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| Uncomfortably numb: The people who feel no pain | Uncomfortably numb: The people who feel no pain |
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| Being unable to feel pain may sound appealing, but it would be extremely hazardous to your health. Pain is, for most of us, a very unpleasant feeling, but it serves the important evolutionary purpose of alerting us to potentially life-threatening injuries. Without it, people are more prone to hurting themselves and so, because they can be completely oblivious to serious injuries, a life without pain is often cut short. | |
| Take 16-year-old Ashlyn Blocker from Patterson, Georgia, who has been completely unable to sense any kind of physical pain since the day she was born. As a newborn, she barely made a sound, and when her milk teeth started coming out, she nearly chewed off part of her tongue. Growing up, she burnt the skin off the palm of her hands on a pressure washer that her father had left running, and once ran around on a broken ankle for two whole days before her parents noticed the injury. She was once swarmed and bitten by hundreds of fire ants, has dipped her hands into boiling water, and injured herself in countless other ways, without ever feeling a thing. | Take 16-year-old Ashlyn Blocker from Patterson, Georgia, who has been completely unable to sense any kind of physical pain since the day she was born. As a newborn, she barely made a sound, and when her milk teeth started coming out, she nearly chewed off part of her tongue. Growing up, she burnt the skin off the palm of her hands on a pressure washer that her father had left running, and once ran around on a broken ankle for two whole days before her parents noticed the injury. She was once swarmed and bitten by hundreds of fire ants, has dipped her hands into boiling water, and injured herself in countless other ways, without ever feeling a thing. |
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| Ashlyn is one of a tiny number of people with congenital insensitivity to pain. The condition is so rare, in fact, that the doctor who diagnosed her in 2006 told her parents that she may be the only one in the world who has it. But later that year, a research team led by Geoffrey Woods of the University of Cambridge, identified three distinct mutations in the SCN9A gene, all of which cause the same condition in members of three large families in northern Pakistan, and in 2013, Ashlyn’s doctor Roland Staud and his colleagues reported that her condition is the result of two other mutations in the same gene. | Ashlyn is one of a tiny number of people with congenital insensitivity to pain. The condition is so rare, in fact, that the doctor who diagnosed her in 2006 told her parents that she may be the only one in the world who has it. But later that year, a research team led by Geoffrey Woods of the University of Cambridge, identified three distinct mutations in the SCN9A gene, all of which cause the same condition in members of three large families in northern Pakistan, and in 2013, Ashlyn’s doctor Roland Staud and his colleagues reported that her condition is the result of two other mutations in the same gene. |
| Now, Woods and his colleagues have discovered yet more mutations that cause congenital insensitivity to pain. They studied 11 families form around the world, and identified within them 158 individuals, all of whom suffer from either congenital pain insensitivity or hereditary sensory and autonomic neuropathy, another rare condition that also causes loss of pain sensation by damaging the nerves that carry pain signals up the spinal cord and then into the brain. | Now, Woods and his colleagues have discovered yet more mutations that cause congenital insensitivity to pain. They studied 11 families form around the world, and identified within them 158 individuals, all of whom suffer from either congenital pain insensitivity or hereditary sensory and autonomic neuropathy, another rare condition that also causes loss of pain sensation by damaging the nerves that carry pain signals up the spinal cord and then into the brain. |
| Using state-of-the-art DNA sequencing techniques, the researchers analysed and compared their genomes, and identified no less than 10 different mutations that cause congenital insensitivity to pain, all within a gene called PRDM12, located on the long arm of chromosome 9. | Using state-of-the-art DNA sequencing techniques, the researchers analysed and compared their genomes, and identified no less than 10 different mutations that cause congenital insensitivity to pain, all within a gene called PRDM12, located on the long arm of chromosome 9. |
