No pain, no gain (of function) – Patrick Flynn – Medium

A rare genetic mutation in the gene that encodes the ion channel, NaV1.9, disrupts pain perception in people and in mice.

Some people do not feel pain. Even severe tissue damage in these individuals does not elicit a response. The causes of this disorder are not well known, but clinical research suggests that genetics play a role.

Pain perception in healthy individuals requires information to travel from the peripheral body parts to the spinal cord and brain by way of pain-sensing neurons. Any defect along this pathway may prevent pain. A key molecular component of this pathway is the ion channel. When activated, an ion channel allows a particular ion to flow into or out of a neuron. Movement of sodium ions into the neuron is largely responsible for a neuron’s activation.

In 2006, investigators identified a genetic change, or mutation, in members of a Pakistani family who are pain-insensitive. The mutation disrupts sodium ion channel (NaV1.7) function and presumably prevents the transmission of pain information to the brain. Investigators in the present study wanted to know if a young German girl, who was born insensitive to pain, carried a genetic mutation that caused the disorder. The answer to this question is not only important to better understand this rare pain disorder, but also to better understand pain perception in general.

Leipold et al. compared the genome of the pain-insensitive girl to her healthy parents’ genomes. They discovered a rare mutation in a gene that codes for a sodium channel, called NaV1.9. This channel is found specifically in pain neurons. The same mutation was found in a Swedish man who also could not feel pain. The rarity of these mutations suggest that the genetic alteration does, in fact, cause pain insensitivity.

Next, investigators created an analogous mutation in mice. These mice were much less responsive to thermal and mechanical stimuli than normal mice, but were not completely insensitive. Investigators then recorded cellular ionic currents from these mice, and found that mutant cells expressing the modified sodium ion channel are activated more easily and were inactivated more slowly. The modified ion channel is overactive, yet pain is reduced.

Findings from this investigation point out a mutation that causes congenital pain-insensitivity in humans. These results provide invaluable information about the causes of sensory loss, but also genetic influences on pain in general. Response to pain medicines vary widely among individuals, possibly because of genetic variability. By understanding the role of NaV1.9 in pain perception, medical professionals will provide more effective and safer ways to treat pain.

Leipold, Enrico, et al. “A de novo gain-of-function mutation in SCN11A causes loss of pain perception.” Nature Genetics. 45 (2013): 1399–1404.

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