A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection.
A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection.
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发表时间：
1995-06
影响因子：
9.8
通讯作者：
U. Francke;M. Berg;K. Tynan;T. Brenn;Wanguo Liu;T. Aoyama;C. Gasner;D. Miller;H. Furthmayr
中科院分区：
文献类型：
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作者：
U. Francke;M. Berg;K. Tynan;T. Brenn;Wanguo Liu;T. Aoyama;C. Gasner;D. Miller;H. Furthmayr
已在 10 名亲属中发现升主动脉疾病，从轻度主动脉根部肿大到动脉瘤和/或夹层，其中没有人患有经典马凡综合征 (MFS)。对受影响家族成员的整个 fibrillin-1 (FBN1) cDNA 的单链构象分析显示，第 3379 位核苷酸处存在 G 到 A 的转变，预示着 Gly1127Ser 取代。该位置的甘氨酸在 FBN1 和其他蛋白质的 EGF 样结构域中高度保守。这种突变存在于 10 名受影响的家庭成员中的 9 名和 1 名年轻的未受影响的成员中，但在其他未受影响的成员、正常对照的 168 条染色体以及其他具有 MFS 或相关表型的个体的 188 条染色体中未发现这种突变。 FBN1 基因内标记单倍型排除了另一个等位基因在调节该家族表型中发挥重要作用的可能性。脉冲追踪研究显示，在 Gly1127Ser 载体培养的成纤维细胞中，原纤维蛋白合成正常，但细胞外基质中的原纤维蛋白沉积减少。我们假设 Gly1127Ser FBN1 突变导致基质沉积减少。我们认为，与半胱氨酸或其他对导致经典 MFS 的钙结合很重要的氨基酸的取代相比，此类突变对 EGF 样结构域折叠的破坏程度可能较小。因此，Gly1127Ser 突变会产生一种轻微形式的常染色体显性遗传性弹性组织无力，从而在以后的生活中容易发生升主动脉瘤和夹层。
Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-strand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 3379, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. This mutation was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members, in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations such as this one may disrupt EGF-like domain folding less drastically than do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, therefore, produces a mild form of autosomal dominantly inherited weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection later in life.