Milewicz D M, Michael K, Fisher N, Coselli J S, Markello T, Biddinger A
Department of Internal Medicine, University of Texas-Houston Medical School, USA.
Circulation. 1996 Dec 1;94(11):2708-11. doi: 10.1161/01.cir.94.11.2708.
Mutations in the FBN1 gene are the cause of the Marfan syndrome, an autosomal dominant disorder with skeletal, ocular, and cardiovascular complications. Aneurysms or dissections of the ascending thoracic aorta are the major cardiovascular complications of the disorder. We tested the hypothesis that FBN1 mutations cause thoracic aortic aneurysms or dissections in patients who do not have the Marfan syndrome.
The FBN1 gene was screened for mutations by use of genomic DNA from two patients with thoracic aortic aneurysms who did not have the Marfan syndrome. Individual FBN1 exons were amplified with intron-based exon-specific primers; the DNA fragments were screened for mutations using single-stranded conformational polymorphism analysis; and aberrantly migrating bands were sequenced directly. We identified a missense mutation in one patient, D1155N in exon 27. Dermal fibroblasts from the affected individual were used to study the effect of the missense mutation D1155N on fibrillin-1 cellular processing. The mutation decreased the amount of fibrillin-1 deposited into the pericellular matrix. A second putative FBN1 mutation was identified in the second patient, P1837S in exon 44. Although this alteration was not observed in 234 chromosomes from unrelated individuals, the alteration may represent a rare polymorphism.
Results of these studies support the hypothesis that FBN1 mutations cause thoracic aortic aneurysms in patients who do not have the Marfan syndrome. This information is important for understanding the pathogenesis of aortic aneurysms and identification of individuals at risk for developing thoracic aortic aneurysms or dissections.
FBN1基因突变是马方综合征的病因，这是一种常染色体显性疾病，伴有骨骼、眼部和心血管并发症。升主动脉瘤或夹层是该疾病的主要心血管并发症。我们检验了一个假设，即FBN1基因突变会导致非马方综合征患者发生胸主动脉瘤或夹层。
利用两名非马方综合征胸主动脉瘤患者的基因组DNA对FBN1基因进行突变筛查。使用基于内含子的外显子特异性引物扩增各个FBN1外显子；利用单链构象多态性分析筛选DNA片段中的突变；对异常迁移条带直接进行测序。我们在一名患者中鉴定出一个错义突变，位于第27外显子的D1155N。利用来自该患病个体的皮肤成纤维细胞研究错义突变D1155N对原纤维蛋白-1细胞加工的影响。该突变减少了沉积到细胞周围基质中的原纤维蛋白-1的量。在第二名患者中鉴定出第二个假定的FBN1突变，位于第44外显子的P1837S。尽管在来自无关个体的234条染色体中未观察到这种改变，但这种改变可能代表一种罕见的多态性。
这些研究结果支持了FBN1基因突变会导致非马方综合征患者发生胸主动脉瘤这一假设。这一信息对于理解主动脉瘤的发病机制以及识别有发生胸主动脉瘤或夹层风险的个体具有重要意义。
