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This study was designed to evaluate echocardiographic measurements in Han Chinese preterm and term infants and to build percentile curves of normal echocardiographic measurements values related to the weight.From December 2014 to December 2021, a total of 797 male infants and 773 female infants born in * were included in the study. The echocardiographic measurements of each subject were as follows: left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular posterior wall thickness at end-diastole (LVPWd), left ventricular posterior wall thickness at end-systole (LVPWs), interventricular septal thickness at end-diastole (IVSd), interventricular septal thickness at end-systole (IVSs), ascending aorta diameter (AO), left atrium (LA) dimension, left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS) and left ventricular mass (LVM). The correlations between echocardiography measurements and birth weight (BW), length (L), gestational age (GA), and body surface area (BSA) were analyzed.There was a good correlation between the echocardiographic measurements and birth weight and percentile curves of the echocardiographic measurements were established according to different birth weight. The echocardiographic measurements were not affected by gender. However, LVEF and LVFS did not change with BW or gender.The percentile curves of normal values make it possible to classify echocardiographic measurements for left heart structures and function as normal or abnormal and is helpful for the diagnosis of neonatal heart disease in preterm and term infants.

Background The high risks for childhood respiratory diseases are associated with exposure to ambient air pollution. However, there are few studies that have explored the association between air pollution exposure and respiratory diseases among young children (particularly aged 0–2 years) based on the entire population in a megalopolis. Methods Daily hospital admission records were obtained from 54 municipal hospitals in Wuhan city, China. We included all children (aged 0–2 years) hospitalized with respiratory diseases between January 2017 and December 2018. Individual air pollution exposure assessment was used in Land Use Regression model and inverse distance weighted. Case-crossover design and conditional logistic regression models were adopted to estimate the hospitalization risk associated with air pollutants. Results We identified 62,425 hospitalizations due to respiratory diseases, of which 36,295 were pneumonia. Particulate matter with an aerodynamic diameter less than 2.5 μm (PM2.5) and nitrogen dioxide (NO2) were significantly associated with respiratory diseases and pneumonia. ORs of pneumonia were 1.0179 (95% CI 1.0097–1.0260) for PM2.5 and 1.0131 (95% CI 1.0042–1.0220) for NO2 at lag 0–7 days. Subgroup analysis suggested that NO2, Ozone (O3) and sulfur dioxide (SO2) only showed effects on pneumonia hospitalizations on male patients, but PM2.5 had effects on patients of both genders. Except O3, all pollutants were strongly associated with pneumonia in cold season. In addition, children who aged elder months and who were in central urban areas had a higher hospitalization risk. Conclusions Air pollution is associated with higher hospitalization risk for respiratory diseases, especially pneumonia, among young children, and the risk is related to gender, month age, season and residential location.

As a nontraditional environmental regulation, environmental information disclosure (EID) can influence the environmental behaviors of economic agents through information transparency, but research on EID and energy efficiency is still incomplete. Therefore, this study investigates the association between EID policies and green total factor energy efficiency (GTFEE) enhancement in Chinese prefecture-level cities from the perspective of regional resource endowment characteristics. The study uses the generalized multiperiod DID method and 2004–2019 panel data from 282 prefecture-level cities. Based on a quasi-natural experiment involving the new ambient air quality standards (NAAQSs) introduced in 2012, the study finds that the implementation of this EID policy significantly promotes GTFEE improvement in China’s resource-based cities. Furthermore, the driving mechanism and heterogeneous effects are analyzed: 1. both the optimization of industrial structure and green innovation capability strengthen the improvement effect of the NAAQSs on GTFEE; and 2. both the type of industrial base and the initial public monitoring motivation positively influence the improvement effect of the NAAQSs on GTFEE.

Congenital heart disease (CHD) is the most frequent kind of birth deformity in human beings and the leading cause of neonatal mortality worldwide. Although genetic etiologies encompassing aneuploidy, copy number variations, and mutations in over 100 genes have been uncovered to be involved in the pathogenesis of CHD, the genetic components predisposing to CHD in most cases remain unclear. We recruited a family with CHD from the Chinese Han population in the present investigation. Through whole-exome sequencing analysis of selected family members, a new

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode β-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

As the most common form of developmental malformation affecting the heart and endothoracic great vessels, congenital heart disease (CHD) confers substantial morbidity and mortality as well as socioeconomic burden on humans globally. Aggregating convincing evidence highlights the genetic origin of CHD, and damaging variations in over 100 genes have been implicated with CHD. Nevertheless, the genetic basis underpinning CHD remains largely elusive. In this study, via whole-exosome sequencing analysis of a four-generation family inflicted with autosomal-dominant CHD, a heterozygous SMAD1 variation, NM_005900.3: c.264C > A; p.(Tyr88 ∗ ), was detected and validated by Sanger sequencing analysis to be in cosegregation with CHD in the whole family. The truncating variation was not observed in 362 unrelated healthy volunteers employed as control persons. Dual-luciferase reporter gene assay in cultured COS7 cells demonstrated that Tyr88 ∗ -mutant SMAD1 failed to transactivate the genes TBX20 and NKX2.5, two already well-established CHD-causative genes. Additionally, the variation nullified the synergistic transcriptional activation between SMAD1 and MYOCD, another recognized CHD-causative gene. These data indicate SMAD1 as a new gene responsible for CHD, which provides new insight into the genetic mechanism underlying CHD, suggesting certain significance for genetic risk assessment and precise antenatal prevention of the family members inflicted with CHD.

