A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR.Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 × 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.Aneurysm and dissection are major diseases of the aorta and are often asymptomatic until a life-threatening event like ischemic organ damage or rupture occurs. Marfan Syndrome (MFS) is a diverse yet clinically recognized subgroup of people at risk for aneurysm, including dissecting aneurysm, and constitutes a significant fraction (estimated at 5–7.5% [1,2]) of all individuals with ascending and thoracic aortic aneurysmal disease. MFS incidence is estimated to be 1 in 5–10,000 [3]. Our long-term goal is to develop an assay that will identify people at risk for aneurysm before the disease process has reached an advanced state. This report is a small step in that direction.In this study, we focus on individuals diagnosed with Marfan syndrome. The prevalence of MFS combined with its clinical recognition makes it an excellent model system for studies on aneurysmal disease. MFS is an autosomal dominant heritable disorder caused by mutations in the fibrillin-1 (FBN1) gene [4,5], with more tha