A MAJOR INVOLVEMENT OF THE CARDIOVASCULAR-SYSTEM IN PATIENTS AFFECTEDBY MARFAN-SYNDROME - NOVEL MUTATIONS IN FIBRILLIN-1 GENE

The aim of our study was to characterize the molecular defect in Itali an 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 cardiovas cular system, We searched for a molecular defect in three patients wit h classic Marfan syndrome (MFS). The mutations were detected applying heteroduplex analysis to each of the 65 exons of the FBN1 gene amplifi ed by polymerase chain reaction (PCR), Exons containing heteroduplex b ands were sequenced directly from PCR products, This study reports the detection of three unique missense mutations in the FBN1 gene in thre e Italian patients: a 44-year-old adult male and 36-year-old-female af fected by classic MFS (with all the cardinal manifestations in the car diovascular, ocular and skeletal systems), and an 11-year-old male aff ected by infantile (earlier onset) classic MFS. The first two are spor adic cases and present a Cys-->Arg amino acid substitution (T-->C subs titution at nucleotide 7729) in exon 62 and a Cys-tyr amino acid subst itution (G-->A substitution at nucleotide 6695) in exon 54. The third is a familial case which presents a Cys-->trp aminoacidic 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 cluste r seems to produce an even more severe phenotype. The early characteri zation may be of clinical relevance for prevention and early surgical treatment of aortic aneurysm or dissection. (C) 1997 Academic Press Li mited.