Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations
Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations
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DOI：
10.1073/pnas.96.6.2919
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Seidman, CE
中科院分区：
文献类型：
--
作者：
Basson, CT;Huang, TS;Seidman, CE
为了更好地了解 TBX5（一种含有转录因子的 T 盒）在前肢和心脏发育中的作用，我们研究了由 10 种不同的 TBX5 突变引起的 Holt-Oram 综合征的临床特征。预计会产生无效等位基因的缺陷会导致四肢和心脏的严重异常。相比之下，错义突变产生了不同的表型：Gly80Arg 导致显着的心脏畸形，但仅导致轻微的骨骼异常； Arg237Gln 和 Arg237Trp 导致广泛的上肢畸形，但心脏异常不太明显。错义突变改变的氨基酸位于与 DNA 结合的相关 T 盒转录因子 Xbra 的三维结构上。残基 80 在与目标 DNA 大沟相互作用的 T 盒序列中高度保守；残基 237 位于 T 盒结构域中，选择性地结合 DNA 小沟。这些结构数据与每个错义突变产生的主要心脏或骨骼表型一起表明，TBX5 的器官特异性基因激活取决于与不同靶 DNA 序列的生物物理相互作用。
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.