Heterozygous TGFBR2 mutations in Marfan syndrome
Heterozygous TGFBR2 mutations in Marfan syndrome
复制标题
DOI：
10.1038/ng1392
复制
发表时间：
2004-08-01
期刊：
影响因子：
30.8
通讯作者：
Matsumoto, N
中科院分区：
文献类型：
--
作者：
Mizuguchi, T;Collod-Beroud, G;Matsumoto, N
马凡氏综合征是一种细胞外基质疾病，主要表现在眼睛、骨骼和心血管系统，与15q21.1处的基因编码蛋白（FBN 1）缺陷相关（参考文献1）。第二种类型的疾病（马凡综合征2型; OMIM 154705）与一个法国大家族（家族MS 1）中位于3 p25-p24.2的第二个基因座MFS 2相关（2）。在一名患有马凡氏综合征的日本个体中，3p24.1染色体断裂点破坏了编码TGF-β受体2（TGFBR 2）的基因，这使我们认为TGFBR 2是与马凡氏综合征在MSF 2位点相关的潜在基因。TGFBR 2的1524 G--> A突变（导致同义氨基酸替换Q508 Q）导致异常剪接并与MS 1家族中的MFS 2分离。我们在四个无关的先证者中发现了另外三个错义突变，导致细胞外基质形成中TGF-β信号传导活性的功能丧失。这些结果表明，TGFBR 2（一种与几种恶性肿瘤有关的假定肿瘤抑制基因）的杂合突变也与遗传性结缔组织疾病有关。
Marfan syndrome is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton and cardiovascular systems associated with defects in the gene encoding fibrillin (FBN1) at 15q21.1 (ref. 1). A second type of the disorder ( Marfan syndrome type 2; OMIM 154705) is associated with a second locus, MFS2, at 3p25-p24.2 in a large French family (family MS1)(2). Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor 2 (TGFBR2) in a Japanese individual with Marfan syndrome led us to consider TGFBR2 as the gene underlying association with Marfan syndrome at the MSF2 locus. The mutation 1524G --> A in TGFBR2 ( causing the synonymous amino acid substitution Q508Q) resulted in abnormal splicing and segregated with MFS2 in family MS1. We identified three other missense mutations in four unrelated probands, which led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor-suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders.