Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome
Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome
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DOI：
10.1093/cvr/cvq178
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发表时间：
2010-10-01
影响因子：
10.8
通讯作者：
Postma, Alex V.
中科院分区：
文献类型：
--
作者：
Boogerd, Cornelis J. J.;Dooijes, Dennis;Postma, Alex V.
Holt-Oram综合征（HOS）是一种以上肢和心脏畸形为特征的心脏/手综合征。T-box转录因子5（TBX 5）的突变是这种综合征的基础，其中大多数导致过早停止。在这项研究中，我们对HOS患者中发现的五种（新型）错义TBX 5突变进行了功能分析，其中大多数患者患有严重的心脏畸形。突变蛋白的功能表征显示DNA结合能力的急剧丧失，以及与已知心脏相互作用伙伴NKX 2 -5和GATA 4的结合减少。这些相互作用的干扰导致功能丧失，如通过大鼠心脏衍生细胞中Nppa和FGF 10的活化降低所测量的，尽管具有可变的严重性。五种突变中有两种是特殊的：一种p.H220del与额外的心外缺陷相关，可能通过干扰其他T盒依赖性途径，另一种p.I106V仅导致肢体缺陷，这由其与心脏特异性相互作用伴侣的正常相互作用支持。我们的数据与TBX 5中这些新的错义突变导致功能性单倍不足并导致靶基因转录激活降低的假设一致，这可能是HOS发病机制的核心。
Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome, the majority of which lead to premature stops. In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations.Functional characterization of mutant proteins shows a dramatic loss of DNA-binding capacity, as well as diminished binding to known cardiac interaction partners NKX2-5 and GATA4. The disturbance of these interactions leads to a loss of function, as measured by the reduced activation of Nppa and FGF10 in rat heart derived cells, although with variable severity. Two out of the five mutations are peculiar: one, p.H220del, is associated with additional extra-cardiac defects, perhaps by interfering with other T-box dependant pathways, and another, p.I106V, leads to limb defects only, which is supported by its normal interaction with cardiac-specific interaction partners.Overall, our data are consistent with the hypothesis that these novel missense mutations in TBX5 lead to functional haploinsufficiency and result in a reduced transcriptional activation of target genes, which is likely central to the pathogenesis of HOS.