Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis
Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis
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DOI：
10.1038/ng.744
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发表时间：
2011-02-01
期刊：
影响因子：
30.8
通讯作者：
Bertoli-Avella, Aida M.
中科院分区：
文献类型：
--
作者：
van de laar, Ingrid M. B. H.;Oldenburg, Rogier A.;Bertoli-Avella, Aida M.
胸主动脉瘤和夹层是结缔组织疾病的主要特征，如马凡综合征和Loeys-Dietz综合征。我们描述了一种新的综合征，表现为动脉瘤、夹层和整个动脉树的弯曲，并伴有轻微的头面部特征以及骨骼和皮肤异常。与其他动脉瘤综合征不同的是，这些患者中的大多数都表现为早发性骨关节炎。我们将遗传位点定位在染色体15q22.2-24.2上，表明该病是由SMAD3突变引起的。该基因编码转化生长因子-β途径的一个成员，该途径是转化生长因子-β信号传递所必需的(1-3)。Smad3基因突变导致包括Smad3在内的转化生长因子-β途径中的几个关键角色的主动脉表达增加。分子诊断将使早期和可靠地识别有重大心血管并发症风险的病例和亲属。我们的研究结果表明，转化生长因子-β途径是主动脉瘤和骨关节炎新疗法开发的主要药理靶点。
Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-beta pathway that is essential for TGF-beta signal transmission(1-3). SMAD3 mutations lead to increased aortic expression of several key players in the TGF-beta pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-beta pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.