Johns Hopkins Magazine -- November 2000
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Opening photo: Dopf (l) in the lab with Wilson

S C I E N C E    &    T E C H N O L O G Y

Cellular Clues to a Baffling Disease

When Hopkins cell biologist Kathy Wilson began researching a cellular structure called the nuclear envelope 15 years ago, she had no idea it would lead to studies to uncover the cause of Emery-Dreifuss muscular dystrophy (EDMD).

The nuclear envelope was rather unappreciated. A two-layer membrane made of proteins and fats and forming the boundary between the nucleus and the cytoplasm of a cell, it took a backseat to the real show stoppers--the genes. Many scientists, says Wilson, "naively assumed" it served only a structural role, as the "scaffolding" of the nucleus.

But the discovery of a protein called emerin challenged this theory. In 1994, researchers in Pavia, Italy, reported that mutations in a gene called emerin caused a sex-linked version of EDMD. Two years later, British researchers discovered that emerin was normally located in the nuclear envelope--but that patients with sex-linked EDMD did not produce any emerin at all, or produced defective emerin.

This finding, says Wilson, "was like a bolt of lightning," suggesting that emerin and other nuclear envelope proteins performed a function more specialized than mere scaffolding.

Then last year, French researchers discovered that some cases of EDMD, which were not sex-linked, stem from a mutation in another nuclear envelope protein: lamin A. Wilson now believes that emerin, lamin A, and perhaps other such proteins help control gene expression, the turning "on" and "off" of genes.

The theory is rather complicated, but in general, the idea is that the expression of a gene engages a whole series of genes and proteins, such that, if one gene or protein in the chain is defective, other genes do not get "turned on" and the proteins for which they code do not get synthesized. Conversely, some genes in the pathway may not get "turned off" when they are supposed to, resulting in the production of too much of a particular protein.

Wilson and graduate student Michael Zastrow are now testing that hypothesis using a mouse model of EDMD. The mice lack the lamin A gene. The researchers are screening these "knockout" mice and normal mice using microarray technology, which can show the expression of thousands of genes at a time. Differences in the gene expression profiles of the two types of mice will indicate which genes are compromised in EDMD.

Those results could help pharmacologists develop drugs that target the proteins that are under- or overexpressed in EDMD.
--Melissa Hendricks