Congenital Heart Disease Caused by Mutations in the Transcription Factor
            <i>NKX2-5</i>

Schott, Jean‐Jacques; Benson, D. Woodrow; Basson, Craig T.; Pease, W E; Silberbach, G. Michael; Moak, Jeffrey P.; Maron, Barry J.; Seidman, Christine E.

doi:10.1126/science.281.5373.108

Cited by 1,188 publications

(810 citation statements)

References 14 publications

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“…Because tbx5 encodes a transcription factor, mutations of the gene are presumed to disrupt development by altering the transcriptional function of Tbx5 protein, thereby affecting target gene expression. Strikingly, Tbx5 cooperatively regulates cardiac transcription with Nkx2.5 and Gata4, two proteins encoded by genes with mutations associated with atrial septal defects similar to what is observed in HOS (Basson et al, 1997;Li et al, 1997;Schott et al, 1998;Garg et al, 2003;Linhares et al, 2004;Plageman and Yutzey, 2004). To understand how mutations in TBX5 cause developmental defects, it is important to know what genes Tbx5 regulates during embryogenesis.…”

Section: Introductionmentioning

confidence: 89%

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Plageman

Yutzey

2006

Developmental Dynamics

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Tbx5 is a member of the T-box family of transcription factors and is associated with Holt-Oram syndrome (HOS), a congenital disorder characterized by heart and limb defects. Although implicated in several processes during development, only a few genes regulated by Tbx5 have been reported. To identify candidate genes regulated by Tbx5 during heart development, a microarray approach was used. A cardiacderived mouse cell line (1H) was infected with adenoviruses expressing Tbx5 or ␤-galactosidase and RNA was isolated for analysis using an Affymetrix gene chip representing over 39,000 transcripts. Real-time reverse transcriptase-polymerase chain reaction confirmed Tbx5 induction of a subset of the genes, including nppa, photoreceptor cadherin, brain creatine kinase, hairy/enhancer-of-split related 2, and gelsolin. In situ hybridization analysis indicated overlapping expression of these genes with tbx5 in the embryonic mouse heart. In addition, the effect of HOS-associated mutations on the ability of Tbx5 to induce target gene expression was evaluated. Together, these data identify several genes induced by Tbx5 that are potentially important during cardiac development. These genes represent new candidate gene targets of Tbx5 that may be related to congenital heart malformations associated with HOS. Developmental Dynamics 235:2868 -2880, 2006.

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Section: Introductionmentioning

confidence: 89%

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Plageman

Yutzey

2006

Developmental Dynamics

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“…2 Recent studies have identified a series of genes that contribute to inherited and sporadic CHD, and most of these genes encode cardiac transcription factors such as Nkx2.5, TBX5 and GATA4. [3][4][5][6] GATA family members (GATA1-6) contain two zinc-finger domains that bind to a consensus site, (A/T) GATA (A/G), and mediate interactions with diverse factors. 7 GATA4, 5 and 6 are expressed early in the heart tissue and endodermal derivatives.…”

Section: Introductionmentioning

confidence: 99%

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

et al. 2010

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GATA6 is a member of the GATA family of transcription factors, and its expression and functions overlap with those of GATA4 during heart development. Mutations in GATA4 have been related to human congenital heart diseases (CHDs) in several studies, whereas mutations in GATA6 have only recently been reported in patients with persistent truncus arteriosus. Animal experiments have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, thereby highlighting the potential involvement of GATA6 defects in the pathogenesis of CHDs. Here, we screened the GATA6 in 270 individuals with sporadic CHDs by direct sequencing. After identification of the mutation, a luciferase reporter assay and real-time quantitative polymerase chain reaction were performed to detect functional changes in the mutant transcription factor. The same heterozygous missense mutation (Ser184Asn) was identified in three patients, including one with tetralogy of Fallot and two with atrial septal defects. This mutation was not found in 500 unrelated ethnically matched healthy subjects. Direct sequencing of this region in the parents of these three patients revealed the same mutation in one of the parents for each patient, and one of the parent carriers presented with a bicuspid aortic valve. Biological analysis revealed clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro. All these data suggest that GATA6 Ser184Asn is a novel mutation associated with CHDs and has an important role in disease pathogenesis.

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“…Most CHD occur sporadic, but in recent years an increasing number of familial cases with various types of CHD have been reported. [2][3][4] Although mutations in several genes have been identified in a small subset of patients and families with CHD, eg, NKX2.5, 2 GATA4 3 and NOTCH1, 5 the mechanisms underlying human cardiogenesis and CHDs remain largely unknown. Some CHD patients and families also display cardiac arrhythmias, which can occur due to the anatomical defect itself or sometimes due to surgical interventions.…”

Section: Introductionmentioning

confidence: 99%

“…6 Moreover, in some patients arrhythmias are the direct consequence of the underlying genetic defect, in absence of any structural defect. 2,7 Ectopic atrial rhythms originate when a focus outside the sinus node takes over the pacemaker function. Consequently, the direction of atrial activation may be altered, which can be seen as an abnormal P-wave axis on the electrocardiogram (ECG).…”

Section: Introductionmentioning

confidence: 99%

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

et al. 2011

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Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

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Congenital Heart Disease Caused by Mutations in the Transcription Factor NKX2-5

Cited by 1,188 publications

References 14 publications

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

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