CCD Research Mouse Sheds New Light on Human Disease

Since 1993 — when mutations in the RYR1 gene were first linked to central core disease (CCD)— researchers have been trying to figure out exactly how these mutations cause the disease and what can be done to combat their deleterious effects.

Now, investigators in the United States, Canada and Germany have added an important piece to the CCD puzzle, through careful studies of mice with a particular mutation in the RYR1 gene that commonly causes human CCD.

Background on CCD biology

A great deal has been learned since the 1990s about the biology of CCD, a disease in which "cores" that lack metabolic activity mysteriously appear in muscle fibers.

Normally, the RYR1 protein forms a channel that releases calcium in response to a signal from a nerve fiber. A quick burst of calcium allows the muscle fiber to contract, after which the calcium retreats to storage areas and awaits its next release command. Between calcium bursts, muscle fibers relax.

Until recently, it was thought that almost all of the many mutations in the RYR1 gene that can lead to CCD caused the RYR1 channel to develop a slow calcium leak.

These leaks interfere with the ability of muscle fibers to generate a calcium burst necessary for a complete contraction, while at the same time depleting the fiber's calcium stores and in some way leading to the destruction of muscle tissue and the formation of empty cores. (The precise mechanism of core formation still isn't clear.)

In addition, calcium leaks appear to predispose people with CCD to a dangerous reaction to inhaled anesthetics known as malignant hyperthermia.

Calcium leaks describe what many mutations in the RYR1 gene do — but not all. Recently, it's been found that some mutations actually block calcium, reducing the amount that’s released from the RYR1 channel.

The consequences of either type of RYR1 mutation — those that cause slow leaks of calcium or those that block calcium — are similar in that they both lead to a decrease in calcium flow through the RYR1 channel when the muscle is signaled to contract. This results in weakness, and over time, leads to muscle fibers with cores.

One difference in the two types of mutations may be that calcium-blocking mutations may not lead to susceptibility to malignant hyperthermia in response to inhaled anesthetics, the way leakage mutations apparently do.

About the new findings

Robert Dirksen at the University of Rochester (N.Y.) coordinated the study team, which included investigators at that institution, and at the University of North Carolina, the University of Toronto and Ulm University in Germany. Ryan Loy at the University of Rochester was the lead author on the paper, which was published online Dec. 13, 2010, in the Journal of General Physiology. Dirksen is a former MDA research grantee, although MDA did not fund this study.

The investigators bred mice with a mutation in the RYR1 gene called I4895T, which is comparable to the I4898T mutation that’s a common cause of CCD in humans. They then conducted careful measurements of muscle strength and analyzed the muscle tissues of these mice.

They found that RYR1 channels in the I4985T mice did not allow enough calcium to move through the open channel when the muscle was stimulated to contract. That's in marked contrast to mice bred to have another common CCD-causing mutation, in which a persistent calcium leak is present in the RYR1 channel.

The scientists also found that the I4985T mice showed reduced grip and upper-body strength compared to normal mice.

Dirksen's team didn't see the cores that are the hallmark of CCD in the I4985T mice they bred in these experiments, but they speculate that this may be because they only studied mice up to the age of 4 to 6 months. Dirksen and other investigators have reported telltale signs of cores in older I4985T mice in other studies.

The researchers say that the I4895T mice provide strong evidence that this gene flaw acts in a manner that is quite different from mutations that cause a persistent calcium leak.

They also say they don't believe this mutation would lead to malignant hyperthermia reactions to anesthesia.

Meaning for people with CCD

There are no immediate implications for people with CCD, except that those with this particular calcium-blocking mutation may not have to concern themselves as much with malignant hyperthermia reactions as those who have other CCD-causing mutations.

That, however, remains to be confirmed. Meanwhile, all CCD patients undergoing surgery should be sure the surgical team is aware of their condition before they're given anesthesia, so that appropriate precautions can be taken.

As for long-term implications, the findings add to the storehouse of knowledge about the causes of CCD and its molecular underpinnings — knowledge that is crucial for the development of new and effective therapies.

Some future treatments for CCD may be targeted to particular types of disease-causing genetic mutations, so genetic testing of individuals with CCD may become highly relevant.

"Specifically, while two apparently fundamentally different CCD mechanisms — 'leakage' versus 'blockage'— can lead to similar clinical outcomes, they may respond very differently to different treatment regimens," Dirksen said.

These results indicate that genetic testing and mutation-specific therapies represent a form of personalized medicine that is clearly on the horizon for future treatment and management of malignant hyperthermia, central core disease and other genetically inherited muscle disorders, said Dirksen.

“For example, a drug that reduces calcium flow through the RYR1 channel might help an individual possessing a leakage mutation, but might exacerbate symptoms of someone exhibiting a blockage mutation," he explained.

Information about genetic testing can be obtained through MDA clinics and through Gene Tests, a website supported by the National Institutes of Health that lists genetic testing laboratories.

For more about CCD biology, see the MDA Quest magazine package In Focus: Central Core Disease.  It includes these articles:

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