A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm
A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm
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DOI：
10.1038/ejhg.2013.252
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发表时间：
2014-07-01
影响因子：
5.2
通讯作者：
Rosenberger, Georg
中科院分区：
文献类型：
--
作者：
Leutermann, Ruth;Sheikhzadeh, Sara;Rosenberger, Georg
许多常染色体显性遗传疾病，如马凡氏综合征（MFS）和Loeys-Dietz综合征（LDS），与胸主动脉瘤和夹层（TAAD）的易感性相关。在大多数情况下，编码转化生长因子-β（TGF-β）信号传导途径组分（如FBN 1、TGFBR 1、TGFBR 2和SMAD 3）的基因突变是该疾病的基础。最近，具有与MFS-LDS谱重叠的其他临床特征的TAAD的家族综合征形式已被描述为由编码TGF-β丝氨酸/苏氨酸激酶受体（TGFBR）的TGF-β 2配体的TGF-β 2中的杂合功能丧失突变引起。我们通过对88名具有Marfan样表型和/或TAAD的个体进行测序，分析了TGFB 2基因，这些个体在引起胸主动脉疾病的已知基因中没有突变。我们确定了新的杂合c.1165dupA突变TGFB 2的外显子7在一个家庭的三个成员，一个51岁的男性，他的兄弟和侄子与主动脉瘤，颈动脉迂曲和/或骨骼异常，以及颅面畸形。1-bp重复导致移码，导致在7个TGF-β 2-不相关氨基酸后具有提前终止密码子的稳定转录物（p.Ser389Lysfs*8）。由于产生的蛋白质是不太可能的功能，并考虑从文献中的数据，我们支持的概念，功能性单倍不足的TGF-β 2易患胸主动脉疾病。总之，TGFB 2是TAAD综合征患者中很少突变的基因，我们的TGFB 2突变阳性个体的临床特征符合LDS方案，而不是MFS相关疾病。
A number of autosomal dominantly inherited disorders, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), are associated with predisposition to thoracic aortic aneurysms and dissections (TAADs). In the majority of cases, mutations in genes encoding components of the transforming growth factor-beta (TGF-beta) signaling pathway, such as FBN1, TGFBR1, TGFBR2 and SMAD3, underlie the disease. Recently, a familial syndromic form of TAAD with other clinical features that overlap the MFS-LDS spectrum has been described to be caused by heterozygous loss-of-function mutations in TGFB2, encoding the TGF-beta 2 ligand of TGF-beta serine/threonine kinase receptors (TGFBRs). We analyzed the TGFB2 gene by sequencing in a cohort of 88 individuals with a Marfan-like phenotype and/or TAAD, who did not have mutations in known genes causing thoracic aortic disease. We identified the novel heterozygous c.1165dupA mutation in exon 7 of TGFB2 in three members of a family, a 51-year-old male, his brother and nephew with aortic aneurysms, cervical arterial tortuosity and/or skeletal abnormalities as well as craniofacial dysmorphisms. The 1-bp duplication causes a frameshift leading to a stable transcript with a premature stop codon after seven TGF-beta 2-unrelated amino acids (p.Ser389Lysfs*8). As the resulting protein is unlikely functional and by considering data from the literature, we support the notion that functional haploinsufficiency for TGF-beta 2 predisposes to thoracic aortic disease. Taken together, TGFB2 is a rarely mutated gene in patients with syndromic TAAD, and the clinical features of our TGFB2 mutation-positive individuals fit in the scheme of LDS, rather than MFS-related disorders.