Dietz H C, McIntosh I, Sakai L Y, Corson G M, Chalberg S C, Pyeritz R E, Francomano C A
Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Genomics. 1993 Aug;17(2):468-75. doi: 10.1006/geno.1993.1349.
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.
原纤维蛋白（FBN1）是细胞外微原纤维的一种糖蛋白成分，其缺陷会导致马凡综合征。这种疾病的特征是表型严重程度在家族间和家族内存在显著差异。为了理解这一临床观察结果的分子基础，我们在15号染色体上筛选了原纤维蛋白基因（FBN1），包括新克隆的5'编码序列，以寻找一系列具有广泛临床表现和严重程度的患者中的致病改变。迄今为止鉴定出的所有错义突变，包括本文讨论的两个新突变，都与典型的、中度至重度疾病相关，并且发生在对钙结合到表皮生长因子（EGF）样结构域具有推定意义的残基处。相比之下，两个新突变产生了mRNA翻译终止的过早信号，并与突变等位基因转录本数量的减少相关，它们导致了一系列的表型严重程度。突变转录本数量最低的患者病情最轻。这些数据支持了钙结合到EGF样结构域的改变在马凡综合征发病机制中的作用，并提示了这种疾病发病机制的显性负性机制。