Congenital bicuspid aortic valve (BAV), the most common form of birth defect in humans, is associated with substantial morbidity and mortality. Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of BAV. However, BAV is a genetically heterogeneous disease and the genetic determinants underpinning BAV in an overwhelming majority of patients remain unknown. In the present study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc-finger transcription factor essential for the normal development of the aortic valves, were sequenced in 152 unrelated patients with congenital BAV. The available relatives of a proband harboring an identified GATA6 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA6. The functional characteristics of the mutation were analyzed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.E386X, was identified in a family with BAV transmitted in an autosomal dominant mode. The nonsense mutation was absent in 400 control chromosomes. Biological assays revealed that the mutant GATA6 protein had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA6 and GATA4, another transcription factor causally linked to BAV. In conclusion, this study firstly associates GATA6 loss-of-function mutation with enhanced susceptibility to familial BAV, which provides novel insight into the molecular mechanism of BAV, implying potential implications for genetic counseling and personalized management of BAV patients.

Congenital heart defect (CHD) is the most common type of birth defect in humans and a leading cause of infant morbidity and mortality. Previous studies have demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, the genetic basis of CHD remains poorly understood due to substantial genetic heterogeneity. In this study, the coding exons and splicing boundaries of the NR2F2 gene, which encodes a pleiotropic transcription factor required for normal cardiovascular development, were sequenced in 168 unrelated patients with CHD, and a novel mutation (c.247G > T, equivalent to p.G83X) was detected in a patient with double outlet right ventricle as well as ventricular septal defect. Genetic scanning of the mutation carrier's relatives available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the index patient's pedigree displayed that the mutation co-segregated with CHD, which was transmitted as an autosomal dominant trait with complete penetrance. The nonsense mutation was absent in 230 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system revealed that the mutant NR2F2 protein had no transcriptional activity as compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transcriptional activation between NR2F2 and GATA4, another core cardiac transcription factor associated with CHD. This study firstly associates NR2F2 loss-of-function mutation with an increased susceptibility to double outlet right ventricle in humans, which provides further significant insight into the molecular mechanisms underpinning CHD, suggesting potential implications for genetic counseling of CHD families and personalized treatment of CHD patients.

Aggregating evidence suggests that genetic determinants play a pivotal role in the pathogenesis of the congenitally bicuspid aortic valve (BAV). BAV is of pronounced genetic heterogeneity, and the genetic components underlying BAV in an overwhelming majority of patients remain elusive. In the current study, the whole coding exons and adjacent introns, as well as 5′ and 3′ untranslated regions of the GATA4 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, were screened by direct sequencing in 150 index patients with congenital BAV. The available family members of an identified mutation carrier and 300 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA4 . The functional effect of the mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.E147X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 600 control chromosomes. Functional deciphers revealed that the mutant GATA4 protein lost transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA4 and NKX2.5, another transcription factor responsible for BAV. In conclusion, this study associates the GATA4 loss-of-function mutation with enhanced susceptibility to a BAV, thus providing novel insight into the molecular mechanism underpinning the BAV.

Yin-Chen-Hao-Tang (YCHT), a classic Chinese herbal formula, is characterized by its strong therapeutic effects of liver regulation and relief of jaundice, especially Yanghuang syndrome (YHS). YHS is a type of jaundice with damp-heat pathogenesis, and it is considered a complicated Chinese medicine syndrome (CMS). The accurate mechanism for healing YHS has not yet been completely reported. The purpose of the current research is to investigate the expression of endogenous biomarkers in YHS mice and evaluate the clinical therapeutic effect of YCHT. Serum samples were analyzed using UPLC-Q/TOF-MS techniques in order to determine differential metabolites to elucidate the functional mechanism of YCHT on YHS through metabolite profiling combined with multivariate analysis. Simultaneously, the exact diversification of YHS mice was elucidated using blood biochemistry indexes and histopathological examination, and the results indicated that YHS is markedly improved by YCHT. Unsupervised principal component analysis (PCA) patterns were constructed to dissect the variances of metabolic profiling. Overall, 22 potential biomarkers were identified using a metabolomics approach based on an accurate MS/MS approach, clustering and distinguishing analysis. The present work demonstrates that the effectiveness of YCHT against YHS prompts distinct discrepancies in metabolic profiles by adjusting biomarkers and regulating metabolic disorders. A total of 15 metabolic pathways were involved in biological disturbance. This demonstrates that metabolomic techniques are powerful means to explore the pathogenesis of CMS and the therapeutic effects of traditional Chinese formulae.

Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD.

Congenital heart disease (CHD) is the most common form of birth defect in humans, and remains a leading non‑infectious cause of infant mortality worldwide. An increasing number of studies have demonstrated that genetic defects serve a pivotal role in the pathogenesis of CHD, and mutations in >60 genes have been causally associated with CHD. CHD is a heterogeneous disease and the genetic basis of CHD in the majority of patients remains poorly understood. In the present study, the coding exons and flanking introns of the mesoderm posterior 1 (MESP1) gene, which encodes a basic helix‑loop‑helix transcription factor required for normal cardiovascular development, were sequenced in 178 unrelated patients with CHD. The available relatives of the index patient carrying an identified mutation and 200 unrelated, ethnically‑matched healthy individuals, who were used as controls, were genotyped for MESP1. The functional characteristics of the MESP1 mutation were determined using a dual‑luciferase reporter assay system. As a result, a novel de novo heterozygous MESP1 mutation, p.Q118X, was identified in an index patient with double outlet right ventricle (DORV) and a ventricular septal defect. The nonsense mutation was absent in the 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional assays indicated that the mutant MESP1 protein had no transcriptional activity when compared with its wild‑type counterpart. The present study firstly provided experimental evidence supporting the concept that a MESP1 loss‑of‑function mutation may contribute to the development of DORV in humans, which presents a significant insight into the molecular pathogenesis of CHD. The results highlight the potential implications for the genetic counseling and personalized treatment of patients with CHD.

