Holt-Oram Syndrome With Intermediate Atrioventricular Canal Defect, and Aortic Coarctation: Functional Characterization of a De Novo TBX5 Mutation
Holt-Oram Syndrome With Intermediate Atrioventricular Canal Defect, and Aortic Coarctation: Functional Characterization of a De Novo TBX5 Mutation
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DOI：
10.1002/ajmg.a.36459
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发表时间：
2014-06-01
影响因子：
2
通讯作者：
Albanese, Sonia
中科院分区：
文献类型：
--
作者：
Baban, Anwar;Pitto, Letizia;Albanese, Sonia
霍尔特-奥拉姆综合征 (HOS) 是一种罕见的常染色体显性遗传疾病，其特征是上肢缺陷和先天性心脏缺陷 (CHD)，这些缺陷通常是简单的间隔和传导缺陷，复杂的 CHD 较少见。我们报道了一名 9 岁男孩，其具有 HOS 的临床和放射学特征，包括双侧不对称拇指发育不良、广泛性短指、由于尺骨骨联结导致的旋后受限、肩部倾斜以及伴有主动脉缩窄的中间房室管缺损 (AVCD)。在 TBX5 基因中发现了先前描述的从头突变 (Arg279ter)。由于非典型先心病，对该突变进行了分子表征。为了研究TBX5的突变转录本是否能够逃脱转录后监视机制并产生截短的TBX5蛋白，我们分析了HOS和WT心脏组织中的TBX5转录本和蛋白质模式。我们的结果表明突变体 TBX5 转录物被细胞监视机制清除。该数据为以下假设提供了一些支持：显性失活突变会严重损害 WT 等位基因，可能太危险而无法维持。文献表明，HOS 在与 AVCD 相关的综合征中相对常见。 (c) 2014 年 Wiley 期刊公司。
Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by upper limb defects and congenital heart defects (CHD), which are often simple septal and conduction defects, less frequently complex CHDs. We report on a 9 year-old boy with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited supination due to radioulnar synostosis, and sloping shoulders, and intermediate atrioventricular canal defect (AVCD) with aortic coarctation. A de novo, previously described mutation, (Arg279ter) was identified in the TBX5 gene. Molecular characterization of this mutation was carried out due to the atypical CHD. In order to investigate whether the mutated transcript of TBX5 was able to escape the post-transcriptional surveillance mechanism and to produce a truncated TBX5 protein, we analyzed the TBX5 transcript, and protein pattern in HOS, and WT cardiac tissues. Our results demonstrate that the mutant TBX5 transcript is cleared by the cellular mechanism of surveillance. This data provides some support for the hypothesis that a dominant negative mutation, which strongly impairs the WT allele, might be too hazardous to be maintained. The literature suggests that HOS is relatively common among syndromes associated with AVCD. (c) 2014 Wiley Periodicals, Inc.