Researchers at University of Texas Southwestern Medical Center have discovered a gene that may play a role in a rare muscular disease in humans.

While the researchers studied mice, they are now looking for patients who have mutations in this newly discovered muscle gene, Srpk3.
Mice that lack the gene have a condition much like the human disease, centronuclear myopathy.

" It's easy to imagine that human patients could have symptoms similar to those we saw in mice," said Osamu Nakagawa, the paper's lead author. " The human research is just starting, but already we found patients who may have mutations in the gene."

The researchers' work appears in the Genes and Development.

There are several forms of centronuclear myopathy, including one that is apparent at birth. Children with the condition have trouble moving or breathing and often must depend on ventilators. Other forms show up later in life.

The first stage of the UT Southwestern study involved searching for important muscle genes downstream of muscle-specific gene regulation.
Scientists have known that one protein, called MEF2, is essential to the formation of skeletal muscles and heart, but didn't know its exact mechanism.

The researchers found that one of MEF2's jobs is to activate the gene they discovered, Srpk3. Nakagawa compared Srpk3 to a light bulb and MEF2 to the switch: MEF2 binds to DNA, and that action turns on the gene that creates the Srpk3 protein.

The second part of their study was to see what happened in two groups of mice: one without the Srpk3 protein, and one with too much.

In both cases, the muscles were defective. Most of the group without Srpk3 showed the same defect as people with centronuclear myopathy – the nuclei of their muscle cells were in the center of the cells instead of at the edges where they are normally.

The mice with too much Srpk3 also showed marked muscle damage. Their muscles degenerated, and they showed deformities. They died at about 2 months of age or earlier.

" Srpk3 could be an additional disease gene," Nakagawa said. " It's still a hypothesis. We are trying to be very careful and conservative in discussing possible human mutations, but we are actively analyzing the functions of mutations in Srpk3."

The next step is to find what Srpk3 does – for instance, does it act on a particular protein that the researchers can identify, Nakagawa said.
They know Srpk3 is a molecule that regulates functions of other proteins in the cells, but they have to find which proteins are its targets. By studying what the Srpk3 protein does, they will try to find out if it directly causes disease in humans.

Source: UT Southwestern Medical Center, 2005


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