Congenital heart defects (CHDs), a wide variety of developmental abnormalities in the structures of the heart and the great thoracic blood vessels, are the most common form of birth defect in humans worldwide. CHDs are accountable for substantial morbidity and are still the leading cause of birth defect‑related deaths. Recent studies have demonstrated the pivotal roles of genetic defects in the pathogenesis of CHDs, and a great number of genetic mutations have been associated with CHDs. Nevertheless, CHDs are a genetically heterogeneous disorder and the genetic basis underlying CHDs in an overwhelming majority of cases remains unclear. In the present study, the coding exons and flanking introns of the heart and neural crest derivatives expressed transcript 1 (HAND1) gene, which encodes a basic helix‑loop‑helix transcription factor crucial for cardiovascular development, were sequenced in 158 unrelated patients with CHDs, and a de novo heterozygous mutation, p.K132X, was identified in a patient with double outlet right ventricle (DORV), as well as ventricular septal defect. The nonsense mutation, which was predicted to produce a truncated HAND1 protein lacking 84 carboxyl‑terminal amino acids, was absent in 600 control chromosomes. Functional analyses revealed that the HAND1 K132X mutant had no transcriptional activity. Furthermore, the mutation disrupted the synergistic activation between HAND1 and GATA binding protein 4 (GATA4), another cardiac core transcription factor causally linked to CHDs. To the best of our knowledge, this is the first report on the association of HAND1 loss‑of‑function mutation with an enhanced susceptibility to DORV in humans. These findings expand the phenotypic spectrum linked to HAND1 mutations, suggesting potential implications for the development of novelo prophylactic and therapeutic strategies for DORV.

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225CG; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.

Atrial fibrillation (AF), the most common type of cardiac rhythm disturbance encountered in clinical practice, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. A recent study has revealed that the TBX5 gene, which encodes a T-box transcription factor key to cardiovascular development, was associated with AF and atypical Holt-Oram syndrome. However, the prevalence and spectrum of TBX5 mutation in patients with lone AF remain unclear. In this study, the coding regions and splicing junction sites of TBX5 were sequenced in 192 unrelated patients with lone AF and 300 unrelated ethnically-matched healthy individuals used as controls. The causative potential of the identified TBX5 variation was evaluated by MutationTaster and PolyPhen-2. The functional effect of the mutant TBX5 was assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.H170D, was identified in a patient, with a mutational prevalence of approximately 0.52%. This mutation, which was absent in the 300 control individuals, altered the amino acid completely conserved evolutionarily across species, and was predicted to be disease-causing. Functional deciphers showed that the mutant TBX5 was associated with significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation between TBX5 and NKX2-5 or GATA4. The findings expand the mutational spectrum of TBX5 linked to AF and provide new evidence that dysfunctional TBX5 may contribute to lone AF.

Congenital heart disease (CHD), the most common type of developmental abnormality, is associated with substantial morbidity and mortality in humans worldwide. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed 2 (HAND2), has been demonstrated to be crucial for normal cardiovascular development in animal models. However, whether a genetically defective HAND2 contributes to congenital heart disease (CHD) in humans remains to be explored. In this study, the entire coding region and splicing boundaries of the HAND2 gene were sequenced in a cohort of 145 unrelated patients with CHD. A total of 200 unrelated, ethnically-matched healthy individuals used as controls were also genotyped for HAND2. The functional effect of the mutant HAND2 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous HAND2 mutation, p.L47P, was identified in a patient with tetralogy of Fallot (TOF). The misense mutation, which altered the amino acid conserved evolutionarily among species, was absent in 400 control chromosomes. Functional analyses unveiled that the mutant HAND2 had a significantly decreased transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation between HAND2 and GATA4 or NKX2.5, other two cardiac key transcription factors involved in the pathogenesis of CHD. To the best of our knowledge, this study is the first to report the association of a HAND2 loss-of-function mutation with an increased vulnerability to TOF in humans, which provides novel insight into the molecular mechanism underpinning CHD, suggesting potential implications for the genetic counseling of families with CHD.

Yinchenhao Tang (YCHT), a classic traditional Chinese medicine (TCM) formulae, plays an important role in the treatment of Yang Huang syndrome (YHS). With the emergence of new biomarkers of YHS uncovered via metabonomics, the underlying functional mechanisms are still not clear. Functional metabolomics aims at converting biomarkers derived from metabonomics into disease mechanisms. Here, an integrated non-target metabolomics and IPA strategy were used to investigate the YCHT intervention on YHS. Our metabolomics study has shown that the potential protective effect of YCHT on YHS mice leads to significant changes in the metabolic profile by modulating the biomarkers and regulating the metabolic disorders. Twenty two differential metabolite biomarkers and fifteen involved metabolic pathways were correlated with the regulation of YCHT treatment on YHS. Functional metabolomics identified a core biomarker, D-glucuronic acid in pentose and glucuronate interconversion pathways, which was directly related to the target prediction of UDP-glucuronosyltransferase 1A1 and eventually leaded to a series of disturbances. In conclusion, this study shows that functional metabolomics can discover metabolic pathways as promising targets.

