The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele

Hum Mol Genet. 2015 May 15;24(10):2764-70. doi: 10.1093/hmg/ddv037. Epub 2015 Feb 4.


Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Child
  • Child, Preschool
  • Codon, Nonsense
  • Ectopia Lentis / genetics
  • Female
  • Fibrillin-1
  • Fibrillins
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Marfan Syndrome / diagnosis
  • Marfan Syndrome / genetics*
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Young Adult


  • Codon, Nonsense
  • FBN1 protein, human
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins