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January 2001
Vol. 4, No. 1, p. 48.
diseases and disorders
Rulers (and others) subject to a reign of error
Figure 1. Schematic representation of Caco-2 permeablility assay.
Giant stature. Lincoln’s greatness in political stature was underscored by his unusual height, which may have been a result of MFS.
Abraham Lincoln. Mary Queen of Scots. Akhenaton and his son Tutankhamen. Each led a nation, each was cut down early in life and, if medical researchers and historians are correct, each shared one more trait. They all suffered from a disorder called Marfan’s syndrome (MFS).

Affecting 1 in 10,000 individuals, MFS is the most common inherited disorder of the connective tissues. People with the disease suffer cardiovascular abnormalities, including heart valve malfunction and a progressive widening of the aorta that can lead to leakage or tearing of the artery. In fact, aortic aneurysm is the leading cause of death among MFS sufferers. Sufferers may also exhibit curvature of the spine (scoliosis), an abnormally shaped chest, abnormal height, and joint looseness that results in long limbs. People with MFS are typically also nearsighted and must be monitored for possible dislocation of the retina.

Figure 1. Schematic representation of Caco-2 permeablility assay.
From chromosome arm to cardiac harm. The Marfan’s syndrome gene encodes fibrillin-1, a protein involved in the formation of connective tissu, including those of the heart.
Many components of the extracellular matrix of connective tissue were suspected as MFS-causing candidates, but immunofluorescence experiments published in 1986 identified the true culprit. The binding of monoclonal antibodies against fibrillin, a 350-kD glycoprotein, to dermal fibroblast cultures from MFS patients was lower than in comparable cultures from unaffected individuals. By 1991, the cDNA for fibrillin-1 (FBN1) and the gene for MFS were found to co-localize to a 110-kb region of chromosome 15, specifically 15q21.1. Since then, a second fibrillin protein (FBN2) has been identified.

Not surprisingly, the cysteine-rich (~14% of its amino acid content) fibrillin-1 is found in tissues that are rich in elastic fibers, which, like Spandex, allow these tissues to stretch without tearing. These fibers are composed of an elastin core that is surrounded by a sheath of microfibrils, fibers composed largely of fibrillin-1 aggregates. The numerous cysteine residues may mediate this aggregation. In the early stages of elastic fiber development, microfibrils are thought to act as a scaffold onto which elastin is deposited. As the fiber grows and matures, the microfibrils move to the outside.

More than 80 mutations of FBN1 have been identified, associated with various degrees of MFS severity. Those mutations that diminish the overall level of fibrillin-1, typically by premature translation termination, are associated with the milder disease phenotypes. This suggests that the more severe phenotypes are the result of a destabilization or disruption of microfibrils by mutant or improperly processed forms of the protein.

Currently, diagnosis of the syndrome is based largely on a physical analysis of suspected sufferers. Tests include routine echocardiograms to look for coronary malformations, slit-lamp eye exams, and skeletal exams, and are supplemented by a family history analysis. Until the pathogenesis of the disorder is better understood, it will be difficult to develop treatments. In the meantime, researchers have concentrated their efforts on methods that modulate the expression of the mutant FBN1 gene, using techniques such as antisense RNA. In addition, -blocker treatments have been used to lower cardiac stress and thus minimize the chances of aortic aneurysms.

Sources: Canadian Marfan Association (www.marfan.ca); National Marfan Foundation (www.marfan.org); Kilpatrick, M. W.; Phylactou, L. A. Mol. Med. Today 1998, 4 (9), 376–381.

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