Congenital heart disease (CHD), the most prevalent birth defect in humans worldwide, is still a leading non‑infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of CHD, and more than 50 genes have been linked to various types of CHD. Nevertheless, CHD is a heterogeneous disorder and the genetic components underpinning CHD in an overwhelming majority of cases remain unknown. In the present study, the entire coding exons and flanking introns of the TBX20 gene, which codes for a T-box transcription factor essential for the proper development of the heart, were sequenced in a cohort of 146 unrelated patients with CHD. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as the controls were also genotyped for TBX20. The functional characteristics of the TBX20 mutation were assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX20 mutation, p.R143W, was identified in an index patient with double outlet right ventricle (DORV). Genetic analyses of the pedigree of the proband revealed that in the family, the mutation co-segregated with DORV transmitted in an autosomal dominant pattern with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional analysis revealed that mutant TBX20 had a significantly diminished transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this study is the first to report the association of TBX20 loss-of-function mutation with increased susceptibility to DORV in humans, which provides novel insight into the molecular mechanisms responsible for CHD, suggesting potential implications for the antenatal prophylaxis of CHD.

Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans and is associated with substantial morbidity and mortality. Emerging evidence demonstrates that genetic risk factors play an important role in the pathogenesis of BAV. However, BAV is a genetically heterogenous disorder, and the genetic defects underpinning BAV in most patients remain to be identified. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor essential for the normal development of the aortic valve, were sequenced in 142 unrelated patients with BAV. The available relatives of the mutation carrier and 200 unrelated healthy subjects used as controls were also genotyped for NKX2.5. The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.K192X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 400 control chromosomes. Functional analyses revealed that the mutant NKX2.5 had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation abolished the synergistic transcriptional activation between NKX2.5 and GATA5, another transcription factor crucial for the aortic valvular morphogenesis. In conclusion, this study is the first to link an NKX2.5 loss-of-function mutation to enhanced susceptibility to human BAV, providing novel insight into the molecular mechanism of BAV and suggesting potential implications for genetic counseling and clinical care of families presenting with BAV.

Yin-Chen-Hao-Tang (YCHT), the classic formulae of traditional Chinese medicine (TCM), is widely used to treat dampness-heat jaundice syndrome (DHJS) and various liver diseases. However, the therapeutic mechanism of YCHT is yet to have an integrated biological interpretation. In this work, we used metabolomics technology to reveal the adjustment of small molecule metabolites in body during the treatment of YCHT. Aim to discover the serum biomarkers which are associated with the treatment of DHJS against YCHT. Pathological results and biochemical indicators showed that the hepatic injury and liver index abnormalities caused by DHJS was effectively improve after treatment with YCHT. On the basis of effective treatment, ultra-high performance liquid chromatography (UPLC-G2Si-HDMS) combined with the multivariate statistical analysis method was utilized to analyze the serum samples. Finally, 22 biomarkers were identified by using mass spectrometry and illuminated the correlative metabolic pathways which play a significant role and as therapeutic targets in the treatment of DHJS. This work demonstrated that mass spectrometry metabolomics provides a new insight to elucidate the action mechanism of formulae.

Congenital heart defect (CHD) represents the most prevalent birth defect, and accounts for substantial morbidity and mortality in humans. Aggregating evidence demonstrates the genetic basis for CHD. However, CHD is a heterogeneous disease, and the genetic determinants underlying CHD in most patients remain unknown. In the present study, a cohort of 186 unrelated cases with CHD and 300 unrelated control individuals were recruited. The coding exons and flanking introns of the MEF2C gene, which encodes a transcription factor crucial for proper cardiovascular development, were sequenced in all study participants. The functional effect of an identified MEF2C mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect. Analysis of the proband's pedigree showed that the mutation co-segregated with CHD with complete penetrance. The missense mutation, which changed the evolutionarily conserved amino acid, was absent in 300 control individuals. Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity. Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD. This study firstly associates MEF2C loss-of-function mutation with DORV in humans, which provides novel insight into the molecular pathogenesis of CHD, suggesting potential implications for genetic counseling and personalized treatment of CHD patients.

Congenital heart disease (CHD) is the most common form of birth defect and is the most prevalent non-infectious cause of infant death. A growing body of evidence documents that genetic defects are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remain unclear. In this study, the coding exons and flanking introns of the Nkx2.6 gene, which codes for a homeodomain-containing transcription factor important for normal cardiovascular development, were sequenced in 320 unrelated patients with CHD, and two novel heterozygous Nkx2.6 mutations, p.V176M and p.K177X, were identified in two unrelated patients with CHD, respectively, including a patient with tetralogy of Fallot and a patient with double outlet of right ventricle and ventricular septal defect. The mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across species. Due to unknown transcriptional targets of Nkx2.6, the functional consequences of the identified mutations at transcriptional activity were evaluated by using Nkx2.5 as a surrogate. Alignment between human Nkx2.6 and Nkx2.5 proteins showed that V176M-mutant Nkx2.6 was equivalent to V182M-mutant Nkx2.5 and K177X-mutant Nkx2.6 was equal to K183X-mutant Nkx2.5, and introduction of V182M or K183X into Nkx2.5 significantly diminished its transcriptional activating function when compared with its wild-type counterpart. To our knowledge, this is the first report on the association of Nkx2.6 loss-of-function mutation with increased susceptibility to tetralogy of Fallot or double outlet of right ventricle and ventricular septal defect, providing novel insight into the molecular mechanism of CHD.

