 0.07−0.86). NGS results were confirmed by genotyping rs74035787 polymorphism (p = 0.001; OR:0.38, 95%CI: 0.21−0.66). Moreover, it is also associated when stratification by sex (p = 0.003; OR:0.20, 95%CI: 0.06−0.53), and age (≥50 years old p = 0.001, OR:0.33, 95%CI: 0.16−0.63) Moreover, the risk of HCM in the carriers of the GG genotype of the rs1424019 polymorphism was significantly higher than that of the AA/AG genotypes carriers in the elderly subjects (p = 0.045, OR:1.24, 95%CI: 1.01−1.53). On the other hand, we observed significant differences in the rs74035787 A/rs1424019 G haplotype frequency (p = 0.0035; OR: 0.20, 95%CI: 0.07−0.59). Conclusions: Our study suggested a significant association between FENDRR gene variants and HCM.

Congenital long QT syndrome: Should citric fruits be avoided? A case report of a cLQTS type 1 with unusual QTc prolongation with citric juices.

Congenital long QT syndromes (cLQTS) are relatively rare diseases in which QT interval is prolonged due to several mutations on ion channels involved in cardiac cell repolarization. This condition confers higher risk of malignant arrhythmias and sudden cardiac death, and it is widely accepted that substances that prolong QT interval should be avoided by these patients. Most of these substances are antibiotics and non-antibiotics drugs, but almost nothing is known about frequently consumed fruits and juices. We report the case of a patient with a previously asymptomatic cLQTS type 1 (cLQTS1) with unusual QT prolongation of 167 milliseconds (ms) related to the consumption of large amounts of citric juices (oranges and lemons). A literature review was done for better understanding of its influence on QT interval duration and to know the concentration of flavonoids on citric fruits. .

Rare genetic variants in GATA transcription factors in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a very heterogeneous disease. Although primarily caused by mutations in genes encoding sarcomeric proteins, other genes might explain that heterogeneity. Potential candidate genes are GATA transcription factors that regulate the expression of proteins associated with HCM. Exons of GATA2, GATA4, and GATA6 genes were sequenced in 212 patients with unrelated HCM previously analyzed for genes encoding the most frequently mutated sarcomeric proteins. Functional effects of variants were predicted by in silico analyses. 3 potentially pathogenic variants were identified: c.-77G>A in GATA2, p.Ala343Thr (rs370588269) in GATA4, and p.Pro555Ala (rs146243018) in GATA6 Multivariate analyses showed that angina was more frequent in patients carrying sarcomeric and GATA rare variants (55% vs 23.2% in non-carriers of GATA rare variants, OR (95% CI) 7.12 (1.23 to 41.27), p=0.029). Among patients without a known causal mutation, GATA rare variants were associated with a greater maximum posterior wall thickness (16.4±4.4 vs 14.0±3.1 mm in non-carriers, p=0.021). Thus, variants having a putative effect on GATA genes would alter the expression of their target genes and could modify the hypertrophic response. Therefore, although relatively infrequent in patients with HCM, they may represent a novel insight into the molecular mechanisms related to the pathogenesis of HCM.

Surveillance after cardiac arrest in patients with Brugada syndrome without an implantable defibrillator: An alarm effect of the previous syncope.

BACKGROUND: Debate regarding the prognosis of asymptomatic patients with Brugada syndrome (BrS) is possibly affected by the selection bias of survivors of sudden cardiac arrest (SCA). We aimed to determine variables influencing surveillance after SCA. METHODS: We analyzed a BrS cohort of 145 patients belonging to 37 families. We compared the clinical data and circumstances surrounding SCA (i.e., place of occurrence and people accompanying the subject) in 10 patients who survived an episode of SCA (Group A) vs. 27 deceased relatives (first or second degree) who suffered sudden cardiac death (SCD; Group B). Information concerning Group B was agreed upon by at least 3 relatives. A sub-analysis was performed considering families carrying a mutation in SCN5A (Group B-Mutant). RESULTS: Syncope was unique in predicting SCA in the BrS cohort. Comparing Groups A vs. B, there were no differences in the mean age at time of SCA/SCD (46.2 [SD 17.1] vs. 39.9 [SD 14.5] years; p=0.271), gender (male 60% vs. 74.1%; p=0.442), prior cardiomyopathy (0%), administration of cardiovascular treatments (anti-hypertensive and lipid-lowering drugs; 20% vs. 14.8%; p=0.653) or conventional cardiovascular risk factors. Environmental circumstances surrounding the SCA/SCD were not significantly different between groups. Prior syncope was more frequent in Group A (80% vs. 3.7%; p<0.001) and unique in predicting surveillance (p<0.001). Group B-Mutant displayed equivalent data. CONCLUSIONS: A previous syncope, as an alarm symptom, might contribute to better surveillance of SCA compared with subjects with SCA as the debut of BrS. The latter might behave as a factor of selection bias.

