4 NOVEL FBN1 MUTATIONS - SIGNIFICANCE FOR MUTANT TRANSCRIPT LEVEL AND EGF-LIKE DOMAIN CALCIUM-BINDING IN THE PATHOGENESIS OF MARFAN-SYNDROME
4 NOVEL FBN1 MUTATIONS - SIGNIFICANCE FOR MUTANT TRANSCRIPT LEVEL AND EGF-LIKE DOMAIN CALCIUM-BINDING IN THE PATHOGENESIS OF MARFAN-SYNDROME
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DOI：
10.1006/geno.1993.1349
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发表时间：
1993-08-01
期刊：
影响因子：
4.4
通讯作者：
FRANCOMANO, CA
中科院分区：
文献类型：
--
作者：
DIETZ, HC;MCINTOSH, I;FRANCOMANO, CA
细胞外微纤维的糖蛋白成分--这种疾病的特点是显着的表型严重程度的家庭间和家庭内的变化。为了了解这一临床观察的分子基础，我们筛选了15号染色体上的FBN基因（FBN 1），包括新克隆的5′端编码序列，在一组具有广泛表现和临床严重程度的患者中进行致病性改变。迄今为止鉴定的所有错义突变，包括本文讨论的两种新突变，均与经典和中度至重度疾病相关，并且发生在对钙结合至表皮生长因子（EGF）样结构域具有推定意义的残基处。相比之下，两个新的突变，产生提前终止mRNA翻译的信号，并与突变等位基因转录物的量减少产生一系列的表型严重性。具有最低量的突变转录物的患者具有最温和的疾病。这些数据支持改变的钙结合EGF样结构域的马凡氏综合征的发病机制中的作用，并建议这种疾病的发病机制的显性负性机制。
Defects of fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, cause Marfan syndrome. This disorder is characterized by marked inter- and intrafamilial variation in phenotypic severity. To understand the molecular basis for this clinical observation, we have screened the fibrillin gene (FBN1) on chromosome 15, including the newly cloned 5′ coding sequence, for disease-producing alterations in a panel of patients with a wide range of manifestations and clinical severity. All the missense mutations identified to date, including two novel mutations discussed here, are associated with classic and moderate to severe disease and occur at residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. In contrast, two new mutations that create premature signals for termination of translation of mRNA and are associated with reduction in the amount of mutant allele transcript produce a range of phenotypic severity. The patient with the lowest amount of mutant transcript has the mildest disease. These data support a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggest a dominant negative mechanism for the pathogenesis of this disorder.