A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation
A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation
复制标题
DOI：
10.1161/circresaha.107.168294
复制
发表时间：
2008-06-06
影响因子：
20.1
通讯作者：
Moorman, Antoon F. M.
中科院分区：
文献类型：
--
作者：
Postma, Alex V.;van de Meerakker, Judith B. A.;Moorman, Antoon F. M.
霍尔特-奥拉姆综合征（HOS）是一种心/手综合征，临床特征为上肢和心脏畸形。 T 盒转录因子 5 (TBX5) 突变是该综合征的基础。在这里，我们描述了一个大的非典型居屋家族，其中受影响的患者有轻度骨骼变形和阵发性心房颤动，但很少有先天性心脏病。 TBX5 的测序揭示了一种新的突变 c.373G > A，导致所有受调查受影响的家庭成员中出现错义突变 p.Gly125Arg，与该疾病共分离。我们证明，与野生型 TBX5 相比，该突变导致正常的 Nkx2-5 相互作用，正确靶向细胞核，显着增强 DNA 结合和 Nppa(Anf) 和 Cx40 启动子的激活，并显着增强 Nppa、Cx40、Kcnj2 和 Tbx3 的表达。因此，与之前发表的 HOS 突变相反，p.G125R TBX5 突变导致功能获得。我们推测功能获得机制是轻度骨骼表型和阵发性心房颤动的基础，并表明 TBX5 在（阵发性）心房颤动的发展中可能发挥作用，其基础是通过 TBX5 直接刺激靶基因或通过 TBX5 刺激的 TBX3 间接刺激靶基因。这些发现可能需要重新审视迄今为止未归类为 HOS 或非典型但表现为阵发性心房颤动的家庭和个人的表型，因为这些可能是额外 TBX5 功能获得性突变的结果。
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. Here, we describe a large atypical HOS family in which affected patients have mild skeletal deformations and paroxysmal atrial fibrillation, but few have congenital heart disease. Sequencing of TBX5 revealed a novel mutation, c.373G > A, resulting in the missense mutation p.Gly125Arg, in all investigated affected family members, cosegregating with the disease. We demonstrate that the mutation results in normal Nkx2-5 interaction, is correctly targeted to the nucleus, has significantly enhanced DNA binding and activation of both the Nppa(Anf) and Cx40 promoter, and significantly augments expression of Nppa, Cx40, Kcnj2, and Tbx3 in comparison with wild-type TBX5. Thus, contrary to previously published HOS mutations, the p.G125R TBX5 mutation results in a gain-of-function. We speculate that the gain-of-function mechanism underlies the mild skeletal phenotype and paroxysmal atrial fibrillation and suggest a possible role of TBX5 in the development of ( paroxysmal) atrial fibrillation based on a gain-of-function either through a direct stimulation of target genes via TBX5 or indirectly via TBX5 stimulated TBX3. These findings may warrant a renewed look at the phenotypes of families and individuals hitherto not classified as HOS or as atypical but presenting with paroxysmal atrial fibrillation, because these may possibly be the result of additional TBX5 gain-of-function mutations.