Understanding the Genetic and Non-genetic Interconnections in the Aetiology of Isolated Congenital Heart Disease: An Updated Review: Part 1.

Purpose Of Review: Congenital heart disease (CHD) is the most frequently occurring birth defect. Majority of the earlier reviews focussed on the association of genetic factors with CHD. A few epidemiological studies provide convincing evidence for environmental factors in the causation of CHD.

Understanding the Genetic and Non-Genetic Interconnections in the Aetiology of Syndromic Congenital Heart Disease: An Updated Review: Part 2.

Purpose Of Review: Approximately 30% of syndromic cases diagnosed with CHD, which lure us to further investigate the molecular and clinical challenges behind syndromic CHD (sCHD). The aetiology of sCHD in a majority of cases remains enigmatic due to involvement of multiple factors, namely genetic, epigenetic and environmental modifiable risk factors for the development of the disease. Here, we aim to update the role of genetic contributors including chromosomal abnormalities, copy number variations (CNVs) and single gene mutations in cardiac specific genes, maternal lifestyle conditions, environmental exposures and epigenetic modifiers in causing CHD in different genetic syndromes.

Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy.

Background: Synonymous variations have always been ignored while studying the underlying genetic mechanisms for most of the human diseases. However, recent studies have suggested that these silent changes in the genome can alter the protein expression and folding.

Methods And Results: CSRP3, which is a well-known candidate gene associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), was screened for 100 idiopathic DCM cases and 100 controls.

Implication of rare genetic variants of NODAL and ACVR1B in congenital heart disease patients from Indian population.

NODAL signaling plays an essential role in vertebrate embryonic patterning and heart development. Accumulating evidences suggest that genetic mutations in TGF-β/NODAL signaling pathway can cause congenital heart disease in humans. To investigate the implication of NODAL signaling in isolated cardiovascular malformation, we have screened 300 non-syndromic CHD cases and 200 controls for NODAL and ACVR1B by Sanger sequencing and identified two rare missense (c.

Dilated cardiomyopathy: a new insight into the rare but common cause of heart failure.

Heart failure is a global health burden responsible for high morbidity and mortality with a prevalence of greater than 60 million individuals worldwide. One of the major causes of heart failure is dilated cardiomyopathy (DCM), characterized by associated systolic dysfunction. During the last few decades, there have been remarkable advances in our understanding about the genetics of dilated cardiomyopathy.

Functional analysis of novel genetic variants of NKX2-5 associated with nonsyndromic congenital heart disease.

NKX2-5, a master cardiac regulatory transcription factor was the first known genetic cause of congenital heart diseases (CHDs). To further investigate its role in CHD pathogenesis, we performed mutational screening of 285 CHD probands and 200 healthy controls. Five coding sequence variants were identified in six CHD cases (2.

A gain-of-function mutation in CITED2 is associated with congenital heart disease.

CITED2 is a transcription co-activator that interacts with TFAP2 and CBP/ P300 transcription factors to regulate the proliferation and differentiation of the cardiac progenitor cells. It acts upstream to NODAL-PITX2 pathways and regulates the left-right asymmetry. Both human genetic and model organism studies have shown that altered expression of CITED2 causes various forms of congenital heart disease.

Implication of GATA4 synonymous variants in congenital heart disease: A comprehensive in-silico approach.

Synonymous variations, previously considered as neutral, are recently shown to have a significant impact on mRNA structure and stability thereby affecting protein expression and function. Their role in disease pathogenesis is also emerging. GATA4 is an important transcription factor involved in cardiac development and a well-known candidate gene associated with congenital heart disease (CHD).

Functionally significant, novel GATA4 variants are frequently associated with Tetralogy of Fallot.

Transcription factor GATA4 is known to play crucial role during heart development, regulating expression of several other key cardiogenic factors. Various GATA4 mutations are reported in familial as well as sporadic cases of congenital heart defects (CHDs). To estimate the prevalence and pathogenic potential of GATA4 variants in our CHD cohort, we have screened 285 CHD cases along with 200 controls by Sanger sequencing and identified 9 genetic variants (c.

Epidemiology of Congenital Heart Disease in India.

Objective: Congenital heart defects (CHDs) affect a large number of newborns and account for a high proportion of infant mortality worldwide. There are regional differences in the prevalence and distribution pattern of CHDs. The aim of this study is to estimate the distribution pattern and prevalence of CHDs among the population of north-central India and to compare the results with studies in other regions of the country to get an overview of prevalence of CHDs in India.

Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species.

Unraveling the gene regulatory networks that govern development and function of the mammalian heart is critical for the rational design of therapeutic interventions in human heart disease. Using the Drosophila heart as a platform for identifying novel gene interactions leading to heart disease, we found that the Rho-GTPase Cdc42 cooperates with the cardiac transcription factor Tinman/Nkx2-5. Compound Cdc42, tinman heterozygous mutant flies exhibited impaired cardiac output and altered myofibrillar architecture, and adult heart-specific interference with Cdc42 function is sufficient to cause these same defects.

