A single genetic mutation that leads to early onset of cold-aggravated, peripheral pain in humans has been identified in a European family. A molecular mechanism underlying the temperature dependence of this type of pain is presented this week in Nature Communications and linked to altered ion channel function in cells.

Ingo Kurth and colleagues study a three-generation family of European ancestry who suffer from cold-aggravated pain - including a six-year-old girl, her father, her paternal aunt, her paternal aunt’s daughter and her paternal grandmother - and perform whole-exome sequencing on two of the family members. They identify a specific genetic mutation that results in modifications to a sodium ion channel, which in turn changes the excitability of sensory neurons. Normally, the activity of these neurons is reduced at lower temperatures, but when the mutation is present, the neurons remain highly active even under cold conditions. The researchers propose that this increased excitability in pain-sensing neurons may lead to heightened cold-pain sensitivity.

These results are consistent with previous experiments in rodents and aid our understanding of this common pain disorder.