Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations

Craig T. Basson, Taosheng Huang, Robert C. Lin, David R. Bachinsky, Stanislawa Weremowicz, Alicia Vaglio, Rina Bruzzone, Roberto Quadrelli, Margherita Lerone, Giovanni Romeo, Margherita Silengo, Alexandre Pereira, Jose Krieger, Sonia F. Mesquita, Mitsuhiro Kamisago, Cynthia C. Morton, Mary Ella M. Pierpont, Chistoph W. Müller, J. G. Seidman, Christine E. Seidman

Research output: Contribution to journalArticlepeer-review

294 Scopus citations


To better understand the role of TBX5, a T-box containing transcription factor in forelimb and heart development, we have studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities both in limb and heart. In contrast, missense mutations produced distinct phenotypes: Gly80Arg caused significant cardiac malformations but only minor skeletal abnormalities; and Arg237Gln and Arg237Trp caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the three-dimensional structure of a related T-box transcription factor, Xbra, bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggest that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences.

Original languageEnglish (US)
Pages (from-to)2919-2924
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Mar 16 1999


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