Role of TGF-β signaling in tumorigenesis

Transforming growth factor β (TGF β) is one of the crucial cytokine playing an important role in developmental and pathological conditions. TGF β is primarily Smad mediated signal transducers but it can also cross talk with c-Jun N-terminal kinases (JNK), Mitogen-activated protein kinases (MAP), Phosphoinositide 3 (PI-3) kinase, Akt/protein kinase B signaling pathways to enhance cancer development. During early stages of cancer the TGF β induces a protective cytostatic effect. In advanced stages, TGF β fails to down regulate Myc, a transcription factor which represses expression of p21Cip1 and p15Ink4b involved proliferation and differentiation of normal epithelial cells and thus losses its cytostatic property. TGF β also involves in various metastatic processes including angiogenesis, extracellular modification, epithelial-mesenchymal transition, cell migration, immune suppression. Several preclinical animal model studies have encouraging outcomes, suggesting TGF β as a potential therapeutic target in advanced cancers

A Dysmorphic Child with a Pericentric Inversion of Chromosome 8

An 8-year-old boy was referred to our institute with dysmorphic features such as mild lupus, micrognathia, low hair line, hypoplasia, hemi atrophy of left side of the face, abnormal size of ears, hypothenar, hypoplasia of chin, and tongue tie. MRI scan was found to be normal and EEG suggestive of generalized seizure disorder. Cytogenetic evaluation of the proband revealed a pericentric inversion of chromosome 8 with 46, XY, and inv 8 (p11.2; q21.2) karyotype

miRNA regulation during cardiac development and remodeling in cardiomyopathy

miRNAs have been found to play a major role in cardiomyopathy, a heart muscle disorder characterized by cardiac dysfunction. Several miRNAs including those involved in heart development are found to be dysregulated in cardiomyopathy. These miRNAs act either directly or indirectly by controlling the genes involved in normal development and functioning of the heart. Indirectly it also targets modifier genes and genes involved in signaling pathways. In this review, miRNAs involved in heart development, including dysregulation of miRNA which regulate various genes, modifiers and notch signaling pathway genes leading to cardiomyopathy are discussed. A study of these miRNAs would give an insight into the mechanisms involved in the processes of heart development and disease. Apart from this, information gathered from these studies would also generate suitable therapeutic targets in the form of antagomirs which are chemically engineered oligonucleotides used for silencing miRNAs

Long QT syndrome- a genetic insight

Long QT syndrome is a rare arrhythmogenic disorder characterized by a prolongation of the QT interval on Electrocardiogram (ECG) with a propensity to ventricular tachyarrhythmia, leading to syncope, cardiac arrest or sudden death. It is regarded as the “Rosetta Stone” for studying the genetic basis of ventricular arrhythmogenesis. It is caused mainly due to mutations in sodium and potassium channel genes or in the genes involved in the signal transduction pathway. Molecular, genetic and functional studies revealed the impliction of about 13 genes in this disorder. Studies have also revealed the variation in mutations in different ethnic groups, thus necessitating a complete genetic analysis in all the known ethnic groups of the world. This would help to develop personalized medicine, molecular diagnosis, risk stratification, establish a genotype-phenotype correlation, to find the epidemiological variables responsible for the etiology of the disease and identify the possible mode of inheritance

Clinical Picture Of Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy Patients From Indian Origin

Objective: Among the inherited cardiomyopathies, Arrhythmogenic right ventricular dysplasia/cardiomyopathy is unique with a peculiar pathology of fibro-fatty replacement. Studies have been carried out all over the world and several groups have reported clinical heterogeneity in manifestation of ARVD/C related symptoms. Present study is an attempt to identify the clinical profile of ARVD/C patients from Asian Indian origin.Methods: 31 patients in the span of three years were diagnosed with ARVD/C. Diagnosis was based on proposed task force criteria.Results: The mean age at diagnosis was 32.9 ± 16.4 years with slight tilt in male to female ratio (1.46). About 80% cases had palpitations, syncope in 45.16% and dyspnea in 22.5%, whereas 16% of patients were asymptomatic. About 50% of patients revealed a family history of confirmed ARVD/C or sudden death of a family member without any known cause. ECG showed T-wave inversion in about 60% cases, prolongation of QRS was observed in 20% cases. RV dilatation was observed in 80% of patients and 66.7% showed systolic dysfunction. RV free wall motion abnormalities were found in 33% patients. Most of the early onset cases with less than 30 years of age showed family history indicative of ARVD/C. Familial study in three patients indicated early onset of condition in younger generations in two families. Conclusion: ARVD/C in India shows relatively early age at onset when compared with other Asian populations with more than half of patients showing the disease below the age of 30 years. History in most of the early onset cases revealed family history indicating strong genetic influence

Linkage analysis of three families with arrythmogenic right ventricular cardiomyopathy in India

