Human Molecular Genetics, Vol 5, 1581-1587, Copyright © 1996 by Oxford University Press
W Liu, C Qian, K Comeau, T Brenn, H Furthmayr and U Francke
Marfan syndrome (MFS), a heritable connective tissue disorder, is caused by
mutations in the gene coding for fibrillin-1 (FBN1), an extracellular
matrix protein. One of the three major categories of FBN1 mutations
involves exon-skipping. To rapidly detect such mutations, we developed a
long RT-PCR method. Either three segments covering the entire FBN1 coding
sequence or a single 8.9 kb FBN1 coding segment were amplified from
reverse-transcribed total fibroblast RNA. Restriction fragment patterns of
these RT-PCR products were compared and abnormal fragments were directly
sequenced. Six exon-skipping mutations were identified in a panel of 60 MFS
probands. All skipped exons encode calcium binding epidermal growth factor
(EGF)-like domains and maintain the reading frame. In five probands,
exon-skipping was due to point mutations in splice site sequences, and one
had a 6 bp deletion in a donor splice site. Pulse-chase analysis of
labelled fibrillin protein revealed normal levels of synthesis but
significantly reduced matrix deposition. This dominant-negative effect of
the mutant monomers is considered in the light of current models of
fibrillin assembly. Probands with this type of FBN1 mutation include the
most severe forms of MFS, such as neonatally lethal presentations.
ARTICLES
Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome
Howard Hughes Medical Institute, Stanford University Medical Center, CA 94305, USA.
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