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Different TBX5 interactions in heart and limb defined by Holt–Oram syndrome mutations
Open accessAbstract
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.
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Cited by
Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways
Benson, D. W., Silberbach, G. M., Kavanaugh-McHugh, A., Cottrill, C., Zhang, Y., Riggs, S., Smalls, O., Johnson, M. C., Watson, M. S., Seidman, J. G., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci8154 · Cited by 690
Self-citationPierpont, M. E., Brueckner, M., Chung, W. K., Garg, V., Lacro, R. V., McGuire, A. L., Mital, S., Priest, J. R., Pu, W. T., Roberts, A., et al. (2018) · Circulation · doi:10.1161/cir.0000000000000606 · Cited by 654
Self-citationIsl1Cre reveals a common Bmp pathway in heart and limb development
Yang, L., Cai, C.-L., Lin, L., Qyang, Y., Chung, C., Monteiro, R. M., Mummery, C. L., Fishman, G. I., Cogen, A., & Evans, S. (2006) · Development · doi:10.1242/dev.02322 · Cited by 267
The Spectrum of Mutations in TBX3: Genotype/Phenotype Relationship in Ulnar-Mammary Syndrome
Bamshad, M., Le, T., Watkins, W. S., Dixon, M. E., Kramer, B. E., Roeder, A. D., Carey, J. C., Root, S., Schinzel, A., Van Maldergem, L., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302417 · Cited by 175
Self-citationCharacterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome
Ghosh, T. K. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.18.1983 · Cited by 150
Metadata
- Authors
- Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Müller, C. W., Seidman, J. G., & Seidman, C. E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1999-03-16
- Volume
- 96
- Issue
- 6
- Pages
- 2919-2924
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2099883675
- Cited by
- 378
- References
- 0
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Open access
- green
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- Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Müller, C. W., Seidman, J. G., & Seidman, C. E. (1999). Different TBX5 interactions in heart and limb defined by Holt–Oram syndrome mutations. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.96.6.2919
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