Mutations in FBN1 Sequences Coding for EGFcb Motifs in Individuals with Ascending Aortic Aneurysms
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Microfibrils are the major constituents of connective tissues, providing structural integrity and serving as the scaffolding for deposition of tropoelastin to form elastic fibers. A variety of proteins compose the structure of microfibrils, the most prominent of which is fibrillin-1 encoded by FBN 1 on human chromosome ISq21. Fibrillin-1 monomers contain large numbers of calcium binding epidermal growth factor-like motifs (EGFcb), which play an important role in the elasticity and strength of connective tissues. Mutations in FBN1 cause Marfan syndrome (MFS), an autosomal dominant connective tissue disorder with prominent manifestations in the skeleton, eye and cardiovascular system. A number of conditions related to MFS are also due to FBN 1 mutations and are referred to as Marfan-like disorders. The most life threatening of the Marfan-like disorders are ascending aortic aneurysms (AAA). AAA develop due to high blood pressure in the aorta, leading to eventual rupture or dissection of the tissue. In this study, the FBN1 genomes of individuals with AAA were studied using polymerase chain reaction as well as a novel, but powerful technique known as denaturing high performance liquid chromatography (DHPLC). DHPLC makes the technical challenge of searching a large gene such as FBN 1 (110 kb) for mutations much easier and accurate than in the past. Four de novo mutations were discovered in four unrelated individuals with aortic aneurysms in this study, with each mutation residing in EGFcb-like coding regions of FBN 1. This study investigates the relationship between the four FBN 1 mutations and the loss of aortic tissue strength, loss of aortic tissue elasticity, and abnormally high blood pressure, with respect to the development of aortic aneurysms.