Tetraology of Fallot (TOF) is the most common form of cyanotic congenital heart disease and is a major cause of significant morbidity and mortality. Emerging evidence demonstrates that genetic risk factors are involved in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic defects responsible for TOF remain largely unclear. In the present study, the whole coding region of the GATA5 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 130 unrelated patients with TOF. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were analyzed using a luciferase reporter assay system. As a result, 2 novel heterozygous GATA5 mutations, p.R187G and p.H207R, were identified in 2 families with autosomal dominantly inherited TOF, respectively. The variations were absent in 400 control alleles and the altered amino acids were completely conserved evolutionarily. Functional analysis showed that the GATA5 mutants were associated with significantly decreased transcriptional activation compared with their wild-type counterpart. To our knowledge, this is the first report on the association of GATA5 loss-of-function mutations with TOF, suggesting potential implications for the early prophylaxis and allele-specific therapy of human TOF.

Plateau pika (Ochotona curzoniae) is a key component of alpine meadow ecosystem in the Qinghai-Tibetan Plateau, and the increase of its number leads plant components of alpine meadow ecosystem to adaptively response. A field survey was carried out to determine the response of alpine meadow community to population densities of plateau pika by using available burrow density to replace the population density of plateau pika. This study showed that the height of alpine meadow communities gradually increased, and the cover of alpine meadow communities firstly decreased, and then increased as the available burrow density increased. With the increase of available burrow density, the richness index of alpine meadow communities firstly decreased and then increased, and the evenness index of alpine meadow communities firstly increased and then decreased, however, the diversity index of alpine meadow communities firstly increased, and then decreased, finally increased. In the increasing process of available burrow density, the total plant biomass and the unpalatable plant biomass firstly decreased and then increased, and the palatable plant biomass firstly increased and then decreased, indicating that the palatable plant biomass was the highest and the unpalatable plant biomass was the lowest at 14 available burrow per 625 m2. In the economic groups of plant biomass, the weed biomass was the highest and the legume biomass was the lowest at any available burrow densities, and the grass biomass and the sedge biomass were related to available burrow densities, indicating that the sedge biomass were bigger than the grass biomass at 3 available burrow per 625 m2, inverse at 54 available burrow per 625 m2, similar between 3 and 34 available burrow per 625 m2. Accompanying by the increase of available burrow densities, the legume biomass and the sedge biomass significantly decreased (P

Rangeland degradation not only affects animal production but also threatens ecological quality throughout the world. In this study, a functional classification index (FCIi) for rangelands was designed to determine the management pattern of different sub-rangeland vegetation types this index combines the productive value (GP(i)), ecological services value (GE(i)), ecological sensitivity (ESIi) and seasonal grazing importance (SGI(i)) of each rangeland subtype and can be used for coordinating the relationships between animal production and ecological conservation. On the basis of the FCIi of each rangeland subtype, the northern Tibetan rangelands were classified into a conservation sector, mixed sector and production sector. The conservation sector covering 0 center dot 47 million ha accounted for 13 center dot 9 per cent of the total rangeland area, and this had significant ecological and social values but was of low productivity. In the conservation sector, grazing should be forbidden so that degraded rangelands can be restored. The mixed sector covered 2 center dot 16 million ha, 63 center dot 9 per cent of the total rangeland area, and offered multiple benefits, in which increasing the number of head of livestock for sale would improve the income of local herders. A 0 center dot 75 million ha production sector accounted for 22 center dot 2 per cent of the total rangeland area and was applied to maximise economic benefits by establishing modern pasture systems to increase the income of local herders and thus partly offset the losses arising from the conservation sector. This study suggested that the area of the three functional sectors should be adjusted at appropriate times according to the changes in productivity and ecological values of each rangeland subtype. Copyright (c) 2012 John Wiley & Sons, Ltd.

Summary Background Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and is a major cause of substantial morbidity and mortality in infants. Accumulating evidence implicates genetic defects, especially in cardiac transcription factors, in the pathogenesis of VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified. Material/Methods A cohort of 230 unrelated patients with congenital VSD was included in the investigation. A total of 200 unrelated ethnically matched healthy individuals were recruited as controls. The entire coding region of GATA4, a gene encoding a zinc-finger transcription factor essential for normal cardiac morphogenesis, was sequenced initially in 230 unrelated VSD patients. The available relatives of the mutation carriers and 200 control subjects were subsequently genotyped for the presence of identified mutations. Results Four heterozygous missense GATA4 mutations of p.Q55R, p.G96R, p.N197S, and p.K404R were identified in 4 unrelated patients with VSD. These mutations were not detected in 200 control individuals nor described in the human SNP database. Genetic analysis of the relatives of the mutation carriers showed that in each family the mutation co-segregated with VSD. Conclusions These findings expand the mutation spectrum of GATA4 linked to VSD and provide new insight into the molecular etiology responsible for VSD, suggesting potential implications for the genetic diagnosis and gene-specific therapy for VSD.

Classification of grasslands is a convenient method to measure and manage the sustainability of Chinese grasslands. In this study, a timely and reliable procedure was examined using remote-sensing (RS) techniques. Linear regression analysis between field survey data and Moderate-Resolution Imaging Spectroradiometer (MODIS) data showed that among 17 vegetation indices (VIs) evaluated, the enhanced vegetation index (EVI) was the best VI to simulate forage dry biomass and cover in the Gannan region. The results of precision estimation of the models showed that power and logarithm regression satisfactorily simulated grassland dry biomass and grassland cover, respectively. The index of classification management of grasslands (ICGs) was used to subdivide grasslands into conservation grasslands and moderately productive grasslands in the Gannan region, where no grasslands fell into intensively productive grasslands. Conservation grasslands accounted for 2.04% of the available grasslands, whereas moderately produ...

