RT Journal Article
SR Electronic
T1 A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 230
OP 235
DO 10.1136/jmg.2009.069997
VO 47
IS 4
A1 Maximilian G Posch
A1 Michael Gramlich
A1 Margaret Sunde
A1 Katharina R Schmitt
A1 Stella H Y Lee
A1 Silke Richter
A1 Andrea Kersten
A1 Andreas Perrot
A1 Anna N Panek
A1 Iman H Al Khatib
A1 Georges Nemer
A1 André Mégarbané
A1 Rainer Dietz
A1 Brigitte Stiller
A1 Felix Berger
A1 Richard P Harvey
A1 Cemil Özcelik
YR 2010
UL http://jmg.bmj.com/content/47/4/230.abstract
AB Background Ostium 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.Methods The 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.Results We 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.Conclusions We 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.