title: Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons.
abstract: Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: G
authors.initials: G
authors.lastname: Nijbroek
authors.forename: S
authors.initials: S
authors.lastname: Sood
authors.forename: I
authors.initials: I
authors.lastname: McIntosh
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
authors.forename: E
authors.initials: E
authors.lastname: Bull
authors.forename: L
authors.initials: L
authors.lastname: Pereira
authors.forename: F
authors.initials: F
authors.lastname: Ramirez
authors.forename: R E
authors.initials: RE
authors.lastname: Pyeritz
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000032:analysis*; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D009692:Nucleic Acid Heteroduplexes / Q000032:analysis*; D016133:Polymerase Chain Reaction
chemical_list: D009692:Nucleic Acid Heteroduplexes; D004247:DNA