A novel poly(safranine)-modified electrode has been constructed for the determination of 4-nitrophenol (4-NP) in natural water sample. The electrochemical behavior of poly(safranine) film electrode and its electrocatalytic activity toward 4NP were studied in detail by cyclic voltammetry (CV) and adsorptive linear stripping voltammetry (LSV). All experimental parameters were optimized and LSV was proposed for its determination. In optimal working conditions, the reduction current of 4-NP at this poly(safranine)-modified electrode exhibited a good linear relationship with 4-NP concentration in the range of 8.0 × 10 ‒8 to 4.0 × 10 ‒5 mol L ‒1 . The detection limit was 3.0 × 10 ‒8 mol L ‒1 . The high sensitivity and selectivity of the sensor were demonstrated by its practical application for the determination of trace amounts of 4-NP in natural water and fruit samples.

Snow is an important land cover on the earth's surface. It is characterized by its changing nature. Monitoring snow cover extent plays a significant role in dynamic studies and prevention of snow-caused disasters in pastoral areas. Using NASA EOS Terra/MODIS snow cover products and in situ observation data during the four snow seasons from November 1 to March 31 of year 2001 to 2005 in northern Xinjiang area, the accuracy of MODIS snow cover mapping algorithm under varied snow depth and land cover types was analyzed. The overall accuracy of MODIS daily snow cover mapping algorithm in clear sky condition is high at 98.5%; snow agreement reaches 98.2%, and ranges from 77.8% to 100% over the 4-year period for individual sites. Snow depth (SD) is one of the major factors affecting the accuracy of MODIS snow cover maps. MODIS does not identify any snow for SD less than 0.5 cm. The overall accuracy increases with snow depth if SD is equal to or greater than 3 cm, and decreases for SD below 3 cm. Land cover has an important influence in the accuracy of MODIS snow cover maps. The use of MOD10A1 snow cover products is severely affected by cloud cover. The 8-day composite products of MOD10A2 can effectively minimize the effect of cloud cover in most cases. Cloud cover in excess of 10% occurs on 99% of the MOD10A1 products and 14.7% of the MOD10A2 products analyzed during the four snow seasons. User-defined multiple day composite images based on MOD10A1, with flexibilities of selecting composite period, starting and ending date and composite sequence of MOD10A1 products, have an advantage in effectively monitoring snow cover extent for regional snow-caused disasters in pastoral areas.

To evaluate the implementation and effect of the program of treatment and assistance to advanced schistosomiasis patients in Qianjiang City.The data about the program from 2004 to 2012 were collected and analyzed, and the analysis of cost-effectiveness was performed. Meanwhile, 160 patients were sampled and surveyed about the recovery of their health.From 2004 to 2012, totally 2 363 person-times' patients received the treatment, and 339 patients were cured clinically. On average, each patient received 3.11 times of treatment and 22.28 d of hospitalization, the treatment cost was 5,382.87 yuan per year for each patient, and the cost-effectiveness was 12.7 thousand yuan per life-year-saved.The program of treatment and assistance to advanced schistosomiasis patients cures a part of patients and improves the working capacity and life quality of the patients.

Congenital heart disease (CHD), the most common type of birth defect, is still the leading non-infectious cause of infant morbidity and mortality in humans. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic components underpinning CHD in an overwhelming majority of patients remain unclear. In the present study, the coding exons and flanking introns of the PITX2 gene, which encodes a paired-like homeodomain transcription factor 2essential for cardiovascular morphogenesis as well as maxillary facial development, was sequenced in 196 unrelated patients with CHD and subsequently in the mutation carrier's family members available. As a result, a novel heterozygous PITX2 mutation, p.Q102X for PITX2a, or p.Q148X for PITX2b, or p.Q155X for PITX2c, was identified in a family with endocardial cushion defect (ECD) and Axenfeld-Rieger syndrome (ARS). Genetic analysis of the pedigree showed that the nonsense mutation co-segregated with ECD and ARS transmitted in an autosomal dominant pattern with complete penetrance. The mutation was absent in 800 control chromosomes from an ethnically matched population. Functional analysis by using a dual-luciferase reporter assay system revealed that the mutant PITX2 had no transcriptional activity and that the mutation eliminated synergistic transcriptional activation between PITX2 and NKX2.5, another transcription factor pivotal for cardiogenesis. To our knowledge, this is the first report on the association of PITX2 loss-of-function mutation with increased susceptibility to ECD and ARS. The findings provide novel insight into the molecular mechanisms underpinning ECD and ARS, suggesting the potential implications for the antenatal prophylaxis and personalized treatment of CHD and ARS.

A voltammetric sensor for the determination of parathion has been developed based on the use of a poly(carmine) film electrode. The reduction of parathion at the poly(carmine) modified glassy carbon electrode (GCE) is studied by cyclic voltammetry (CV) and linear scan voltammetry (LSV). Parathion yields a well-defined reduction peak at a potential of −0.595 V on the poly(carmine) modified GCE in pH 6.0 phosphate buffer solution (PBS). Compared with that on a bare GCE, the reduction peak current of parathion is significantly enhanced. All the experimental parameters are optimized for the determination of parathion. The reduction peak current is linear with the parathion concentration in the range of 5.0 × 10−8 to 1.0 × 10−5 mol L−1, and the detection limit is 1.0 × 10−8 mol L−1.

