TGF-β/NODAL信号通路基因在心脏发育和先天性心脏病致病机制的关系

先天性心脏病是最常见的新生儿先天畸形,它是由胚胎期心脏结构的异常发育造成的.据2014年中国卫生和计划生育统计年鉴显示,我国有75‰的新生儿承受着先天性心脏病带来的痛苦.研究已证明它是一种多基因病,牵涉到多种信号通路.TGF-β/Nodal信号通路被证明在心脏形成和左右轴建立的过程中起到重要的作用.TGF-β与环状心的形成和心肌纤维化,动脉圆锥干畸形,动脉导管未闭等先心病密切相关;Nodal以及其下游基因参与心脏不对称发育.此篇综述旨在总结TGF-β/Nodal信号通路及其相关基因在心脏发育中的作用,为揭示TGF-β/NODAL信号通路和先心病发病机制之间的关系提供帮助.     

小儿先天性心脏病与染色体异常的关系

先天性心脏病（congenital heart disease,CHD）是目前最常见的先天性畸形,也是引起婴幼儿死亡的首要原因。先心病是一种多基因遗传病,主要由于胚胎期遗传因素和环境因素共同作用导致心脏血管异常发育所引起,遗传度为55％-65％。先心病不但涉及多种基因,且与这些基因在不同时间和不同空间的先后表达和相互作用有关,其中任何基因表达质或量的异常,都可能影响心脏的发育,导致先心病的发生。     

干细胞心肌分化与发育的表观甲基化修饰调控

<正>先天性心脏病是导致新生儿死亡的主要疾病之一,由于心脏发育过程是个复杂的级联调控网络,引起胚胎心脏畸形的原因非常复杂,包括大量的转录因子及其相关的信号通路的相互作用。抑制和干扰这些转录因子的表达能诱导心肌异常发育,造成心功能受损。本研究选择常见的环境危险因素——吸烟(尼古丁)为研究对象,分别从体内胚胎心脏的动物模型和体外干细胞心肌细胞分化模型探讨尼古丁如何影响心脏早期发育和心肌分化,并探讨其表观遗传学的调控机制,结果显示:长期、     

心脏特异转录因子NKX2-5、TBX5、GATA4与先天性心脏病的研究进展

许多基因严格时空顺序的表达调控着心脏的正常发育,其中任一个基因的异常都可能导致先天性心脏病的发生。NKX2-5、TBX5、GATA4是心脏早期发育中最重要的3个转录因子,三者质或量的异常均会导致心脏畸形。大量研究提示,三者存在着复杂的相互作用,且位于许多基因的上游,可能以复合体的形式调控着心脏中许多转录因子的正确表达。本文对其特点、功能及可能的作用机制做一综述。     

先天性心脏病筛查管理模式探讨

先天性心脏病是由于各种原因导致胎儿期心脏及大血管发育异常而致的先天性畸形。国内发病率约为6‰~8‰,意味着我国每年有12~20万的先天性心脏病患儿出生。其中复杂的或生后不经及时有效处理易早期死亡的先天性心脏病约占30%。因此探讨先天性心脏病的筛查与管理模式,加强先天性心脏病的规范化诊疗,对降低先天性心脏病所导致的儿童死亡率和致残率,减轻家庭的经济负担和精神负担具有重要意义。     

先天性心脏病病因研究进展

先天性心脏病是新生儿先天缺陷中最为常见的疾病之一.先天性心脏病(congenital heart disease,CHD)是由于心脏、血管在胚胎发育过程中的障碍所至的心脏、血管形态、结构、功能、代谢上的异常.据北京市出生缺陷监测数据显示,先天性心脏病已经成为出生缺陷发生的第一位原因,并成为围产儿死亡和儿童死亡的主要原因.先天性心脏病的病因目前还不能完全阐明,但多数学者认为,除了少数先天性心脏病是单基因突变和染色体畸变引起的,大多数CHD属于多基因遗传病,是由遗传因素和环境因素相互作用引起的,一些先天性心脏病高发家系的研究也证实了这点[1].     

