A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype

Am J Hum Genet. 1994 Dec;55(6):1083-91.


We describe here the identification of defined mutations in both alleles of the fibrillin gene (FBN1) in a compound-heterozygote Marfan syndrome (MFS) child who had a very severe form of MFS resulting in death from cardiac failure at the age of 4 mo. The nonconsanguineous parents were both affected with MFS. The father's heterozygous point mutation has earlier been reported to result in W217G substitution, the mother was here shown to carry a heterozygous point mutation resulting in G2627R substitution, and the child had inherited both these mutations. The mutant FBN1 alleles were demonstrated to be transcribed with equal efficiency compared with the normal alleles, but metabolic labeling of fibroblast cultures from the child and both parents showed reduced biosynthesis and secretion of profibrillin. Also, the respective amounts of fibrillin in cell-culture media and extracellular-matrix extracts were markedly diminished, particularly in the cell cultures from father and child. In addition, immunofluorescence analysis of the cell cultures of all three family members revealed a drastically reduced amount of microfibrils, and virtually no visible fibrils could be seen in the case of the compound-heterozygote child. These findings demonstrate incomplete dominance of fibrillin mutations and underline the fatal consequences of the complete absence of normal fibrillin molecules in the microfibrils.

Publication types

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

MeSH terms

  • Actin Cytoskeleton / ultrastructure
  • Alleles
  • Amino Acid Sequence
  • Base Sequence
  • Female
  • Fibrillin-1
  • Fibrillins
  • Genes, Lethal
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Marfan Syndrome / genetics*
  • Microfilament Proteins / genetics*
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Phenotype
  • Protein Precursors / genetics
  • RNA, Messenger / genetics


  • FBN1 protein, human
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • Protein Precursors
  • RNA, Messenger