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

Abstract

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 thewildtype (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from80Marfan patientswith premature termination codons and in skin fibroblasts from80 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 themean level of FBN1mRNAwas a half of the control population.Differential allelic expression analysis inMarfan fibroblasts showed that over 90%of FBN1mRNAwas transcribed fromthewild allele and themutated allelewasnot detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelicmRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WTFBN1mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.