title: The pathogenicity of the Pro1148Ala substitution in the FBN1 gene: causing or predisposing to Marfan syndrome and aortic aneurysm, or clinically innocent?
abstract: In individuals with the Marfan syndrome (MFS), mutations have been identified in the fibrillin-1 gene (FBN1) at 15q21.1. A proline-to-alanine change at position 1148 in exon 27 (Pro1148Ala) has been reported in probands with MFS, aortic aneurysm or Marfanoid-craniosynostosis. It was suggested that this mutation could be a risk factor for aortic dilatation, since it was rarely observed in control populations. To investigate further the pathogenicity of this substitution, we screened 416 unrelated control individuals by allele-specific oligonucleotide (ASO) hybridization. We found 16 individuals who carried the alanine allele (3.8%), 3 of whom were homozygous. Five were of Latin American and eight were of Asian extraction. We also screened 133 probands with MFS, aortic aneurysm or related connective tissue disorders and found 4 (3%) that were heterozygous for the 1148Ala allele. All positive results were confirmed by DNA sequencing. In 20 individuals with 1148Ala, we confirmed the association with the rarer A allele at the IVS27-5G-->A polymorphism. Our results suggest that the Pro1148Ala change is a polymorphism of ancient evolutionary origin that is more prevalent in Asian and Latin American than in Caucasian or African populations.
authors.affiliation: Howard Hughes Medical Institute, Beckman Center, Stanford University Medical Center, CA 94305-5428, USA.
authors.forename: I
authors.initials: I
authors.lastname: Schrijver
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: U
authors.initials: U
authors.lastname: Francke
mesh_terms: D000409:Alanine; D000595:Amino Acid Sequence; D000818:Animals; D001014:Aortic Aneurysm / Q000235:genetics*; D001208:Asia / Q000208:ethnology; D001483:Base Sequence; D005075:Biological Evolution; D002417:Cattle; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D003240:Connective Tissue Diseases / Q000235:genetics; D017931:DNA Primers; D004198:Disease Susceptibility; D004330:Drosophila / Q000235:genetics; D005091:Exons; D000071838:Fibrillin-1; D000071837:Fibrillins; D006720:Homozygote; D006801:Humans; D007438:Introns; D007843:Latin America / Q000208:ethnology; D008382:Marfan Syndrome / Q000235:genetics*; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011392:Proline; D044469:Racial Groups; D012016:Reference Values; D012867:Skin; D014481:United States; D054392:Adipokines
chemical_list: D000409:Alanine; D017931:DNA Primers; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D011392:Proline; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse