title: Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome.
abstract: Marfan syndrome results from mutations in an extracellular matrix glycoprotein, fibrillin. Previous studies have characterized approximately 6.9-kb of the estimated 10-kb fibrillin transcript. We have now completed the primary structure of fibrillin, elucidated the exon/intron organization of the gene and derived a physical map of the genetic locus. Pre-fibrillin consists of 2,871 amino acids which, excluding the signal peptide, are arranged into five structurally distinct regions. The largest of these regions comprises about 75% of the entire protein and consists of numerous repeated cysteine-rich sequences homologous to the peptide motifs of the epidermal growth factor (EGF) and transforming growth factor-beta binding protein (TGF-bp). Forty-three of the forty-six EGF-like repeats contain a calcium binding consensus sequence (EGF-CB) conceivably mediating protein-protein interactions. Fibrillin exhibits a few additional cysteine-rich modules that are apparently unique to this macromolecule and may represent evolutionary variants of the EGF-CB and TGF-bp motifs. Almost all of the cysteine-rich repeats are encoded by single exons; consequently, the fibrillin gene is relatively large (approximately 110-kb) and highly fragmented (65 exons). This study provides the first comprehensive analysis of the fibrillin gene and relevant information for the full characterization of Marfan syndrome mutations.
authors.affiliation: Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029.
authors.forename: L
authors.initials: L
authors.lastname: Pereira
authors.forename: M
authors.initials: M
authors.lastname: D'Alessio
authors.forename: F
authors.initials: F
authors.lastname: Ramirez
authors.forename: J R
authors.initials: JR
authors.lastname: Lynch
authors.forename: B
authors.initials: B
authors.lastname: Sykes
authors.forename: T
authors.initials: T
authors.lastname: Pangilinan
authors.forename: J
authors.initials: J
authors.lastname: Bonadio
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping; D015825:Chromosomes, Fungal; D003001:Cloning, Molecular; D003545:Cysteine / Q000235:genetics; D004247:DNA / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D005091:Exons; D000071837:Fibrillins; D015723:Gene Library; D015894:Genome, Human; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D012091:Repetitive Sequences, Nucleic Acid; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000071837:Fibrillins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D004247:DNA; D003545:Cysteine