Spotlight on Neurogenetics

Miriam Meisler
Professor
Ph.D., Ohio State University

Of mice and mutations

As a young woman, Miriam Meisler watched her mother endure the ravages of a neurological tumor, an experience that shaped Meisler's career path and research directions. Working in her lab today, unraveling the complexities of such diseases as epilepsy, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Charcot-Marie-Tooth neuropathy, Meisler marvels at how the understanding of neurological disorders has changed since she began her career 40 years ago.

"We've come from knowing the identity of a only few hundred human genes and having the enormous black box of the rest of the genome in the background of our thinking, to a point where we have a 'parts list' of all the genes in the human genome, and it's now a matter of working out their functions and the pathological consequences of their mutations," she says. "It's an amazing moment in human history. We're moving into the era of being able to intervene and design rational treatments."

Meisler uses the laboratory mouse to track down mutations related to human disease and to explore the effects of specific genetic defects. Thanks to the rodent's genetic and physiological similarity to humans and the ease with which its genome can be manipulated and analyzed, the mouse – which develops many of the same disorders as humans -- has become "the premier mammalian model system for genetic research," according to the National Institutes of Health.

One shaky, disoriented mouse initiated a project in Meisler's lab that led to the discovery of a gene involved in Charcot-Marie-Tooth disease (CMT), a common, inherited movement disorder.

"We had a mutant arise in our mouse colony that had a tremor and had lost its ability to sense what direction it was going," Meisler says. "It would turn in circles and couldn't walk forward, and it had a very short lifespan."

Former graduate student Clement Chow, now a postdoctoral fellow at Cornell University, isolated the faulty gene, called FIG4. Other workers in the lab examined the mutant mouse's nervous system to figure out what physiological defect was causing the wobbly gait. They noticed that the fatty sheath surrounding the long fiber of the sciatic nerve was defective, and the nerve's appearance provided the clue they needed to link the mutation to CMT.

"The histology looked just like a textbook case of Charcot-Marie-Tooth," Meisler says. The next step was screening human patients with CMT to see if any had mutations of the same gene. Sure enough, four of the 95 patients tested had the mutation.

The finding led to the description CMT4J, a form of the disease for which no cause had previously been identified. Within a year, a genetic test for that specific type of CMT was available to patients. Now Meisler's lab is investigating ways of preventing or reversing the effects of the mutation.

In other work, Meisler's group employs a different approach. Rather than waiting for a mutation to spontaneously appear and then tracking down the errant gene, they induce specific mutations in mice to test hypotheses about the underlying causes of neurological problems.

"Our work with epilepsy is an example," says Meisler. "We started by asking what would happen if we introduced a mutation into a neuronal sodium channel gene that would prevent it from closing completely." The sodium channel is a cellular gateway that plays a key role in the conduction of nerve impulses, so anything that prevents the channel from working properly could have a devastating effect on neurological function.

"When we introduced the mutation into the mouse, the result was seizures," Meisler says. The resemblance to epilepsy was unmistakable, and soon after that work was done, medical geneticists in France and Switzerland published papers showing that two human families with epilepsy had genes that mapped to the same chromosome region where Meisler's group had introduced the mutation in mice. Further research in the Meisler lab revealed that both families had sodium channel mutations.

"Since then, 700 patients have been found with mutations in the same gene," says Meisler. "It's the major known cause of inherited epilepsy, so that discovery has had a big impact, and it all came out of the mutant mouse."