Background: Arrythmogenic Right Ventricular Cardiomyopathy (ARVC) is a primary myocardial disorder morphologically characterized by subtle to severe replacement of the right ventricular myocardium by fatty and fibrous tissue. ARVC is known to be highly prevalent in European population with recent reports implicating it to be a major cause of sudden death in young individuals even from American and Asian population. Aim: To implicate or exclude TMEM43 (ARVC-5), DSP(ARVC-8) genes and the yet to be identified gene at ARVC-6 locus in the pathogenesis in three families affected with ARVC from India. Materials and Methods: Three families comprising of 42 affected/unaffected members were included in the study. Three microsatellite markers, D3S3613 (ARVC5) D10S1664 (ARVC6), D6S309 (ARVC8) were genotyped by PCR-based native PAGE. Two-point Linkage analysis was performed using LINKAGE program version 5.2 . Results and Discussion: LOD scores from linkage analysis for the microsatellite marker D10S1664 (ARVC-6) in families KS and REV have shown positive value hinting the involvement of this locus in the etiology of ARVC, while linkage analysis in the SB family ruled out involvement of DSP, TMEM43 and ARVC-6, as negative LOD scores were obtained with all three loci. Therefore, linkage analysis carried out in the present study indicates that ARVC-6 (cumulative LOD score is equal to plus 1.203376 at q is equal to 0.05) could be the locus harboring the mutated gene in two out of three families

KvLQT1 and KCNE1 K+ channel gene polymorphisms in long QT syndrome

Long QT Syndrome (LQTS), a disorder of the cardiac repolarization process with prolongation of the QT interval (QTc ≥0.46 seconds), is an ion-channelopathy. Mutations in either KCNQ1 or KCNE1 genes are susceptible to LQTS. Hence, screening of KCNQ1 and KCNE1 genes is taken up to evaluate the genetic correlation of these genes in Long QT patients of Indian origin. A total of 33 Long QT Syndrome patients and 100 healthy subjects were enrolled for the present study. PCR-SSCP protocol was utilised for screening of KCNQ1 and KCNE1 genes followed by In-silico and statistical analysis. The clinical profile of the Long QT syndrome patients in our study revealed a higher percentage of females with the mean age also being higher in females when compared to males. The two variations (S546S and IVS13+36A>G) in KCNQ1 and the S38G polymorphism in KCNE1 gene were identified and their association with Long QT syndrome is being reported for the first time in Indian population. S546S is located in the KCNQ1 C terminus close to this domain and IVS13+36A>G is located in the intronic region in close proximity to the coding region for C-terminal domain; these may therefore affect the functional protein through non-assembly. S38G leads to a substitution of serine to glycine at 38th amino acid position (S38G) in the transmembrane domain of KCNE1. Our study reports compound heterozygosity/genetic compound ofS546S and IVS13+36A>G of KCNQ1 gene. Haplotype frequencies and linkage disequilibrium analysis revealed a significant association between the three biomarkers. Compound heterozygosity of the polymorphisms influence downstream signalling and KCNQ1-KCNE1 interactions

Atrial natriuretic peptide gene - a potential biomarker for Long QT syndrome

This study highlights the possible implication of NPPA (natriuretic peptide precursor A) gene in the etiology of Long QT syndrome (LQTS) by population-based as well as familial study. Three SNPs of NPPA- C-664G, C1363A and T1766C were examined by molecular analyses in LQTS, controls and first degree relatives (FDRs). This study revealed a possible association of 1364 C>A SNP ‘C’ allele with LQTS (p = 0.0013). All three SNPs were in tight linkage disequilibrium. The familial study highlights the association of NPPA SNP with cLQTS and implicating it as a potential biomarker in South Indian population

Genetic variation in exon 5 of troponin - I gene in hypertrophic cardiomyopathy cases

Background: Cardiomyopathies are a heterogeneous group of heart muscle disorders and are classified as 1) Hypertrophic Cardiomyopathy (HCM) 2) Dilated cardiomyopathy (DCM) 3) Restrictive cardiomyopathy (RCM) and 4) Arrhythmogenic right ventricular dysplasia (ARVD) as per WHO classification, of which HCM and DCM are common. HCM is a complex but relatively common form of inherited heart muscle disease with prevalence of 1 in 500 individuals and is commonly associated with sarcomeric gene mutations. Cardiac muscle troponin I (TNNI-3) is one such sarcomeric protein and is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. Mutations in this gene were found to be associated with a history of sudden cardiac death in HCM patients. Aim: Therefore the present study aims to identify for mutations associated with troponin I gene in a set of HCM patients from Indian population. Materials and Methods: Mutational analyses of 92 HCM cases were carried out following PCR based SSCP analysis. Results: The study revealed band pattern variation in 3 cases from a group of 92 HCM patients. This band pattern variation, on sequencing revealed base changes, one at nt 2560 with G>T transversion in exon-5 region with a wobble and others at nt 2479 and nt 2478 with G>C and C>G transversions in the intronic region upstream of the exon 5 on sequencing. Further analysis showed that one of the probands showed apical form of hypertrophy, two others showing asymmetric septal hypertrophy. Two of these probands showed family history of the condition. Conclusions: Hence, the study supports earlier reports of involvement of TNNI-3 in the causation of apical and asymmetrical forms of hypertrophy