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ABSTRACT Tetralogy of Fallot ( TOF) represents the most common form of cyanotic congenital heart disease and accounts for significant morbidity and mortality in humans. Emerging evidence has implicated genetic defects in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic basis for TOF in most patients remains unclear. In this study, the GATA4 gene were sequenced in 52 probands with familial TOF, and three novel heterozygous mutations, including A9P and L51V both located in the putative first transactivational domain and N285S in the C-terminal zinc finger, were identified in three probands, respectively. Genetic analysis of the pedigrees demonstrated that in each family the mutation cosegregated with TOF with complete penetrance. The missense mutations were absent in 800 control chromosomes and the altered amino acids were highly conserved evolutionarily. Functional analysis showed that the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5. To our knowledge, this report associates GATA4 loss-of-function mutations with familial TOF for the first time, providing novel insight into the molecular mechanism involved in TOF and suggesting potential implications for the early prophylaxis and allele-specific therapy of TOF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As the most common form of birth defect in humans, congenital heart disease (CHD) is associated with substantial morbidity and mortality in both children and adults. Increasing evidence demonstrates that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is of great heterogeneity, and in an overwhelming majority of cases, the genetic determinants underpinning CHD remain elusive. In the present investigation, the coding exons and flanking introns of the CASZ1 gene, which codes for a zinc finger transcription factor essential for the cardiovascular morphogenesis, were sequenced in 172 unrelated patients with CHD. As a result, a novel heterozygous CASZ1 mutation, p.L38P, was identified in an index patient with congenital ventricular septal defect (VSD). Genetic scanning of the mutation carrier's available family members revealed that the mutation was present in all affected patients but absent in unaffected individuals. Analysis of the proband's pedigree showed that the mutation co-segregated with VSD, which was transmitted as an autosomal dominant trait with complete penetrance. The missense mutation, which altered the amino acid that was highly conserved evolutionarily, was absent in 200 unrelated, ethnically-matched healthy subjects used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant CASZ1 had significantly reduced transcriptional activity as compared with its wild-type counterpart. To the best of our knowledge, the current study firstly identifies CASZ1 as a new gene predisposing to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD and a potential therapeutic target for CASZ1-associated CHD, suggesting potential implications for personalized prophylaxis and therapy of CHD. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most prevalent developmental abnormality in humans and is the most common non-infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous, and the genetic determinants underpinning CHD in most patients remain unknown. In this study, the whole coding region of the PITX2 gene (isoform c) was sequenced in 185 unrelated patients with CHD. The available relatives of a mutation carrier and 300 unrelated healthy individuals used as controls were also genotyped for PITX2 . The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous PITX2 mutation, p.Q102L, was identified in a patient with tetralogy of Fallot (TOF). Genetic analysis of the index patient's pedigree showed that the mutation co-segregated with TOF. The mutation was absent in 600 reference chromosomes. Biochemical analysis revealed that the Q102L-mutant PITX2 is associated with significantly reduced transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation markedly decreased the synergistic activation between PITX2 and NKX2-5. This study firstly associates PITX2 loss-of-function mutation with increased susceptibility to TOF, providing novel insight into the molecular mechanism of CHD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel GATA4 mutation, p.C271S, was identified in a large family with DCM. [•] The mutation co-segregated with DCM in the family and was absent in 200 controls. [•] The altered amino acid was completely conserved evolutionarily among species. [•] The mutant was associated with significantly decreased transcriptional activity. [•] The mutant remarkably reduced the synergistic activation between GATA4 and NKX2-5. [ABSTRACT FROM AUTHOR]

As two members of the basic helix-loop-helix family of transcription factors, HAND1 and HAND2 are both required for the embryonic cardiogenesis and postnatal ventricular structural remodeling. Recently a HAND1 mutation has been reported to cause dilated cardiomyopathy (DCM). However, the association of a HAND2 mutation with DCM is still to be ascertained. In this research, t he coding regions and splicing junction sites of the HAND2 gene were sequenced in 206 unrelated patients affected with idiopathic DCM, and a new heterozygous HAND2 mutation, NM_021973.2: c.199G > T; p.(Glu67*), was discovered in an index patient with DCM. The nonsense mutation was absent in 300 unrelated, ethnically-matched healthy persons. Genetic scan of the mutation carrier's family members revealed that the genetic mutation co-segregated with DCM, which was transmitted in an autosomal dominant fashion, with complete penetrance. Functional deciphers unveiled that the mutant HAND2 protein had no transcriptional activity. In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM. These research findings firstly suggest HAND2 as a novel gene predisposing to DCM in humans, which adds novel insight to the molecular pathogenesis of DCM, implying potential implications in the design of personized preventive and therapeutic strategies against DCM. [ABSTRACT FROM AUTHOR]