A molecularly imprinted polymer (MIP) membrane for sensing O,O-dimethyl-α-hydroxylphenyl phosphonate (DHP) has been prepared by electropolymerizing o-phenylenediamine on the glassy carbon electrodes in the presence of DHP. Optimization studies with the aim to enhance insulating properties and response kinetics of the polymer membrane were carried out with respect to template molecular concentration, the monomers concentration, the polymer membrane thick and scan rate. Cyclic voltammetry and electrochemical impedance have been used to characterize the behavior of MIP polymer membrane. The capacitive measurements were also certified the imprinting effect of the polymer layers. The experimental results showed that DHP imprinted polymer has better recognition property for the template than that of a blank polymer. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 2222–2227, 2006

Congenital heart disease (CHD) is the most prevalent type of birth defect in humans and is the leading non-infectious cause of infant death worldwide. There is a growing body of evidence demonstrating that genetic defects play an important role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remains unclear. In this study, the coding exons and splice junction sites of the TBX1 gene, which encodes a T-box homeodomain transcription factor essential for proper cardiovascular morphogenesis, were sequenced in 230 unrelated children with CHD. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were subsequently genotyped for TBX1. The functional effect of the TBX1 mutation was predicted by online program MutationTaster and characterized by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX1 mutation, p.Q277X, was identified in an index patient with double outlet right ventricle (DORV) and ventricular septal defect (VSD). Genetic analysis of the proband’s available relatives showed that the mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily across species and was predicted to be disease-causing by MutationTaster. Biochemical analysis revealed that Q277X-mutant TBX1 lost transcriptional activating function when compared with its wild-type counterpart. This study firstly associates TBX1 loss-of-function mutation with enhanced susceptibility to DORV and VSD in humans, which provides novel insight into the molecular mechanism underlying CHD and suggests potential implications for the development of new preventive and therapeutic strategies for CHD.

To evaluate the protective effect of Fangyouling (extracted from herb) on Schistosomajaponicum infection in the field.The residents in 2 villages, Zhaonao Village and Miaochang Village, were divided into Group A (139 persons) and Group B (162 persons), and the residents in Group A embrocated Fangyouling before their contacting the infested water and the residents in Group B did not. All the residents were investigated with questionnaires, and received the blood and stool examinations for schistosomiasis.The positive rates of blood tests were 3.13% and 9.34% in Group A and Group B respectively, the positive rates of stool examinations were 1.92% and 6.44% in Group A and Group B respectively (both P values0.05).Fangyouling has a good protective effect on S. japonicum infection.

Congenital heart disease (CHD) is the most common birth defect and is the most prevalent non-infectious cause of infant death. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic determinants for CHD in an overwhelming majority of patients remain unknown. In this study, the coding regions and splice junctions of the NKX2.6 gene, which encodes a homeodomain transcription factor crucial for cardiovascular development, were sequenced in 210 unrelated CHD patients. As a result, a novel heterozygous NKX2.6 mutation, p.K152Q, was identified in an index patient with ventricular septal defect (VSD). Genetic analysis of the proband’s available family members showed that the mutation cosegregated with VSD transmitted as an autosomal dominant trait with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across species. Due to unknown transcriptional targets of NKX2.6, the functional characteristics of the identified mutation at transcriptional activity were analyzed by using NKX2.5 as a surrogate. Alignment between human NKX2.6 and NKX2.5 proteins displayed that K152Q-mutant NKX2.6 was equivalent to K158Q-mutant NKX2.5, and introduction of K158Q into NKX2.5 significantly reduced its transcriptional activating function when compared with its wild-type counterpart. This study firstly links NKX2.6 loss-of-function mutation with increased susceptibility to isolated VSD, providing novel insight into the molecular mechanism underpinning VSD and contributing to the development of new preventive and therapeutic strategies for this common form of CHD.

To evaluate the effect of a new schistosomiasis control strategy based on the infection source control in four-lake regions of Hubei Province.The new strategy based on the infection source control included the safe water supply, feces harmless treatment, replacing cattle with machine, captive livestock, chemotherapy, Oncomelania hupensis snail control in susceptible areas, hardening ditches, etc, and the new control strategy was implemented for 7 years in 9 counties (cities or districts) of the four-lake regions. The schistosomiasis situations were investigated before and after the intervention of the new strategy.The coverage rates of feces harmless toilets (three format toilets), biogas digesters, and safe water supply were 42.00%, 23.16% and 93.76%, respectively. The number of ditch hardening was 1 960; the area of eliminating snails was 1378.42 hm2; the number of persons who received the health education was 3,524,818 accounting for 92.17% of the total population; the number of person-time of taking active protection measures was 516,636,963. The average annual decline rates of schistosome infection were 24.42% and 38.38% in residents and cattle, respectively. The endemic villages decreased by 4.77%, the villages with snails decreased by 7.05%, and the villages with snails accounted between 63.19% and 66.21% of the total endemic villages. The area with snails decreased by 90.35%, and the advance schistosomiasis patients decreased by 5.55%, and the fatality rate of advanced schistosomiasis patients decreased by 1.24%. No acute schistosomiasis patients occurred. Type One and Two endemic (heavy endemic) villages decreased to zero; Type Three endemic (moderate endemic) villages decreased by 10.22%; but Type Four endemic (mild endemic) villages increased by 66.38%; and Type Five endemic (no endemic for 5 years) villages decreased by 0.22%. The standards of schistosomiasis transmission controlled have achieved on schedule.The implementation of the new schistosomiasis control strategy based on the infection source control in four-lake regions of Hubei Province can effectively control schistosomiasis.

