Major involvement of the cardiovascular system in patients affected by Marfan syndrome: Novel mutations in fibrillin 1 gene

The aim of our study was to characterize the molecular defect in Italian Marfan patients, thus contributing to the effort of correlating the genotype with the phenotype. In particular, our ultimate goal was to identify the region(s) of the fibrillin 1 (FBN1) gene mainly involved in the health of the heart and of the aorta in terms of the cardiovascular system. We searched for a molecular defect in three patients with classic Marfan syndrome (MFS). The mutations were detected applying heteroduplex analysis to each of the 65 exons of the FBN1 gene amplified by polymerase chain reaction (PCR). Exons containing heteroduplex bands were sequenced directly from PCR products. This study reports the detection of three unique missense mutations in the FBN1 gene in three Italian patients: a 44-year-old adult male and 36-year-old female affected by classic MFS (with all the cardinal manifestations in the cardiovascular, ocular and skeletal systems); and an 11-year-old male affected by infantile (earlier onset) classic MFS. The first two are sporadic cases and present a Cys→Arg amino acid substitution (T→C substitution at nucleotide 7729) in exon 62 acid a Cys→Tyr amino acid substitution (G→A substitution at nucleotide 6695) in exon 54. The third is a familial case which presents a Cys→Trp amino acidic substitution (C→G substitution at nucleotide 3546) in exon 28. Our data confirm that cysteine substitutions in calcium binding epidermal growth factor (cbEGF)-like domains cause severe Marfan phenotype, Exon 24-32 cluster seems to produce an even more severe phenotype. The early characterization may be of clinical relevance for prevention and early surgical treatment of aortic aneurysm or dissection.