Lesiones auriculares inducidas por cloroquina: estudio histopatológico / Chloroquine-induced atrial lesions: histopathological studies

La cloroquina y sus derivados son fármacos antipalúdicos utilizados en enfermedades del colágeno y afecciones dermatológicas. Describimos un caso de cardiotoxicidad en una mujer de 59 a˜nos diagnosticada de lupus eritematoso discoide y tratada con cloroquina durante 25 a˜nos. La paciente desarrolló trastornos de la conducción y fallo cardiaco, falleciendo finalmente. El corazón mostró hipertrofia biventricular. Describimos el primer caso de auriculopatía inducida por cloroquina. La microscopia óptica y electrónica demostraron vacuolización autofágica de los miocardiocitos auriculares granulares y agranulares, presencia de cuerpos curvilíneos y figuras mieloides, alteraciones mitocondriales y de miofilamentos. La cardiotoxicidad de la cloroquina afectó más intensamente a la aurícula derecha que al resto del corazón. Ello podría explicar, en parte, la aparición de arritmias que ocurre en algunos casos de cardiomiopatía inducida por cloroquina(AU)

The antimalarian agents chloroquine and its derivatives are used in the treatment of connective tissue disease and dermatological disorders. We report a case of carditoxicity in a 59 year-old woman with a 25 year history of chloroquine treatment for a discoid lupus erythematosus. She developed conduction disturbances, cardiac failure and subsequently died. Macroscopically, cardiac biventricular hypertrophy was evident. Light and electronmicroscopic studies of the granular and agranular myocardiocytes of the atria revealed the presence of autophagic vacuoles, curvilinear bodies and myelin-like figures, myofilaments and mitochondrial change. The right atrium was the most damage region of the heart. These lesions may partly explain the appearance of arrhythmias reported in some cases of chloroquine induced myocardiopathy(AU)

Miocardiopatía hipertrófica: ¿cómo predecir su evolución? / Hypertrophic myocardiopathy: how to predict its evolution?

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Variacion genetica del sistema renina-angiotensina y deporte de resistencia: relacion con el rendimiento y la prevencion de patologias / Genetic variation in the renin angiotensin system and endurance performance. Its relationship with performance and prevention of pathology

Algunos estudios recientes relacionan factores genéticos con patologías asociadas al ejercicio físico. El desarrollo de la enfermedad coronaria (infarto) y la hipertrofia ventricular han sido asociadas a la variación (polimorfismos) en el gen de la Enzima Convertidora de la Angiotensina (ECA). Los individuos homocigotos DD para el polimorfismo I/D de la ECA muestran un incremento significativo de la masa ventricular izquierda en respuesta al entrenamiento, comparados con sujetos con los genotipos II e ID. Los individuos II e ID, que, tienen unos niveles mas bajos de ECA en plasma, tendrían una mayor respuesta anabólica al ejercicio. En este sentido, se ha descrito un aumento de la frecuencia del alelo I entre remeros y alpinistas de elite. Considerando los antecedentes descritos, el objetivo de este trabajo es comparar la distribución de los genotipos dé los polimorfismos de los componentes del sistema renina angiotensina en sujetos sanos y en deportistas de alto nivel, analizando también la relación entre el genotipo y los niveles sanguíneos del enzima. Amplificando el ADN mediante la reacción en cadena de la polimerasa (PCR), determinamos el genotipo de cuarenta y cinco deportistas de élite (25 ciclistas y 20 corredores de fondo) y 400 controles sanos para el polimorfismo del gen de la ECA. El alelo I de la ECA presentaba una frecuencia significativamente mayor (p=0,0029) en los deportistas que en los controles sanos. Los niveles plasmáticos de ECA mostraron una fuerte correlación con el genotipo I/D en nuestra población. En conclusión, por su relación con el desarrollo de patologias cardíacas y con el rendimiento fisico, él polimorfismo de la ECA es un factor genético de interés para el deporte de alto rendimiento. El análisis de este marcador genético podría ser útil en la mejora del rendimiento físico y en la prevención de las patologías asociadas a la práctica deportiva (AU)