| Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. | |
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MedLine Citation:
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PMID: 20519243 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIMS: Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome, the majority of which lead to premature stops. In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations. METHODS AND RESULTS: Functional characterization of mutant proteins shows a dramatic loss of DNA-binding capacity, as well as diminished binding to known cardiac interaction partners NKX2-5 and GATA4. The disturbance of these interactions leads to a loss of function, as measured by the reduced activation of Nppa and FGF10 in rat heart derived cells, although with variable severity. Two out of the five mutations are peculiar: one, p.H220del, is associated with additional extra-cardiac defects, perhaps by interfering with other T-box dependant pathways, and another, p.I106V, leads to limb defects only, which is supported by its normal interaction with cardiac-specific interaction partners. CONCLUSION: Overall, our data are consistent with the hypothesis that these novel missense mutations in TBX5 lead to functional haploinsufficiency and result in a reduced transcriptional activation of target genes, which is likely central to the pathogenesis of HOS. |
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Authors:
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Cornelis J J Boogerd; Dennis Dooijes; Aho Ilgun; Inge B Mathijssen; Roel Hordijk; Ingrid M B H van de Laar; Patrick Rump; Hermine E Veenstra-Knol; Antoon F M Moorman; Phil Barnett; Alex V Postma |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-02 |
Journal Detail:
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Title: Cardiovascular research Volume: 88 ISSN: 1755-3245 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-10 Completed Date: 2011-01-11 Revised Date: 2011-01-12 |
Medline Journal Info:
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Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: England |
Other Details:
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Languages: eng Pagination: 130-9 Citation Subset: IM |
Affiliation:
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Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Abnormalities, Multiple
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genetics,
metabolism Amino Acid Sequence Animals Atrial Natriuretic Factor / genetics Binding Sites Case-Control Studies Cell Line DNA Mutational Analysis Electrophoretic Mobility Shift Assay Fibroblast Growth Factor 10 / genetics GATA4 Transcription Factor / genetics, metabolism Genotype Heart Defects, Congenital / genetics*, metabolism Heart Septal Defects, Atrial / genetics, metabolism Homeodomain Proteins / genetics, metabolism Humans Immunoprecipitation Lower Extremity Deformities, Congenital / genetics, metabolism Models, Molecular Molecular Sequence Data Mutation, Missense* Phenotype Promoter Regions, Genetic Protein Binding Protein Conformation Rats Recombinant Fusion Proteins / metabolism T-Box Domain Proteins / chemistry, genetics*, metabolism Transfection Upper Extremity Deformities, Congenital / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Fibroblast Growth Factor 10; 0/GATA4 Transcription Factor; 0/Homeodomain Proteins; 0/Recombinant Fusion Proteins; 0/T-Box Domain Proteins; 0/T-box transcription factor 5; 85637-73-6/Atrial Natriuretic Factor |
| Comments/Corrections | |
Erratum In:
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Cardiovasc Res. 2011 Jan 1;89(1):253 Note: Mathijssen, Inge B [added] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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