To identify the novel mutations in the GATA6 gene associated with tetralogy of Fallot (TOF).The clinical data and blood samples from 120 unrelated Han Chinese TOF patients and 200 unrelated ethnically matched healthy controls were collected. The coding exons and flanking splice junctions of GATA6 gene were amplified by polymerase chain reaction and sequenced by the technique of di-deoxynucleotide chain termination. The acquired sequences were aligned with those derived from GenBank by the aid of program BLAST to identify the sequence variations. The software ClustalW was applied for the conservation analysis of altered amino acids. The pathogenic probability for each sequence variation was predicted automatically by software MutationTaster.Three novel heterozygous missense GATA6 mutations were identified in 3 TOF patients. Specifically, the triplet substitutions of CTC for CCC at codon 73, CGC for AGC at codon 364 and GGC for GCC at codon 591, predicting the transitions of proline into leucine at amino acid residue 73 (p.P73L), serine into arginine at amino acid residue 364 (p.S364R) and alanine into glycine at amino acid residue 591 (p.A591G), were detected. None of three mutations was observed in 200 healthy controls. A cross-species alignment of GATA6 encoded protein sequences showed that the mutated amino acids were highly conserved evolutionarily and all 3 mutations were predicted to be pathogenic.Novel mutations are identified in the GATA6 gene associated with TOF. Such a finding may contribute to an early prophylaxis and therapy of TOF.

Tetraology of Fallot (TOF) is the most common form of cyanotic congenital heart disease and is a major cause of significant morbidity and mortality. Emerging evidence demonstrates that genetic risk factors are involved in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic defects responsible for TOF remain largely unclear. In the present study, the whole coding region of the GATA5 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 130 unrelated patients with TOF. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were analyzed using a luciferase reporter assay system. As a result, 2 novel heterozygous GATA5 mutations, p.R187G and p.H207R, were identified in 2 families with autosomal dominantly inherited TOF, respectively. The variations were absent in 400 control alleles and the altered amino acids were completely conserved evolutionarily. Functional analysis showed that the GATA5 mutants were associated with significantly decreased transcriptional activation compared with their wild-type counterpart. To our knowledge, this is the first report on the association of GATA5 loss-of-function mutations with TOF, suggesting potential implications for the early prophylaxis and allele-specific therapy of human TOF.

The ventriculoseptal defect (VSD) is the most common form of congenital heart disease and a leading noninfectious cause of infant mortality. Growing evidence demonstrates that genetic defects are associated with congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the molecular basis for VSD in an overwhelming majority of patients remains unknown. In this study, the whole coding region of GATA5, a gene encoding a zinc finger transcription factor crucial for normal cardiogenesis, was sequenced in 120 unrelated patients with VSD. The available relatives of the patient harboring the identified mutation and 200 unrelated individuals used as controls were subsequently genotyped. The causative potential of a sequence variation was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.L199V, was identified in a patient with VSD, which was absent in 400 control chromosomes. Genetic analysis of the mutation carrier’s available family members showed that the substitution co-segregated with VSD transmitted in an autosomal dominant pattern. The p.L199V variation was automatically predicted to be disease causing, and the functional analysis showed that the GATA5 p.L199V mutant protein was associated with significantly reduced transcriptional activation compared with its wild-type counterpart. To the best of the authors’ knowledge, this is the first report on the link of functionally compromised GATA5 to human VSD, suggesting potential implications for the early prophylaxis and personalized treatment of VSD.

Ventricular septal defect (VSD) is the most common form of congenital cardiovascular malformation and an important contributor to the substantially increased morbidity and mortality in infants. Emerging evidence indicates the genetic basis for the pathogenesis of congenital VSD in a significant proportion of patients. However, congenital VSD is a genetically heterogeneous disease and the genetic defects responsible for VSD in the overwhelming majority of cases remain unclear. In this study, the entire coding region of the GATA6 gene, which encodes a zinc-finger transcription factor crucial to normal cardiogenesis, was sequenced in 130 unrelated patients with congenital VSD. The available relatives of the index patient carrying the identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were subsequently genotyped. The functional characteristics of the mutant GATA6 were assessed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous missense GATA6 mutation, p.G220S, was identified in a proband with VSD. The variation was absent in 400 control chromosomes and the altered amino acid was highly conserved evolutionarily across species. Genetic analysis of the family members of the mutation carrier showed that the substitution co-segregated with VSD was inherited as an autosomal dominant trait. Functional analysis demonstrated that the p.G220S mutation of GATA6 was associated with significantly decreased transcriptional activity. The findings provide novel insight into the molecular mechanism involved in VSD, implying the potential clinical implications in the gene-specific prophylaxis and therapy of this common developmental abnormality in neonates.

Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and a major cause for the significantly increased morbidity and mortality among infants. Aggregating evidence indicates that genetic defects are involved in the pathogenesis of congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the genetic determinants for VSD in the majority of patients remain to be identified. In this study, the entire coding region of GATA4, a gene encoding a zinc finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 160 unrelated patients with VSD. The available relatives of the index patient harboring the identified mutation and 200 unrelated control individuals were subsequently genotyped. The disease-causing potential of a sequence alteration was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 variation, p.R43W, was identified in a proband with VSD, that was absent in control subjects. Genetic analysis of the family members of the variation carrier showed that the substitution co-segregated with VSD. The p.R43W variant was predicted to be a pathogenic mutation, and the functional analysis demonstrated that the GATA4 R43W mutant protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. The findings expand the mutational spectrum of GATA4 linked to VSD and provide more insight into the molecular mechanism of VSD.