心脏发育及先天性心脏病的分子遗传学基础

从发育遗传学探讨先天性心脏病的发病机制,是目前的研究热点。本文综述了htl、nodal、Homeobox、TGF-β、Pax3基因在心脏发育过程中的重要作用及细胞间的相互作用与心脏发育的关系,旨在揭示发育遗传与先天性心脏病的关联。     

GATA6对先天性心脏病的影响及其突变位点的检出

GATA6属胚胎发育过程中心脏细胞的早期标志之一,是参与人类先天性心脏病发病机制中的主要候选基因之一,它对心脏发育起重要调控作用。通过对CHD患者的GATA6基因进行测序,我们发现CHD患者的GATA6基因有不同位点的突变,这些突变位点的检出有助于先天性心脏病的研究和治疗。     

芳香烃受体与Wnt在心脏发育中的作用

正我国每年有近120万出生缺陷的新生儿,大部分的先天性心脏病病因仍无法确定,但目前认为遗传与环境互作为重要因素[1]。心脏发生是基因网络精确互作和调控的产物,影响着细胞的分化,迁移,增殖和凋亡等方面生理状态[2]。心脏作为胚胎发育过程中最先形成的器官,其发育受到繁杂的信号网络调控,     

脊椎动物心脏发育相关基因的研究进展

脊椎动物的心脏是一个复杂的腔状结构 ,由中胚层的祖细胞衍生而来。在心脏发育过程中 ,相关基因的正常表达是有功能心脏形成的关键。探究心脏发育相关基因 ,为了解先天性心脏病的发病机制和干预性治疗提供基础。本文就心脏发育的分子机制及其同源盒、螺旋环螺旋转录因子、Ⅵ胶原蛋白、活性T细胞核因子等相关基因的研究作一综述。     

Left-right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease

Proper morphogenesis and positioning of internal organs requires delivery and interpretation of precise signals along the anterior-posterior, dorsal-ventral, and left-right axes. An elegant signaling cascade determines left- versus right-sided identity in visceral organs in a concordant fashion, resulting in a predictable left-right (LR) organ asymmetry in all vertebrates. The complex morphogenesis of the heart and its connections to the vasculature are particularly dependent upon coordinated LR signaling pathways. Disorganization of LR signals can result in myriad congenital heart defects that are a consequence of abnormal looping and remodeling of the primitive heart tube into a multi-chambered organ. A framework for understanding how LR asymmetric signals contribute to normal organogenesis has emerged and begins to explain the basis of many human diseases of LR asymmetry. Here we review the impact of LR signaling pathways on cardiac development and congenital heart disease.     

Epigenetic regulation of cardiac development and function by polycomb group and trithorax group proteins

Heart disease is a leading cause of death and disability in developed countries. Heart disease includes a broad range of diseases that affect the development and/or function of the cardiovascular system. Some of these diseases, such as congenital heart defects, are present at birth. Others develop over time and may be influenced by both genetic and environmental factors. Many of the known heart diseases are associated with abnormal expression of genes. Understanding the factors and mechanisms that regulate gene expression in the heart is essential for the detection, treatment, and prevention of heart diseases. Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are special families of chromatin factors that regulate developmental gene expression in many tissues and organs. Accumulating evidence suggests that these proteins are important regulators of development and function of the heart as well. A better understanding of their roles and functional mechanisms will translate into new opportunities for combating heart disease.     

Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene‐specific

Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE‐related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation of Hedgehog or Nodal signaling pathways, both known as major triggers of HPE, has been shown to play a role in the pathogenesis of CHD, including structural defects and left–right asymmetry defects. In this study, individuals with various types of HPE were investigated clinically and by genomic sequencing. Cardiac phenotypes were assessed in 434 individuals with HPE who underwent targeted sequencing. CHDs were identified in 8% (n = 33) of individuals, including 10 (30%) cases of complex heart disease. Only four individuals (4/33) had damaging variants in the known HPE genes STAG2, SIX3, and SHH. Interestingly, no CHD was identified in the 37 individuals of our cohort with pathogenic variants in ZIC2. These findings suggest that CHD occurs more frequently in HPE‐affected individuals with or without identifiable genetic variants, and this co‐occurrence may be genetically driven and gene‐specific.     

