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Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease.
Kasahara H
,
Lee B
,
Schott JJ
,
Benson DW
,
Seidman JG
,
Seidman CE
,
Izumo S
.
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CSX/NKX2.5 is an evolutionarily conserved homeodomain-containing (HD-containing) transcription factor that is essential for early cardiac development. Recently, ten different heterozygous CSX/NKX2.5 mutations were found in patients with congenital heart defects that are transmitted in an autosomal dominant fashion. To determine the consequence of these mutations, we analyzed nuclear localization, DNA binding, transcriptional activation, and dimerization of mutant CSX/NKX2.5 proteins. All mutant proteins were translated and located to the nucleus, except one splice-donor site mutant whose protein did not accumulate in the cell. All mutants that had truncation or missense mutations in the HD had severely reduced DNA binding activity and little or no transcriptional activation function. In contrast, mutants with intact HDs exhibit normal DNA binding to the monomeric binding site but had three- to ninefold reduction in DNA binding to the dimeric binding sites. HD missense mutations that preserved homodimerization ability inhibited the activation of atrial natriuretic factor by wild-type CSX/NKX2.5. Although our studies do not characterize the genotype-phenotype relationship of the ten human mutations, they identify specific abnormalities of CSX/NKX2.5 function essential for transactivation of target genes.
Azpiazu,
tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila.
1993, Pubmed
Azpiazu,
tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila.
1993,
Pubmed
Benson,
Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
1999,
Pubmed
,
Xenbase
Biben,
Homeodomain factor Nkx2-5 controls left/right asymmetric expression of bHLH gene eHand during murine heart development.
1997,
Pubmed
,
Xenbase
Bodmer,
The gene tinman is required for specification of the heart and visceral muscles in Drosophila.
1993,
Pubmed
Boncinelli,
Homeobox genes and disease.
1997,
Pubmed
Bruneau,
Cardiac expression of the ventricle-specific homeobox gene Irx4 is modulated by Nkx2-5 and dHand.
2000,
Pubmed
,
Xenbase
Chen,
Identification of novel DNA binding targets and regulatory domains of a murine tinman homeodomain factor, nkx-2.5.
1995,
Pubmed
,
Xenbase
Chen,
Activation of the cardiac alpha-actin promoter depends upon serum response factor, Tinman homologue, Nkx-2.5, and intact serum response elements.
1996,
Pubmed
,
Xenbase
Chen,
Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation.
1996,
Pubmed
,
Xenbase
Cleaver,
Overexpression of the tinman-related genes XNkx-2.5 and XNkx-2.3 in Xenopus embryos results in myocardial hyperplasia.
1996,
Pubmed
,
Xenbase
Damante,
Sequence-specific DNA recognition by the thyroid transcription factor-1 homeodomain.
1994,
Pubmed
Duquesnoy,
Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency.
1998,
Pubmed
Durocher,
The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors.
1997,
Pubmed
,
Xenbase
Fu,
Cardiac myogenesis: overexpression of XCsx2 or XMEF2A in whole Xenopus embryos induces the precocious expression of XMHCα gene.
1995,
Pubmed
,
Xenbase
Fu,
Vertebrate tinman homologues XNkx2-3 and XNkx2-5 are required for heart formation in a functionally redundant manner.
1998,
Pubmed
,
Xenbase
Gehring,
Homeodomain proteins.
1994,
Pubmed
Grow,
Tinman function is essential for vertebrate heart development: elimination of cardiac differentiation by dominant inhibitory mutants of the tinman-related genes, XNkx2-3 and XNkx2-5.
1998,
Pubmed
,
Xenbase
Gruschus,
Interactions of the vnd/NK-2 homeodomain with DNA by nuclear magnetic resonance spectroscopy: basis of binding specificity.
1997,
Pubmed
Harvey,
NK-2 homeobox genes and heart development.
1996,
Pubmed
Hu,
Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis.
1998,
Pubmed
Kasahara,
Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5.
1999,
Pubmed
,
Xenbase
Kasahara,
Cardiac and extracardiac expression of Csx/Nkx2.5 homeodomain protein.
1998,
Pubmed
Komuro,
Csx: a murine homeobox-containing gene specifically expressed in the developing heart.
1993,
Pubmed
Lee,
The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression.
1998,
Pubmed
Lints,
Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants.
1993,
Pubmed
Liu,
Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull.
1995,
Pubmed
Lyons,
Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.
1995,
Pubmed
Mead,
BMP-4-responsive regulation of dorsal-ventral patterning by the homeobox protein Mix.1.
1996,
Pubmed
,
Xenbase
Onichtchouk,
Requirement for Xvent-1 and Xvent-2 gene function in dorsoventral patterning of Xenopus mesoderm.
1998,
Pubmed
,
Xenbase
Schott,
Congenital heart disease caused by mutations in the transcription factor NKX2-5.
1998,
Pubmed
,
Xenbase
Sepulveda,
GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression.
1998,
Pubmed
,
Xenbase
Shiojima,
Context-dependent transcriptional cooperation mediated by cardiac transcription factors Csx/Nkx-2.5 and GATA-4.
1999,
Pubmed
Shiojima,
Molecular cloning and characterization of human cardiac homeobox gene CSX1.
1996,
Pubmed
Swain,
Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration.
1997,
Pubmed
Tanaka,
The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development.
1999,
Pubmed
,
Xenbase
Tomura,
Loss-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1beta mutations in familial type 2 diabetes mellitus.
1999,
Pubmed
Turbay,
Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx.
1996,
Pubmed
,
Xenbase
Zou,
CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway.
1997,
Pubmed
,
Xenbase
