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Transcription factor cascades in congenital heart malformation

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Abstract

New observations reveal that GATA-4 mutations are one underlying cause of human cardiac septal defects. Recent data has shed light on a potential multiprotein complex formed by GATA-4, TBX5 and NKX2.5, which might act synergistically to transcriptionally regulate other cardiac specific genes. The addition of GATA-4 to the list of genes involved in human congenital heart malformation prompts consideration of how modern molecular genetic advances should be applied to clinical care.

Section snippets

GATA-4: a crucial transcription factor in mammalian cardiogenesis

Human cytogenetic studies, as well as gene expression and transgenic studies in animals, have justified a role for GATA-4, a member of the conserved GATA zinc-finger transcription factor family, during cardiogenesis. In humans, loss of the chromosome 8p segment containing GATA-4 is associated with CHMs [14]. During murine cardiogenesis, Gata-4 is expressed in the atrial and ventricular myocardia, endocardium, endocardial cushions and outflow tract [15]. Mice with complete loss of Gata-4 die in

Human phenotypes and transcription factor genotypes

Regardless of the ambiguity of the GATA-4–TBX5 interaction, addition of GATA-4 to an NKX2.5 and TBX5 co-dependent set of embryonic cascades that regulate cardiac septation is important. Crucial to the placement of GATA-4 within this network is an appreciation of the similarities and dissimilarities of clinical phenotypes associated with their human mutations. Developmental mechanisms and expression patterns of certain genes are not always conserved between humans and animal models [23].

Should consideration of GATA-4 mutations be incorporated into clinical care?

Because GATA-4 mutations have not previously been demonstrated to cause human disease, these new findings prompt consideration of their potential clinical application. Should GATA-4 genotyping be considered for inclusion in the clinical care of individuals with all CHMs or just those with septation defects? Broad-based population and individual patient screening for GATA-4 mutations is probably premature without a better understanding of the prevalence, penetrance and genotype–phenotype

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