Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains
Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains
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DOI：
10.1002/humu.1380010504
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发表时间：
1992-01-01
期刊：
影响因子：
3.9
通讯作者：
Francomano, Clair A.
中科院分区：
文献类型：
--
作者：
Dietz, Harry C.;Saraiva, Jorge M.;Francomano, Clair A.
马凡综合征是一种常染色体显性遗传性结缔组织疾病，主要累及眼、骨骼和心血管系统。15号染色体上编码纤维蛋白(FBN1)的基因，是细胞外微纤维的一种350 kDa的糖蛋白成分，即使不是所有病例，也是大多数病例的缺陷部位。互补DNA序列揭示了一个主要由表皮生长因子样重复序列组成的基因，每个重复序列包含六个可预测的间隔的半胱氨酸残基。到目前为止，已经报道了两个FBN1基因错义突变。在这里，我们描述了在马凡综合征患者中发现的三个新的FBN1基因错义突变。所有5个特征性错义突变都发生在FBN1基因的类似表皮生长因子的重复序列中。此外，5个序列中有4个涉及半胱氨酸残基的取代，3个取代了表皮生长因子样模体共有序列中的第三个半胱氨酸。这些数据表明，FBN1的EGF样结构域中的特定残基具有特殊的意义，当改变时，在Marfan表型的表达中发挥关键作用。
The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue with prominent involvement of the ocular, skeletal, and cardiovascular systems. The gene on chromosome 15 encoding fibrillin (FBN1), a 350-kDa glycoprotein component of the extracellular microfibril, is the site of defect in most, if not all cases. Complementary DNA sequence reveals a gene composed largely of epidermal growth factor-like repeats, each containing six predictably spaced cysteine residues. To date, two FBN1 gene missense mutations have been reported. Here we describe the identification of three new missense mutations in the FBN1 gene in patients with the Marfan syndrome. All of the 5 characterized missense mutations occur within the epidermal growth factor-like repeats of the FBN1 gene. In addition, 4 of 5 involve the substitution of cysteine residues and 3 of 5 substitute the third cysteine in the epidermal growth factor-like motif consensus sequence. These data suggest that defined residues within EGF-like domains of FBN1 have particular significance and, when altered, play a pivotal role in expression of the Marfan phenotype.