Subscribe to eTOC

GENETIC MUTATIONS IN SAME GENE BOTH ENHANCE AND INHIBIT PAIN

ARTICLE IN BRIEF

  • ✓ Investigators say new understanding about mutations in the SCN9A gene, which produces proteins for the Nav1.7 sodium channel, could lead to major advances in pain control.

Genetic mutations in SCN9A—one of 11 genes that produce proteins for sodium channels in neuronal membranes to propagate signals — play an important role in pain. In some cases, the mutations seem to cause discomfort, while in others they appear to block it. Investigators say that new understanding of these mutations could lead to major advances in pain control.

In 2005, Stephen G. Waxman, MD, PhD, professor of neurology, pharmacology and neurobiology and chair of the department of neurology at Yale University School of Medicine, attributed erythromelalgia, an inherited form of neuropathic pain, to mutations in the SCN9A gene, which produces proteins for the Nav1.7 sodium channel in dorsal root ganglia (Trends Mol Med 2005; 11(12):555–562). Erythromelalgia results from the insertion of one wrong amino acid into a chain of 1,800 amino acid building blocks that make up each sodium channel on neurons linking the feet and hands to the brain, causing them to over-react to warmth. Some people with the disorder soak their feet in ice water to obtain relief, or wear sandals to prevent heat build-up around their feet.

Last month, Caroline R. Fertleman, MD, of the University College Medical School in London, attributed another condition, paroxysmal extreme pain disorder — a rare autosomal dominant condition that causes intense burning rectal, ocular, or submandibular pain with flushing — to mutations in the same gene (Neuron 2006; 52:767–774).

In both disorders, the genetic defect in SCN9A increases the activity of the sodium channel — it is a gain-of-function mutation — lowering the threshold at which the neurons fire and producing vigorous signals perceived by the brain as excruciating pain.

FU1-12

Dr. Stefan Pulst: “Can we modulate the channel? I think in principle that is possible, but more studies are needed.”

PAIN INHIBITION

But in another discovery reported last month involving mutations in the same gene, a team of British researchers explained a rare disorder that prevents otherwise normal people from experiencing the sensation of pain at all (Nature 2006;444:894–898). The authors call it “channelopathy-associated insensitivity to pain,” caused by a loss of function of the voltage-gated sodium channel gene, SCN9A.

C. Geoffrey Woods, MD, a geneticist and physician at the Cambridge Institute for Medical Research, had heard about a 10-year-old boy in Lahore who was well known for street performances in which he would run a knife through his arm or walk over burning coals, but claimed to feel no pain. In one of his frequent trips to Pakistan Dr. Woods set out to examine the boy, but learned he had died after jumping off the roof of a house to show off for friends. After making inquiries, Dr. Woods located six other children, ages 6 to 14, from three families — all part of the same Qureshi clan as the 10-year-old boy — who also did not feel pain.

“All six affected individuals had never felt any pain, at any time, in any part of their body,” the authors wrote. “Even as babies they had shown no evidence of pain appreciation.” However, they seemed normal in every other way.

“Detailed neurological examination revealed that each could correctly perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli,” the authors wrote. “Pain sensation was assessed by squeezing of the Achilles tendon, firm pressure to dorsal fingertips inflicted with a thumbnail and by venesection; all were felt but not described as painful or unpleasant.”

All six had injuries to their lips and tongue from biting themselves during the first four years of life. Also, most showed evidence of fractures that had caused them to limp or to lose use of an arm or a leg for a while, but which caused no pain.

The people who could not feel pain themselves recognized that others did. One boy, for example, learned to act as though he were in pain when he was knocked down playing sports.

FU2-12

Dr. Howard Fields: “To think that a mutation affecting a single protein in a single channel would have such a profound effect on pain sensation … this was completely unexpected. One mutation creates pain, another blocks it. Im sure the drug companies are tooling up to come up with a drug to block this channel, which would be a highly selective painkiller.”

All six family members turned out to have a defect in the SCN9A gene. The SCN9A gene also influences neurons in the sympathetic nervous system, which controls heart rate and other autonomic functions, but the researchers found no abnormalities in sweating, blushing, heart rate, or blood pressure.

EXPERTS COMMENT

Because of his own work with the SCN9A gene, this finding surprised Dr. Waxman. Mice that lack the equivalent of the human SCN9A gene all die shortly after birth, and he suspects that the cause is failure in the sympathetic nervous system.

