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Newly identified gene mutation explains why one family experiences unusual pain response to cold

snowy-handprintIf you’ve ever plunged your hand into a tub of ice water, you know about the overlap between cold and pain: that deep, biting ache makes you want to get your hand out of the water - fast. But while the protective value of that sensation is obvious, scientists have always been a bit mystified by how pain-sensing nerves register cold temperatures.

But now, research on a family with an extremely unusual gene mutation may help clarify what's going on. The mutation, whose discovery was reported online this week in Nature, confers a heightened pain response to cold. The research was initiated by Stanford geneticists and expanded by scientists at three universities in Germany who specialize in hereditary pain syndromes.

The story began with a family who brought their young daughter to Lucile Packard Children's Hospital Stanford to get help for her unusual episodes of pain. When cold, she experiences pain in her joints that radiates out to her arms and legs. The pain lasts 20 to 30 minutes at a time. The little girl's father, paternal grandmother, paternal aunt and first cousin (the aunt's daughter) also experience similar pain episodes, as the new paper explains in detail.

"When we saw her, we were really struck by the fact that the pain was going on in multiple generations of the family," said one of the study's authors, medical geneticist Jon Bernstein, MD, PhD. The pattern of inheritance made Bernstein suspect an autosomal dominant disease, in which only one bad copy of a gene causes symptoms. Although several hereditary pain syndromes are described in the medical literature, none matched the exact pattern of symptoms this family experienced, so the Stanford clinicians asked the German scientists to figure out what was going on.

The German team looked for rare mutations shared by the little girl and her cousin, finding one in a gene that codes for an electrical channel in nerve cell membranes. (Nerves transmit electrical signals via flow of charged ions through tiny protein tubes embedded in the cell membrane. There are several types of these channels.) The scientists' experiments demonstrated that they had discovered a gain-of-function mutation – in which the encoded protein, instead of being rendered nonfunctional, instead alters what it does. In this case, there is a substitution of one amino acid for another in the structure of the affected electrical channel. That change causes pain-sensing nerves to fire at cool temperatures most people don’t find painful.

The same electrical channel, Nav1.9, was also identified as “a key determinant of cold pain sensation” in a paper published earlier this year that examined its activity in rats and mice. That study found that the channel was important to setting animals’ threshold for when cold begins to feel painful, and the new findings fit into that picture nicely.

The German team plans to continue studying the channel’s dynamics to help learn more about the normal threshold between cold and pain, Bernstein said. As for him? “I’m very much looking forward to working with the next family whose case is unsolved,” he told me.

Previously: One mutation, two people and two (or more) outcomes: What gives?, Crying without tears unlocks the mystery of a new genetic disease and Exploring the mystery of pain
Photo by Chris Geatch

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