title: Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome.
abstract: Defects of fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, cause Marfan syndrome. This disorder is characterized by marked inter- and intrafamilial variation in phenotypic severity. To understand the molecular basis for this clinical observation, we have screened the fibrillin gene (FBN1) on chromosome 15, including the newly cloned 5' coding sequence, for disease-producing alterations in a panel of patients with a wide range of manifestations and clinical severity. All the missense mutations identified to date, including two novel mutations discussed here, are associated with classic and moderate to severe disease and occur at residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. In contrast, two new mutations that create premature signals for termination of translation of mRNA and are associated with reduction in the amount of mutant allele transcript produce a range of phenotypic severity. The patient with the lowest amount of mutant transcript has the mildest disease. These data support a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggest a dominant negative mechanism for the pathogenesis of this disorder.
authors.affiliation: Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
authors.forename: I
authors.initials: I
authors.lastname: McIntosh
authors.forename: L Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: G M
authors.initials: GM
authors.lastname: Corson
authors.forename: S C
authors.initials: SC
authors.lastname: Chalberg
authors.forename: R E
authors.initials: RE
authors.lastname: Pyeritz
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D008961:Models, Structural; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D054392:Adipokines
chemical_list: D002118:Calcium; D004247:DNA; D004815:Epidermal Growth Factor; D000071838:Fibrillin-1; D000071837:Fibrillins; D046911:Macromolecular Substances; D008840:Microfilament Proteins; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C000605722:FBN1 protein, human; D054392:Adipokines