Abstract

FBN1 mutations cause Marfan syndrome (MFS), an autosomal dominant disorder of connective tissue. One of the unexplained features of MFS is the pathogenic mechanism that leads to marked inter- and intra-familial clinical variability, despite complete disease penetrance. An FBN1 deletion patient [46,XXdel(15)(q15q22.1)] was identified whose fibrillin-1 protein and mRNA levels were significantly higher than expected for a single FBN1 allele. This suggested that allelic variation in normal FBN1 expression might occur in MFS families, and have potential clinical implications particularly for those with premature termination codon (PTC) mutations who usually display low levels of expression from the mutant allele due to nonsense-mediated decay (NMD). RNA analyses identified a variable reduction in total FBN1 transcript (78+/-2.2 to 27.3+/-2.3%) in three related individuals carrying PTC-causing mutation 932insT, compared with unaffected control individuals. Both pulse chase analysis of fibrillin-1 biosynthesis and RNase protection analyses demonstrated that these differences were due to variation in the expression of the normal FBN1 allele and not NMD of mutant RNA. We suggest that differences in normal FBN1 expression could contribute to the clinical variability seen in this family with MFS, and should be considered as a potential modifier of phenotype in other cases of MFS.