The pathogenicity of the Pro1148Ala substitution in the FBN1 gene: causing or predisposing to Marfan syndrome and aortic aneurysm, or clinically innocent?

Hum Genet. 1997 May;99(5):607-11. doi: 10.1007/s004390050414.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine*
  • Amino Acid Sequence
  • Animals
  • Aortic Aneurysm / genetics*
  • Asia / ethnology
  • Base Sequence
  • Biological Evolution
  • Cattle
  • Cells, Cultured
  • Chromosome Mapping
  • Chromosomes, Human, Pair 15*
  • Connective Tissue Diseases / genetics
  • DNA Primers
  • Disease Susceptibility
  • Drosophila / genetics
  • Exons
  • Fibrillin-1
  • Fibrillins
  • Homozygote
  • Humans
  • Introns
  • Latin America / ethnology
  • Marfan Syndrome / genetics*
  • Mice
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / genetics*
  • Point Mutation*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Proline*
  • Racial Groups
  • Reference Values
  • Skin
  • United States


  • DNA Primers
  • FBN1 protein, human
  • Fbn1 protein, mouse
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • Proline
  • Alanine