A Novel Frameshift Mutation, KCNH2 [p.Asp896ArgfsX79], Leading to Malignant Ventricular Arrhythmia, Identified After Treatment of Gastrointestinal Bleeding.
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ABSTRACT:
SUBMITTER: Kim WC
PROVIDER: S-EPMC8640589 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Drug-mediated or medical condition-mediated disruption of hERG function accounts for the main cause of acquired long-QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG-HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG ) was measured by patch-clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell-based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after-depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long-term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.
| S-EPMC8178274 | biostudies-literature
Project description:Inherited macrothrombocytopenia (IMTP) is a rare disorder characterized by a reduced platelet count and abnormally large platelets. The main clinical symptom of IMTP is mild bleeding in some patients. At present, more than 30 genes have been identified in patients with syndromic and non-syndromic IMTP. In this study, a 3-year-old boy and his mother who presented with mild epistaxis and/or gingival bleeding were diagnosed as having IMTP. Wen then selected whole sequencing to explore the genetic lesion of the patients. After data filtering and mutation validation, a novel frameshift mutation (NM_001130004: c.398_399insTGCG, p.F134AfsX60) of α-actin 1 (ACTN1) was identified in the proband and his mother but absent in other unaffected individuals. Previous studies have proven that mutations in ACTN1 may lead to IMTP with mild to absent bleeding phenotype. The novel mutation, resulting in a truncated protein in exon 4 of the ACTN1 gene, was absent in the public database, such as 1000G and genomAD. Further Western blot revealed that the expression of α-actin 1 in the proband was decreased overtly, which indicated that the novel frameshift mutation may induce non-sense-mediated mRNA decay. In summary, this study not only broadened the variants spectrum of ACTN1 gene, which may contribute to the genetic counseling of IMTP, but also confirmed the diagnosis of IMTP, which may help the management and prognosis for the family members.
| S-EPMC8253534 | biostudies-literature
Project description:Acute myocardial infarction (AMI) is one of the leading causes of death. It is particularly important to predict malignant ventricular arrhythmia (MVA) timely and accurately in patients with AMI. This study aimed to explore biomarkers and to reveal possible mechanisms of MVA in AMI for clinical diagnosis. Blood samples from 190 human subjects were collected to reveal the differentially expressed proteins (DEPs) in three comparisons (AMI/control, AMI+MVA/control, and AMI+MVA/AMI) in proteomics with bioinformatics analysis and validated in new cohorts. The diagnostic value of candidate DEPs predicting AMI+MVA was also evaluated by the receiver operating characteristic curve (ROC). A total of 8,365 peptides and 460 proteins from the LC-MS/MS analysis were identified with 90 in AMI/control, 94 in AMI+MVA/control, and 43 in AMI+MVA/AMI identified as DEPs. TGFBI level had notable decreasing trend in AMI+MVA (161.9 ± 19.0 ng/ml) compared with AMI (P<0.0001) or control (P<0.0001). vWF level in AMI+MVA patients was significantly higher than that in AMI patients (P<0.01) and control (P<0.0001). ROC analysis showed that TGFBI and vWF had the strong and potential value of predicting MVA in AMI. By constructing proteomics profile to identify the protein characteristics this study found that decreased TGFBI and increased vWF are the characteristics of proteins in the MVA patients with AMI. These findings provide new insight into the diagnosis and pathogenesis of the development of MVA. Further, decreased TGFBI and increased vWF are potential predicting biomarkers for diagnosis of MVA in AMI patients.
