Marfan Syndrome Linked to Skipped Exon

Investigators have found that a mutation in the fibrillin 1 (FBN1) gene causes the nuclear splicing machinery to skip exon 51 entirely, resulting in malfunctioning fibrillin protein activity that affects the integrity of the connective tissue and gives rise to the symptoms associated with Marfan syndrome. This finding was reported in the July 15, 2002, edition of Genes & Development.

Originally characterized in 1896, Marfan syndrome, which may have afflicted US President Abraham Lincoln, 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.

A mutation in the FBN1 gene was shown more than ten years ago to be linked to the development of Marfan syndrome. The FBN1 gene has 65 exons, or coding regions, that are separated by noncoding introns, which are spliced out of the pre-mRNA transcript during nuclear processing. In the current study researchers from Johns Hopkins University (Baltimore, MD, USA) found that the mutation in exon 51 of the FBN1 gene caused the disruption of an exonic splicing enhancer (ESE), which resulted in exon 51 not being spliced. Proteins produced by the nonspliced exon have compromised function because the region encoded by exon 51 is critical for normal fibrillin protein activity.

This work aids further understanding of the pathogenesis of Marfan syndrome and possibly some of the other human diseases associated with exon skipping.



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