A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection

Am J Hum Genet. 1995 Jun;56(6):1287-96.


Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-strand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 3379, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. This mutation was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members, in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations such as this one may disrupt EGF-like domain folding less drastically than do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, therefore, produces a mild form of autosomal dominantly inherited weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection later in life.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Aneurysm, Dissecting / etiology*
  • Aneurysm, Dissecting / genetics
  • Aortic Aneurysm / etiology
  • Aortic Aneurysm / genetics
  • Base Sequence
  • Epidermal Growth Factor / genetics
  • Female
  • Fibrillin-1
  • Fibrillins
  • Haplotypes
  • Humans
  • Male
  • Marfan Syndrome / diagnosis
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Netherlands / ethnology
  • Nucleic Acid Hybridization
  • Phenotype
  • Polymorphism, Genetic
  • Risk Factors


  • FBN1 protein, human
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • Epidermal Growth Factor