RESUMO
Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.
Assuntos
Miosinas Cardíacas/genética , Comunicação Interatrial/genética , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Proteínas com Domínio T/genética , Adulto , Substituição de Aminoácidos , Animais , Miosinas Cardíacas/metabolismo , Embrião de Galinha , Criança , Pré-Escolar , Feminino , Ligação Genética , Comunicação Interatrial/embriologia , Humanos , Recém-Nascido , Masculino , Dados de Sequência Molecular , Cadeias Pesadas de Miosina/metabolismo , Linhagem , Proteínas com Domínio T/químicaRESUMO
A novel interaction between GATA4 and TBX5 could explain phenotypic similarities (atrial septal defects) between patients with mutations in GATA4 or TBX5. The cardiac transcription factor GATA4 has not previously been implicated in a human disorder but a recent paper by Garg et al. provides evidence of mutations in GATA4 that cause atrial septal defects. Mutations in TBX5 have already been shown to cause similar atrial septal defects in Holt-Oram syndrome.
Assuntos
Proteínas de Ligação a DNA/genética , Comunicação Interatrial/genética , Miocárdio/metabolismo , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Fator de Transcrição GATA4 , Coração/embriologia , Comunicação Interatrial/patologia , Humanos , Miocárdio/patologia , Ligação ProteicaRESUMO
TBX5 is a transcription factor which plays important roles in the development of the heart and upper limbs. Mutations in this gene produce the inherited disorder Holt-Oram syndrome. Here, we report a physical interaction between TBX5 and MEF2C leading to a synergistic activation of the alpha-cardiac myosin heavy chain (MYH6). Mutants of TBX5, TBX5G80R, and TBX5R279X that produce severe cardiac phenotypes impair the synergy. Using fluorescence resonance energy transfer, we demonstrate the interaction of TBX5 and MEF2C in living cells. We also show that they physically associate through their DNA-binding domains to form a complex on the MYH6 promoter. Morpholino-mediated knockdowns of Tbx5 and Mef2c in zebrafish suggest that the genetic interaction of these proteins is not only required for MYH6 expression but also essential for the early stages of heart development and survival. This is the first report of a functional interaction between a T-box protein and a MADS box factor that may be crucial in cardiomyocyte differentiation.
Assuntos
Miosinas Cardíacas/genética , Coração/crescimento & desenvolvimento , Fatores de Regulação Miogênica/metabolismo , Cadeias Pesadas de Miosina/genética , Proteínas com Domínio T/metabolismo , Animais , Linhagem Celular , Embrião não Mamífero , Humanos , Mutação de Sentido Incorreto , Fatores de Regulação Miogênica/fisiologia , Regiões Promotoras Genéticas , Ratos , Proteínas com Domínio T/genética , Proteínas com Domínio T/fisiologia , Transfecção , Peixe-ZebraRESUMO
The T-box gene family encodes a large family of transcription factors with more than 20 members identified in humans so far, and homologues in many other organisms. A number of human disorders have been linked to mutations in T-box genes, confirming their medical importance. They include Holt- Oram syndrome/TBX5, Ulnar-Mammary syndrome/TBX3, and more recently DiGeorge syndrome/TBX1, ACTH deficiency/TBX19 and cleft palate with ankyloglossia/TBX22. This review describes the key features of these disorders and the involvement of T-box genes in their phenotype.