SMAD4 Mutation Segregating in a Family With Juvenile Polyposis, Aortopathy, and Mitral Valve Dysfunction
SMAD4 Mutation Segregating in a Family With Juvenile Polyposis, Aortopathy, and Mitral Valve Dysfunction
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DOI：
10.1002/ajmg.a.33968
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发表时间：
2011-05-01
影响因子：
2
通讯作者：
Potocki, Lorraine
中科院分区：
文献类型：
--
作者：
Andrabi, Sara;Bekheirnia, Mir Reza;Potocki, Lorraine
幼年息肉综合征(JPS)是由Smad4或BMPR1A杂合突变引起的。由于Smad4突变而患有JPS的个体更有可能出现遗传性出血性毛细血管扩张症(HHT)的迹象。HHT是由Smad4或其他调节转化生长因子-β信号转导的基因突变引起的。TGFb网络中的其他基因包括FBN1、TGFBR1和TGFBR2，它们的突变分别导致马凡综合征(MFS)或Loeys-Dietz综合征(LDS)。由于Smad4、FBN1和TGFBR1/2映射到基因组的不同区域，与这些基因突变相关的疾病预计不会在一个家庭中共分离。我们报告一例家族病史为大动脉病变、二尖瓣功能不全和JPS阳性的患者。Smad4的突变分析表明，该基因与该家族中的这些表型有关。虽然Smad4是TGFb网络中的几个基因之一，尽管之前的单一病例报告描述了HHT中的大血管动脉瘤，但这是JPS表现出的主动脉和二尖瓣疾病的第一个描述。这一观察结果表明，除了HHT，携带Smad4突变的个体还可能存在主动脉扩张和二尖瓣功能不全的风险。我们强调在分子检测之前全面回顾病史的重要性，特别是在无症状的患者中。(C)2011年Wiley-Liss，Inc.
Juvenile polyposis syndrome (JPS) is caused by heterozygous mutations in either SMAD4 or BMPR1A. Individuals with JPS due to mutations in SMAD4 are at greater risk to manifest signs of hereditary hemorrhagic telangiectasia (HHT). HHT is caused by either mutations in SMAD4 or other genes that modulate transforming growth factor-beta (TGF beta) signaling. Additional genes in the TGFb network include FBN1, TGFBR1, and TGFBR2, mutations of which cause either Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS), respectively. As SMAD4, FBN1, and TGFBR1/2 map to different regions of the genome, disorders associated with mutations in these genes are not expected to cosegregate in a family. We report an individual whose family history was positive for aortopathy, mitral valve dysfunction, and JPS. Mutation analysis of SMAD4 implicates this gene for these phenotypes in this family. Although SMAD4 is among several genes in the TGFb network, and although prior single case reports have described large vessel aneurysms in HHT, this is the first description of aortic and mitral disease presenting with JPS. This observation suggests that, in addition to HHT, individuals with SMAD4 mutations may be at risk for aortic dilation and mitral valve dysfunction. We emphasize the importance of comprehensive review of the medical history prior to molecular testing, especially in an asymptomatic patient. (C) 2011 Wiley-Liss, Inc.