“In rodents the Nav1.7 channel is present in nociceptor and sympathetic ganglion nerves,” he noted. “On the basis of that, one would expect to find sympathetic dysfunction.”

For that reason, Dr. Waxman thinks there should be further testing of the sympathetic reflexes of the six children. For example, he would like to see if a Valsalva maneuver — in which a person tries to exhale forcibly with a closed airway so that no air exits through the mouth or nose — does not slow down the heart rate, as expected, or if blood pressure reacts abnormally when they go from a prone to a standing position. “Those tests might show subtle signs of sympathetic dysfunction,” he said.

FU3-12

Dr. Stephen G. Waxman: “Although Nav1.7 channels are present in sympathetic neurons as well as nociceptors, the observations in the people studied by Cox et al. suggest that it may be possible to ameliorate pain by blocking Nav1.7 without producing autonomic side-effects.”

Dr. Waxman was not surprised, however, to find that the SCN9A gene produced a mutation that mirrors the gain-of-function mutation responsible for erythromelalgia. Dr. Waxman believes this new information about the SCN9A gene could lead to major advances in pain control.

“Because Nav1.7 is not present in cardiac muscle or neurons in the central nervous system, subtype-specific blockers of Nav1.7 should not, in principle, have direct actions on these cells and so should have less-severe side-effects than current pain medications,” he wrote in a commentary on the article that appeared in the same issue of Nature (2006;444:831–832). “Although Nav1.7 channels are present in sympathetic neurons as well as nociceptors, the observations in the people studied by Cox, et al. suggest that it may be possible to ameliorate pain by blocking Nav1.7 without producing autonomic side-effects,” he added.

Howard Fields, MD, PhD, professor of neurology, physiology, and psychiatry at the University of California-San Francisco, called the paper on channelopathy “remarkable.”

“To think that a mutation affecting a single protein in a single channel would have such a profound effect on pain sensation … this was completely unexpected,” he said. “One mutation creates pain, another blocks it. I'm sure the drug companies are tooling up to come up with a drug to block this channel, which would be a highly selective painkiller.”

Stefan M. Pulst, MD, director of the division of neurology at Cedars-Sinai Medical Center, also believes this discovery could lead the way to better pain control.“ Can we modulate the channel?” he wondered. “I think in principle that is possible, but more studies are needed.”

Such studies are not so far in the future, he said. “The notable feature of these channels is that they belong to a group of proteins that are among the best understood in terms of their relationships between structure and function, and we can test channel function and the effect of mutations relatively easily in cultured cells,” Dr. Pulst said. “Now we have found mutations that increase the function of the sodium channel and mutations that abolish the function. There may be intermediate mutations that lead to partial loss of function, or to a slight increase — small variations that lead to enhanced or reduced pain perception.”

One important outcome of this knowledge, he said, would be a better understanding of a type of pain that has often been attributed to psychiatric problems. “Some of these (pain) patients have been told there was nothing organically wrong with them,” Dr. Pulst said. “Now we find that there are mutations in single channel that result not in an anatomical abnormality, but in a functional abnormality.”

Dr. Waxman hopes this knowledge will soon produce relief for the neuropathic pain that has driven some patients to suicide. “There are nights I can't sleep knowing how much work is left to be done,” he said.

THE CONNECTION: SCN9A MUTATIONS AND PAIN

Clues that mutations in the SCN9A gene are involved in pain are based on animal studies. The SCN9A gene encodes a sodium channel known as Nav1.7, which is preferentially expressed at high levels in nociceptive dorsal root ganglia neurons and sympathetic ganglion neurons, which are part of the autonomic nervous system. In animal models of inflammatory pain, the dorsal root ganglion neurons showed increased expression of Nav1.7, while mice genetically engineered to lack Nav1.7 in their nociceptors shared reduced responses to inflammatory pain.

REFERENCES

• Waxman SG, Dib-Hajj S. Erythromelalgia: Molecular basis for an inherited pain syndrome. Trends Mol Med 2006;11:555–562.
    • Fertleman CR, Barker MD, Rees, M, et al. SCN9A mutations in paroxysmal extreme pain disorder: Allelic variants underlie distinct channel defects and phenotypes. Neuron 2006;52:767–774.
      • Cox JJ, Reimann F, Woods CG, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444:894–898.
        • Waxman SG. A channel sets the gain on pain. Nature 2006;444:831–832.