title: Cysteine-to-arginine point mutation in a 'hybrid' eight-cysteine domain of FBN1: consequences for fibrillin aggregation and microfibril assembly.
abstract: Mutations in the FBN1 gene encoding the microfibrillar glycoprotein fibrillin cause Marfan syndrome, a relatively common autosomal dominant connective tissue disease. Causative FBN1 mutations appear to be dispersed throughout the coding frame, and to date no predictable genotype: phenotype correlations have emerged. We have identified a point mutation within an eight-cysteine 'hybrid' motif of the fibrillin polypeptide which results in the substitution of an arginine for a cysteine, in a patient severely affected in the cardiovascular, skeletal and ocular systems. We have utilised cell cultures from various tissues of this patient to investigate the effects of this mutation on fibrillin expression and deposition, and the consequences in terms of microfibril assembly and organisation. We have established that there is no difference in the expression of normal and mutant alleles, and fibrillin synthesis, secretion and deposition are also normal. However, the rate of fibrillin aggregation is reduced and microfibrillar assemblies are both remarkably scarce and morphologically abnormal. These data clearly demonstrate that the mutated allele interferes with normal assembly, and strongly implicate this particular region of the fibrillin-1 molecule in stabilising microfibrillar assemblies.
authors.affiliation: School of Biological Sciences, University of Manchester, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Kielty
authors.forename: T
authors.initials: T
authors.lastname: Rantamäki
authors.forename: A H
authors.initials: AH
authors.lastname: Child
authors.forename: C A
authors.initials: CA
authors.lastname: Shuttleworth
authors.forename: L
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000648:ultrastructure; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D000071838:Fibrillin-1; D000071837:Fibrillins; D015870:Gene Expression; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008854:Microscopy, Electron; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D054392:Adipokines
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D000071838:Fibrillin-1; D000071837:Fibrillins; D046911:Macromolecular Substances; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines