A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function.
A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function.
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DOI：
10.1002/mgg3.234
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发表时间：
2016-09
影响因子：
2
通讯作者：
Krane, Markus
中科院分区：
文献类型：
--
作者：
Dressen, Martina;Lahm, Harald;Lahm, Armin;Wolf, Klaudia;Doppler, Stefanie;Deutsch, Marcus-Andre;Cleuziou, Julie;von Ohain, Jelena Pabst;Schoen, Patric;Ewert, Peter;Malcic, Ivan;Lange, Ruediger;Krane, Markus
关键词：
Holt-Oram综合征（HOS）是一种常染色体显性遗传病，发病率为10万分之一。它的定义是上肢异常和严重程度不同的先天性心脏缺陷。我们描述了一个戏剧性的表现型男性，15个月大的病人正在调查严格的诊断标准的HOS。遗传分析揭示了迄今未发表的TBX5突变，该突变在父母健康的患者中从头发生。TBX5属于T - box转录因子大家族，在形态发生和细胞类型规范中起重要作用。位于DNA结合域920位（C→A）的突变导致85位（脯氨酸→苏氨酸）的氨基酸变化。蛋白质结构的三维分析预测了相应肽键的顺式到反式变化，从而可能引发蛋白质的主要构象和功能改变。在荧光素酶检测中，p.p pro85thr突变显著降低了NPPA启动子的激活（97%），与野生型TBX5蛋白相比，未能在HEK 293细胞中诱导NPPA表达。突变不会干扰蛋白质的核定位。这些结果表明，p.Pro85Thr突变的显著功能改变导致了患者的独特表型。
The Holt–Oram syndrome (HOS) is an autosomal dominant disorder affecting 1/100.000 live births. It is defined by upper limb anomalies and congenital heart defects with variable severity. We describe a dramatic phenotype of a male, 15‐month‐old patient being investigated for strict diagnostic criteria of HOS. Genetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents. TBX5 belongs to the large family of T‐box transcription factors playing major roles in morphogenesis and cell‐type specification. The mutation located in the DNA‐binding domain at position 920 (C→A) leads to an amino acid change at position 85 (proline → threonine). Three‐dimensional analysis of the protein structure predicted a cis to trans change in the respective peptide bond, thereby probably provoking major conformational and functional alterations of the protein. The p.Pro85Thr mutation showed a dramatically reduced activation (97%) of the NPPA promoter in luciferase assays and failed to induce NPPA expression in HEK 293 cells compared to wild‐type TBX5 protein. The mutation did not interfere with the nuclear localization of the protein. These results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient.
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影响因子：
4
作者：
Fan, C;Duhagon, M A;Wang, Q
通讯作者：
Wang, Q
影响因子：
10.8
作者：
Boogerd, Cornelis J. J.;Dooijes, Dennis;Postma, Alex V.
通讯作者：
Postma, Alex V.
影响因子：
2
作者：
Baban, Anwar;Postma, Alex Vincent;Pongiglione, Giacomo
通讯作者：
Pongiglione, Giacomo
影响因子：
20.1
作者：
Postma, Alex V.;van de Meerakker, Judith B. A.;Moorman, Antoon F. M.
通讯作者：
Moorman, Antoon F. M.
影响因子：
158.5
作者：
BASSON, CT;COWLEY, GS;SEIDMAN, CE
通讯作者：
SEIDMAN, CE