Meng Bo, Li Hongyi, Yang Tao, Huang Shangzhi, Sun Xian, Yuan Huiping
Department of Ophthalmology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
Mol Vis. 2011;17:2421-7. Epub 2011 Sep 17.
To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS).
Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation.
A novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain.
We indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome.
鉴定一个患有马凡综合征（MFS）的中国家系中纤连蛋白-1基因（FBN1）的突变。
对患者及其家庭成员进行全面的体格、眼科和心血管检查。从该家系的6名个体以及170名健康中国个体的静脉血白细胞中提取基因组DNA。通过聚合酶链反应在先证者中扩增FBN1的所有65个编码外显子及其侧翼内含子边界，随后进行直接测序。通过直接测序在其他家庭成员和170名健康中国个体中筛选先证者中鉴定出的突变。使用在线ClustalW工具对6个物种进行蛋白质保守性分析。基于蛋白质数据库对蛋白质结构进行建模，并在DeepView v4.0.1中进行突变以预测突变的功能后果。
在先证者中检测到FBN1第29外显子中一个新的杂合c.3703T>C变化，导致密码子1235处丝氨酸被脯氨酸取代（p.S1235P）。该突变也存在于两名家庭成员中，但在其他未受影响的家庭成员和170名健康中国个体中不存在。位于钙结合表皮生长因子样#15结构域的突变残基在哺乳动物物种中高度保守，可能会诱导该结构域的构象变化。
我们在FBN1中鉴定出一个新的p.S1235P突变，这是该家系中MFS的致病突变。我们的结果扩展了FBN1的突变谱，有助于马凡综合征分子发病机制的研究。
