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
Date
07/21/2000Pubmed ID
10903346Pubmed Central ID
PMC314312DOI
10.1172/JCI9860Scopus ID
2-s2.0-0033912859 (requires institutional sign-in at Scopus site) 149 CitationsAbstract
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 SMESH terms used to index this publication - Major topics in bold
Cell CompartmentationDimerization
Heart Block
Heart Diseases
Heart Septal Defects, Atrial
Homeobox Protein Nkx-2.5
Homeodomain Proteins
Humans
Mutation
Mutation, Missense
Nuclear Proteins
Protein Binding
Protein Biosynthesis
RNA Splicing
Sequence Deletion
Transcription Factors
Transcriptional Activation
Xenopus Proteins
