title: Sequence variations in the 5' upstream regions of the FBN1 gene associated with Marfan syndrome.
abstract: Marfan syndrome (MFS; OMIM#154700) is a connective tissue disorder characterized by manifestations in the ocular, skeletal and cardiovascular systems. MFS is caused by mutation in the fibrillin-1 gene (FBN1; OMIM#134797) and more than 550 mutations have been identified so far. FBN1 is approximately 230 kb in size and contains three evolutionarily conserved alternatively spliced exons B, A and C at the 5'end. In a first systematic attempt to associate sequence variations in the FBN1 5' alternatively spliced exons with MFS, we investigated 41 individuals fulfilling the diagnostic criteria of Ghent nosology or with features of MFS including at least one major criterion or involvement of two organ systems but not fulfilling a strict interpretation of the Ghent nosology, and known to be negative for mutations in the FBN1 exons 1-65 as well as the TGFBR2 and TGFBR1 coding regions. We identified five novel and one previously reported variants in the six unrelated probands and provide preliminary evidence for their role in pathogenesis.
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Krishna Kumar
authors.initials: KK
authors.lastname: Singh
authors.forename: Praphulla Chandra
authors.initials: PC
authors.lastname: Shukla
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rommel
authors.forename: Jörg
authors.initials: J
authors.lastname: Schmidtke
authors.forename: Mine
authors.initials: M
authors.lastname: Arslan-Kirchner
mesh_terms: D024506:5' Flanking Region / Q000235:genetics*; D030201:Activin Receptors, Type I / Q000235:genetics; D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D005091:Exons; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D054392:Adipokines
chemical_list: D030201:Activin Receptors, Type I; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000625841:TGFBR1 protein, human