2024-01-26 | PXD041535 | Pride
Project description:Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation. The majority of mutations associated with MO occur in the exostosin glycosyltransferase genes (EXT)1 or EXT2. In the present study, the genetic causes of the disease were investigated. Polymerase chain reaction amplification, followed by DNA sequencing of the complete EXT1 and EXT2 coding regions, were conducted in a family with MO (n=5). A novel frameshift mutation in exon 3 of EXT2 (c.660delG) was detected. The production of a defective EXT2 protein, lacking 450 C-terminal amino acid residues is predicted to be caused by the c.660delG mutation, located within the exostosin domain of EXT2. The missing residues contain the exostosin and glycosyltransferase family 64 domains, which are critical for the function of EXT2. The novel c.660delG frameshift mutation in the EXT2 gene extends the etiological understanding of MO and may provide an effective reference for genetic counseling and prenatal diagnosis in this family.
| S-EPMC6144921 | biostudies-literature
Project description:Patients with a continuous-flow left ventricular assist device (LVAD) have a 65 % incidence of bleeding events within the first year. The majority of gastrointestinal bleeding (GIB) is from gastrointestinal angiodyplasia (GIAD). The primary aim of the study was to determine whether GIAD was associated with a higher rate of significant bleeding, an increased number of bleeding events per year, and a higher rate of transfusion compared to non-GIAD sources.This retrospective cohort study included 118 individuals who received a LVAD at a tertiary medical center from 2006 through 2014. Patients were subdivided into GIB and non-GIB for comparison of patient demographics, comorbid conditions, and laboratory data. GIB was further divided into sources of GIB, GIAD, obscure, or non-GIAD to establish severity of bleeding, rate of re-bleeding, and transfusion rate.GIAD is associated with an increased number of bleeding events compared to non-GIAD sources of GIB (2.07 vs 1.23, P = 0.01) and a higher number of bleeding events per year (0.806 vs. 0.455 P = 0.001). GIAD compared to non-GIAD sources of GIB was associated with an increased incidence of major bleeding (100 % vs 60 %, P = 0.006) and increased rates of transfusion (8.8 vs 2.95 units, P = 0.0004). Cox Regression analysis between non-GIB and GIAD demonstrated increased risk with age (P = 0.001), history of chronic kidney disease (P = 0.005), and length of stay after LVAD implantation of more than 45 days (P = 0.04). History of hypertension (P = 0.045), diabetes mellitus (P = 0.016), and male gender was associated with decreased risk (P = 0.04).Patients with a continuous-flow LVAD who develop a GIB secondary to GIAD have a higher rate of major bleeding, multiple bleeding events, and require more transfusions to achieve stabilization compared to patients who do not have GIAD.
| S-EPMC4798933 | biostudies-other
Project description: Not available
| S-EPMC10644326 | biostudies-literature
Project description:A patient presenting with several basal cell carcinomas, pigmented nevi, and developmental defects was diagnosed with nevoid basal cell carcinoma syndrome. Gene panel sequencing and Sanger sequencing were used to identify a novel heterozygous frameshift mutation, c.1312dupA:p.Ser438Lysfs, in exon 9 of PTCH1. I-Tasser and PyMol analyses indicated that the mutated protein patched homolog 1 (PTCH1) lacked 12 transmembrane domains and the intracellular and extracellular rings of ECD2 compared with the wild-type protein, resulting in a remarkably different structure from that of the wild-type protein. This case extends our knowledge of the mutation spectrum of NBCCS.
| S-EPMC10946671 | biostudies-literature
Project description:BackgroundLeft ventricular non-compaction (LVNC) is an abnormality of the myocardium, characterized by prominent left ventricular trabeculae and deep inter-trabecular recesses. Long QT syndrome (LQTS) is a cardiac ion channelopathy presenting with a prolonged QT interval on resting electrocardiogram and is associated with increased susceptibility to sudden death. The association between LVNC and LQTS is uncommon.Case presentationWe report an Italian family with a novel pathogenic KCNH2 variant who presented with clinical features of LVNC and LQTS. The proband came to our attention after two syncopal episodes without prodromal symptoms. His ECG showed QTc prolongation and deep T wave inversion in anterior leads, and the echocardiogram fulfilled LVNC criteria. After that, also his sister was found to have LQTS and LVNC, while his father only presented LQTS.ConclusionsPhysicians should be aware of the possible association between LVNC and LQTS. Even if this association is rare, patients with LVNC should be investigated for LQTS to prevent possible severe or even life-threatening arrhythmic episodes.
| S-EPMC9386155 | biostudies-literature
Project description:Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident.
| S-EPMC2964533 | biostudies-literature