Functions of cilia in cardiac development and disease

Errors in embryonic cardiac development are a leading cause of congenital heart defects (CHDs), including morphological abnormalities of the heart that are often detected after birth. In the past few decades, an emerging role for cilia in the pathogenesis of CHD has been identified, but this topic still largely remains an unexplored area. Mouse forward genetic screens and whole exome sequencing analysis of CHD patients have identified enrichment for de novo mutations in ciliary genes or non-ciliary genes, which regulate cilia-related pathways, linking cilia function to aberrant cardiac development. Key events in cardiac morphogenesis, including left–right asymmetric development of the heart, are dependent upon cilia function. Cilia dysfunction during left–right axis formation contributes to CHD as evidenced by the substantial proportion of heterotaxy patients displaying complex CHD. Cilia-transduced signaling also regulates later events during heart development such as cardiac valve formation, outflow tract septation, ventricle development, and atrioventricular septa formation. In this review, we summarize the role of motile and non-motile (primary cilia) in cardiac asymmetry establishment and later events during heart development.     

Immunobiology of TNFSF15 and TNFRSF25

The innate immune response plays a critical role in pathogen clearance. However, dysregulation of innate immunity contributes to acute inflammatory diseases such as sepsis and many chronic inflammatory diseases including asthma, arthritis, and Crohn’s disease. Pathogen recognition receptors including the Toll-like family of receptors play a pivotal role in the initiation of inflammation and in the pathogenesis of many diseases with an inflammatory component. Studies over the last 15 years have identified complex innate immune signal transduction pathways involved in inflammation that have provided many new potential therapeutic targets to treat disease. We are investigating several novel genes that exert spatial and in some cases temporal regulation on innate immunity signaling pathways. These novel genes include Tbc1d23, a RAB-GAP that inhibits innate immunity. In this review, we will discuss inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics.     

Genetic factors in non‐syndromic congenital heart malformations

Wessels MW, Willems PJ. Genetic factors in non‐syndromic congenital heart malformations. The genetic defect in most patients with non‐syndromic congenital heart malformations (CHM) is unknown, although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs sporadically. The multifactorial inheritance hypothesis of common diseases suggesting that the cumulative effect of multiple genetic and environmental risk factors leads to disease, might also apply for CHM. We review here the monogenic disease genes with high‐penetrance mutations, susceptibility genes with reduced‐penetrance mutations, and somatic mutations implicated in non‐syndromic CHM.     

心脏发育过程中常见的相关基因与先天性心脏病

人体心脏发育是一个复杂的过程,包括细胞决定、迁移和分化、心管的形成、环化、房室腔形成等一系列变化.GATA家族基因、NKX家族基因、TBX家族基因、NODAL、NOTCH、WNT、BMP信号通路以及ISLI、ACFCI、DNAH及JAG等基因都与心脏发育密切相关.     

Identification of susceptible genes for complex chronic diseases based on disease risk functional SNPs and interaction networks

Complex chronic diseases are caused by the effects of genetic and environmental factors. Single nucleotide polymorphisms (SNPs), one common type of genetic variations, played vital roles in diseases. We hypothesized that disease risk functional SNPs in coding regions and protein interaction network modules were more likely to contribute to the identification of disease susceptible genes for complex chronic diseases. This could help to further reveal the pathogenesis of complex chronic diseases. Disease risk SNPs were first recognized from public SNP data for coronary heart disease (CHD), hypertension (HT) and type 2 diabetes (T2D). SNPs in coding regions that were classified into nonsense and missense by integrating several SNP functional annotation databases were treated as functional SNPs. Then, regions significantly associated with each disease were screened using random permutations for disease risk functional SNPs. Corresponding to these regions, 155, 169 and 173 potential disease susceptible genes were identified for CHD, HT and T2D, respectively. A disease-related gene product interaction network in environmental context was constructed for interacting gene products of both disease genes and potential disease susceptible genes for these diseases. After functional enrichment analysis for disease associated modules, 5 CHD susceptible genes, 7 HT susceptible genes and 3 T2D susceptible genes were finally identified, some of which had pleiotropic effects. Most of these genes were verified to be related to these diseases in literature. This was similar for disease genes identified from another method proposed by Lee et al. from a different aspect. This research could provide novel perspectives for diagnosis and treatment of complex chronic diseases and susceptible genes identification for other diseases.