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†, and
- Christine E. Seidman§§,¶¶
- *Cardiology Division, Department of Medicine and Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, The New York Hospital, New York, NY 10021; †Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; ‡Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; §Instituto de Genetica Medica, Hospital Italiano, Montevideo, Uruguay; ¶Laboratorio de Genetica Molecolare, Instituto Giannina Gaslini, Genoa, Italy; ‖Instituto Do Coraçao, Univercidade de Sao Paulo, Brazil 01060-970; **Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA 02115; ‡‡Ray and Hattie Anderson Center for the Study of Hereditary Cardiac Disease, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455; ††European Molecular Biology Laboratory, Grenoble Outstation, c/o ILL BP 156, 38042 Grenoble Cedex 9, France; §§Howard Hughes Medical Institute, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Communicated by Philip Leder, Harvard Medical School, Boston, MA (received for review October 21, 1998)
Abstract
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.
Footnotes
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↵ ¶¶ To whom reprint requests should be addressed at: Department of Genetics, Harvard Medical School, Alpert 533, 200 Longwood Avenue, Boston, MA 02115. e-mail: cseidman{at}rascal.med.harvard.edu.
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The sequence reported in this paper has been deposited in the GenBank database (accession nos. U80987 and U89353).
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A Commentary on this article begins on page 2577.
- ABBREVIATION:
- FISH,
- fluorescence in situ hybridization analysis
- Copyright © 1999, The National Academy of Sciences
