Making sense of Marfan syndrome

July 14, 2002

In the July 15 issue of Genes & Development, Drs. Massimo Caputi, Raymond Kendzior Jr. and Karen Beemon of Johns Hopkins University report on their determination of a molecular mechanism of Marfan syndrome pathogenesis - a discovery that may end the decade-long debate over how this relatively common genetic disorder develops.

Originally characterized in 1896, Marfan syndrome is a heritable disorder of the connective tissue, which usually affects the skeletal, respiratory, cardiovascular, and ocular systems, and is commonly associated with tall stature and markedly long limbs. In 1991 scientists discovered that Marfan syndrome is caused by mutations in the fibrillin 1 (FBN1) gene.

Now, more than a decade later, Dr. Beemon and colleagues are lending new insight into the mechanism by which some mutations in the FBN1 gene result in Marfan syndrome.

The FBN1 gene encodes the fibrillin protein, a component of the rod-like microfibrils that comprise the connective tissue. Mutations in the FBN1 gene that compromise fibrillin protein activity can, in turn, affect the integrity of the connective tissue and give rise to the symptoms associated with Marfan syndrome.

The FBN1 gene has 65 exons, or coding regions, that are separated by non-coding introns, which are removed from, or "spliced out of," the pre-mRNA transcript during nuclear processing. In the early 1990s, a Marfan syndrome patient was found to harbor a mutation in FBN1 exon 51 that causes the nuclear splicing machinery to skip exon 51 entirely. Skipping exon 51 is problematic, though, as exon 51-skipped fibrillin proteins have compromised function because the region encoded by exon 51 is critical for normal fibrillin protein activity.

Dr. Beemon and colleagues demonstrate that exon 51 skipping is the result of the disruption of an exonic splicing enhancer (ESE), a DNA sequence within the FBN1 gene that increases splicing efficiency. The scientists discovered that other types of mutations that also disrupt the ESE can cause exon 51 skipping. The authors therefore conclude that FBN1 exon 51 skipping is dependent upon the disruption of an ESE.

Ultimately, this work helps further our understanding of the pathogenesis of Marfan syndrome, and possibly some of the other human diseases associated with exon skipping.

Cold Spring Harbor Laboratory

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