Medical College of Wisconsin
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Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease. J Clin Invest 2000 Jul;106(2):299-308 PMID: 10903346 PMCID: PMC314312

Abstract

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.

Author List

Kasahara H, Lee B, Schott JJ, Benson DW, Seidman JG, Seidman CE, Izumo S

Author

Dudley Woodrow Benson Jr MD, PhD Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Compartmentation
Dimerization
Heart Block
Heart Diseases
Heart Septal Defects, Atrial
Homeodomain Proteins
Humans
Mutation
Mutation, Missense
Nuclear Proteins
Protein Binding
Protein Biosynthesis
RNA Splicing
Sequence Deletion
Transcription Factors
Xenopus Proteins



View this publication's entry at the Pubmed website PMID: 10903346
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