Differential changes in TGF-β/BMP signaling pathway in the right ventricular myocardium of newborns with hypoplastic left heart syndrome.

Background: Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of the left ventricle (LV) and increased biomechanical stress on the right ventricle (RV) from single ventricle physiology. Despite the clinical significance, the signaling pathways active during RV remodeling and disease progression are not known. To address this, we examined differential changes in expression of genes associated with transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signaling in RV tissue isolated from HLHS patients relative to RV and LV tissue from control subjects.

Short-term mechanical unloading and reverse remodeling of failing hearts in children.

Background: Mechanical support using a left ventricular assist device (LVAD) can lead to functional recovery of the myocardium in patients with end-stage heart failure (HF). Molecular remodeling, cytoskeletal disruption, and apoptosis activation are associated with abnormal gene expression in the failing ventricular myocardium of HF subjects and can normalize in response to medium- and long-term mechanical unloading in adults. However, there is little knowledge of the changes in gene expression after short-term mechanical support in children with HF.

alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.

Background: Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-alpha(1) (SNTA1) is known to interact with the cardiac sodium channel (hNa(v)1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa(v)1.

Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease.

neuromancer/Tbx20 (nmr) genes are cardiac T-box transcription factors that are evolutionarily conserved from flies to humans. Along with other known congenital heart disease genes, including tinman/Nkx2-5, dorsocross/Tbx5/6, and pannier/Gata4/6, they are important for specification and morphogenesis of the embryonic heart. The Drosophila heart has proven to be an excellent model to study genes involved in establishing and maintaining the structural integrity of the adult heart, as well as genes involved in maintaining physiological function.

Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations.

NODAL and its signaling pathway are known to play a key role in specification and patterning of vertebrate embryos. Mutations in several genes encoding components of the NODAL signaling pathway have previously been implicated in the pathogenesis of human left-right (LR) patterning defects. Therefore, NODAL, a member of TGF-beta superfamily of developmental regulators, is a strong candidate to be functionally involved in congenital LR axis patterning defects or heterotaxy.

Molecular cloning, expression of testicular transcript abundant in germ cells and immunobiological effects of the recombinant protein.

Problem: It has been well documented that antisperm antibodies can be causative factors for infertility. In this report we have identified a protein on human sperm referred as human sperm-associated protein (HSAP) using serum of an immunoinfertile woman; it is thus a sperm-specific protein--a candidate molecule for control of fertility.

Method Of Study: An immunoinfertile woman serum showing head-head sperm agglutination and acrosomal localization, reacted with human sperm protein of apparent molecular weight of 48 kDa on Western blot.

Molecular genetics of heterotaxy syndromes.

Purpose Of Review: Heterotaxy is a complex set of birth defects in which the normal concordance of asymmetric thoracic and abdominal organs is disturbed. In this review the authors summarize recent research on the etiology of heterotaxy syndromes. Improved understanding of the genetic control of left-right patterning in the early embryo is leading to the identification of candidate genes that may be mutated in heterotaxy patients, and epidemiologic studies are helping to define nongenetic mechanisms of embryopathy.

Transition nuclear proteins are required for normal chromatin condensation and functional sperm development.

The histone-to-protamine transition is important in the formation of spermatozoa. In mammals this involves two steps: replacement of histones by transition nuclear proteins (TPs) and replacement of TPs by protamines. To determine the functions of the TPs and their importance for sperm development, we generated mice lacking both TPs, since mice lacking only TP1 or TP2 were fertile.

Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.

Objectives: We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM).

Background: Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype.

Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly.

Roles of transition nuclear proteins in spermiogenesis.

The transition nuclear proteins (TPs) constitute 90% of the chromatin basic proteins during the steps of spermiogenesis between histone removal and the deposition of the protamines. We first summarize the properties of the two major transition nuclear proteins, TP1 and TP2, and present concepts, based on their time of appearance in vivo and in vitro properties, regarding their roles. Distinct roles for the two TPs in histone displacement, sperm nuclear shaping, chromatin condensation, and maintenance of DNA integrity have been proposed.

Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy.

Alpha T-catenin is a novel member of the alpha-catenin family, which shows most abundant expression in cardiomyocytes and in peritubular myoid cells of the testis, pointing to a specific function for alpha T-catenin in particular muscle tissues. Like other alpha-catenins, alpha T-catenin provides an indispensable link between the cadherin-based cell-cell adhesion complex and the cytoskeleton, to mediate cell-cell adhesion. By isolating genomic clones, combined with database sequence analysis, we have been able to determine the structure of the CTNNA3 and Ctnna3 genes, encoding human and mouse alpha T-catenin, respectively.