Fibrillin-1 (FBN1) gene frameshift mutations in Marfan patients: genotype-phenotype correlation

Marfan syndrome (MFS) is a multisystemic disease associated with mutations in the fibrillin-1 gene. Most of the reported mutations are missense substi tutions mainly affecting the epidermal growth factor (EGF)-like protein dom ain structure and the calcium-binding (cb) site. The aim of our study was t o investigate the correlation between fibrillin-1 frameshift mutations and the clinical phenotype in patients affected by MFS. In 48 out of 66 Marfan patients a pathogenetic mutation was found. We detected novel mutations cau sing premature termination codon in exons 19, 37, 40 and 41 of four Italian patients. The first mutation in exon 19 (cbEGF #8 domain) results in a cli nical phenotype involving mainly the skeletal and cardiovascular systems. I nterestingly, we noticed that, while mutations in exons 37 and 41 (eight cy steine domains #4 and #5) are milder, the mutation in exon 40 (cbEGF #24 do main) is more severe and causes major cardiovascular involvement with thora cic and abdominal aortic aneurysms. It is noteworthy that the degree of the severity in the phenotype of one of our patients and another from the lite rature carrying a mutation in exon 41 could be explained with alterations i n mRNA expression.