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

Adult Male 0301 basic medicine Genotype Fibrillin-1 610 MASS Fibrillins Marfan Syndrome 03 medical and health sciences Frameshift mutation Settore BIO/13 - BIOLOGIA APPLICATA Humans Mass Screening RNA, Messenger Frameshift Mutation Fibrilin-1 gene 0303 health sciences Aortic aneurysm Polymorphism, Genetic Microfilament Proteins DNA Exons Aortic aneurysm; Fibrilin-1 gene; Frameshift mutations; Marfan syndrome; MASS 3. Good health Marfan syndrome Mutagenesis, Insertional Phenotype Female
DOI: 10.1034/j.1399-0004.2001.590610.x Publication Date: 2003-03-11T11:26:35Z
ABSTRACT
Marfan syndrome (MFS) is a multisystemic disease associated with mutations in the fibrillin‐1 gene. Most of the reported mutations are missense substitutions mainly affecting the epidermal growth factor (EGF)‐like protein domain structure and the calcium‐binding (cb) site. The aim of our study was to 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 causing 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 clinical phenotype involving mainly the skeletal and cardiovascular systems. Interestingly, we noticed that, while mutations in exons 37 and 41 (eight cysteine domains #4 and #5) are milder, the mutation in exon 40 (cbEGF #24 domain) is more severe and causes major cardiovascular involvement with thoracic 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 literature carrying a mutation in exon 41 could be explained with alterations in mRNA expression.
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