October 11, 2002

VUMC team finds genetic cause of fatal nerve disease

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Eric Delpire, Ph.D.

VUMC team finds genetic cause of fatal nerve disease

It is a disease with a cumbersome name — peripheral neuropathy with agenesis of the corpus callosum (ACCPN) — and a devastating course. Though it is a rare disease in the world, it occurs at an alarming rate in a region of Quebec, Canada. Scientists at Vanderbilt University Medical Center and at McGill University in Montreal have now identified the genetic cause of ACCPN. Their findings, reported this week online in Nature Genetics, could lead to therapeutic interventions that slow or prevent the disease’s progressive nerve degeneration.

ACCPN is marked by a loss of myelin, the fatty covering on nerve axons that normally makes rapid transmission of signals possible. Delayed motor development is evident in a patient’s first year of life. With time, nerve degeneration compromises both mental and physical abilities, leaving sufferers wheelchair bound or bedridden by the time they reach adolescence. The average life expectancy for ACCPN patients is just 33 years.

In the Charlevoix-Saguenay-Lac-St. Jean region of Quebec, ACCPN strikes 1 in 2,000 individuals, traveling through families in a recessive fashion. Rare cases have also been reported in other parts of the world, said Eric Delpire, Ph.D., associate professor of Anesthesiology and Molecular Physiology & Biophysics and a senior author of the Nature Genetics paper.

Canadian scientists led by Dr. Guy A. Rouleau had previously linked ACCPN to a region of chromosome 15 that was predicted to contain many different genes. They were working on narrowing down the region to find the causative gene when they got a break. Dr. David B. Mount, then an assistant professor of Medicine at Vanderbilt, now at Harvard, had cloned the gene for a protein called a potassium-chloride cotransporter (named KCC3) and with Dr. Alfred L. George Jr., he had mapped the KCC3 gene to the same region of chromosome 15 where ACCPN was linked.

“It was logical to suggest that KCC3 might be a good candidate gene as the cause of ACCPN, and it turned out to be right,” Delpire said.

In patients with ACCPN, the McGill team identified four different KCC3 gene mutations, all of which result in non-functional KCC3 protein. It is the first neurodevelopmental disorder caused by an ion cotransporter defect, Delpire said.

KCC3 is one of several potassium-chloride cotransporters, proteins that reside in the cell membrane and, in response to changes in cell volume and other signals, move the ions potassium and chloride out of the cell. Delpire and colleagues are using a variety of approaches, including engineering “knockout” mice that are missing the cotransporters, to probe the physiological functions of these molecules.

Mice lacking KCC3 mimic some of the symptoms of ACCPN, lending further support to the premise that defects in the KCC3 gene cause the disease, Delpire said. The KCC3 knockout mice have locomotor deficits and peripheral neuropathy similar to the human disease. The mice also have hints of the psychotic disturbances that can trouble ACCPN patients; they show impaired sensorimotor gating, a measure used to assess characteristics of schizophrenia.

The knockout mice do not share one feature of ACCPN — the missing corpus callosum, the wide band of nerve fibers that connects the two sides of the brain. This feature, however, is variable in patients with the disease: one-fourth of all patients have a normal corpus callosum, and the remainder may have complete or only partial absence of the structure.

How defects in a molecule that moves potassium and chloride out of the cell contribute to the pathology of ACCPN is unknown at this point, Delpire said.

The group is exploring the possibility that the KCC3 cotransporter plays a role in cell growth or death, especially in cells called oligodendrocytes, which express the highest levels of the cotransporter, and in Schwann cells, which undergo degeneration in the knockout mice. Both of these cell types support neurons and produce the myelin coating known to be defective in ACCPN. Another possibility, Delpire said, is that the cotransporter normally participates in the process of myelin compaction onto the nerve axon.

“Basically we do not have any clue how KCC3 cotransporter mutations lead to disease,” Delpire said. “It is clear though that this cotransporter plays an important role in the development and maintenance of both the central and peripheral nervous systems.

“Connecting KCC3 to a disease process gives us a very big puzzle to solve,” Delpire added. “We’re looking at 5 to 10 years of very interesting science as we try to sort out the biology behind the defect. It’s very exciting.”

Right now, the identification of a gene responsible for the disease opens the possibility of genetic screening for individuals who might carry one copy of the defective gene. Because it takes two defective copies of the gene to cause the disease, a man and woman who are both carriers are at risk of having a baby with ACCPN. It is estimated that as many as 1 in 20 individuals in the affected region of Quebec carry the mutation. This high frequency is likely due to a so-called “founder effect,” Delpire said, because the region was settled by a small number of individuals who are essentially the ancestors of a large portion of the current population.

In the future, Delpire said, understanding the biology of the disease will likely translate into better therapies for patients suffering from ACCPN. And it could shed light on the pathology of demyelinating diseases in general. There are more than 10 different types of diseases in which nerves lose their myelin coating, and in no case is the underlying biology fully understood, he said.

Other Vanderbilt investigators who participated in the research include Nellie Byun, Jianming Lu, Xuemo Fan, Luyan Song, Rick Welch, Roger England, Frank Q. Zhan, Adriana Mercado, William B. Siesser and Michael P. McDonald. The work was supported by the National Institutes of Health and the Canadian Institute for Health Research.