Human Molecular Genetics Advance Access originally published online on July 22, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 18 2269-2276
DOI: 10.1093/hmg/ddg241
© 2003 Oxford University Press
Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype?
1Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK, 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 3Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, UK and 4Department of Medical Genetics, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
Received February 28, 2003; Accepted July 10, 2003
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.
* To whom correspondence should be addressed. Tel: +44 1865 285347; Fax: +44 1865 285327; Email: penny{at}bioch.ox.ac.uk
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