A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects.

Content Provider	Europe PMC
Author	Posch, Maximilian G Gramlich, Michael Sunde, Margaret Schmitt, Katharina R Lee, Stella H Y Richter, Silke Kersten, Andrea Perrot, Andreas Panek, Anna N Al Khatib, Iman H Nemer, Georges Mégarbané, André Dietz, Rainer Stiller, Brigitte Berger, Felix Harvey, Richard P Özcelik, Cemil
Copyright Year	2010
Abstract	BackgroundOstium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations.MethodsThe coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel mutation were investigated by surface plasmon resonance, CD spectropolarymetry, fluorescence spectrophotometry, luciferase assay and chromatin immunoprecipitation.ResultsWe found a novel mutation in a highly conserved residue in the T-box DNA binding domain (I121M) segregating with CHD in a three generation kindred. Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects. Interestingly, tertiary hydrophobic interactions within the mutant TBX20 T-box were significantly altered leading to a more dynamic structure of the protein. Moreover, Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5. Occupancy of DNA binding sites on target genes was also increased.ConclusionsWe suggest that TBX20-I121M adopts a more fluid tertiary structure leading to enhanced interactions with cofactors and more stable transcriptional complexes on target DNA sequences. Our data, combined with that of others, suggest that human ASDII may be related to loss-of-function as well as gain-of-function TBX20 mutations.
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ISSN	00222593
Journal	Journal of Medical Genetics [J Med Genet]
Volume Number	47
DOI	10.1136/jmg.2009.069997
PubMed Central reference number	PMC2981023
Issue Number	4
PubMed reference number	19762328
e-ISSN	14686244
Language	English
Publisher	BMJ Group
Publisher Date	2009-09-16
Publisher Place	BMA House, Tavistock Square, London, WC1H 9JR
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode. © 2010, Published by the BMJ Publishing Group Limited For permission to use, (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Subject Keyword	Congenital heart defect atrial septal defect patent foramen ovale TBX20 cardiovascular medicine clinical genetics molecular genetics
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)