| Individuals carrying two defective copies of this gene produce a non-functional PRDM12 protein, and as a result of this have been unable to feel any kind of physical pain, or to distinguish between painfully hot and cold temperatures, from birth. Most of them have experienced numerous, painless injuries. As infants and young children, they bit their fingers, toes, and lips so often that they are severely mutilated, and hurt themselves many times and in many other ways. The worst affected have suffered repeated infections while growing up, injuries that scarred their skin and deformed their bones. | Individuals carrying two defective copies of this gene produce a non-functional PRDM12 protein, and as a result of this have been unable to feel any kind of physical pain, or to distinguish between painfully hot and cold temperatures, from birth. Most of them have experienced numerous, painless injuries. As infants and young children, they bit their fingers, toes, and lips so often that they are severely mutilated, and hurt themselves many times and in many other ways. The worst affected have suffered repeated infections while growing up, injuries that scarred their skin and deformed their bones. |
| PRDM12 is the third human gene to be associated with congenital insensitivity to pain. SCN9A was the first such gene to be discovered, and we now know of at least 13 different mutations in it, all of which cause congenital insensitivity to pain. In 2013, another research team reported that they had identified a mutation in a related gene, called SCN11A, which also causes the condition. SCN9A and SCN11A encode sodium channel proteins that pain-sensing fibres need to generate nervous impulses. | |
| Mutations in SCN9A produce a non-functional sodium channel, so that pain fibres can still detect painful stimuli but are unable to send signals about them to the brain. The SCN11A mutation produces over-active sodium channels that interfere with the pain fibres’ ability to produce and send their impulses. | |
| The PRDM12 mutations cause pain insensitivity another way. When Woods and his colleagues examined biopsies from several of the affected people they studied, they found that the skin in their legs contains no nerve endings whatsoever, and that one of the sensory nerves in their legs contains about half the normal number of pain-sensing fibres. This led them to speculate that PRDM12 plays an important role in the development of pain-sensing neurons and their fibres. | The PRDM12 mutations cause pain insensitivity another way. When Woods and his colleagues examined biopsies from several of the affected people they studied, they found that the skin in their legs contains no nerve endings whatsoever, and that one of the sensory nerves in their legs contains about half the normal number of pain-sensing fibres. This led them to speculate that PRDM12 plays an important role in the development of pain-sensing neurons and their fibres. |
| Exploring further, they examined the distribution of PRDM12 in developing mouse embryos, and in pain neurons generated from human stem cells. This revealed that the protein is synthesized at the exact time when pain neurons are forming, and in exactly the right places – in the region where immature pain neurons are first created, along the migration route they take before maturing, and in the dorsal root ganglia and superficial layers of the spinal cord, where their cell bodies and fibres end up, respectively. | Exploring further, they examined the distribution of PRDM12 in developing mouse embryos, and in pain neurons generated from human stem cells. This revealed that the protein is synthesized at the exact time when pain neurons are forming, and in exactly the right places – in the region where immature pain neurons are first created, along the migration route they take before maturing, and in the dorsal root ganglia and superficial layers of the spinal cord, where their cell bodies and fibres end up, respectively. |
| Related: Researchers identify gatekeeper neurons that control pain and itch | Related: Researchers identify gatekeeper neurons that control pain and itch |
| The researchers then reduced the amount of PRDM12 protein synthesized by developing frog embryos, and found that this significantly altered the distribution of pain nerves. The PRDM12 protein is a transcription factor, or a “master control gene” that regulates the activity of dozens of other developmental genes. Woods and his colleagues performed one final set of experiments which suggest that it does so by means of epigenetic modifications that switch these genes on or off by altering chromosome structure. | The researchers then reduced the amount of PRDM12 protein synthesized by developing frog embryos, and found that this significantly altered the distribution of pain nerves. The PRDM12 protein is a transcription factor, or a “master control gene” that regulates the activity of dozens of other developmental genes. Woods and his colleagues performed one final set of experiments which suggest that it does so by means of epigenetic modifications that switch these genes on or off by altering chromosome structure. |
| These results confirm that PDRM12 is essential for the development of pain-sensing neurons, and neatly explain why it causes pain insensitivity when mutated. Whereas people with a mutation in SCN9A or SCN11A have pain fibres that don’t send signals, those carrying a PDRM12 mutation fail to develop pain fibres altogether. | These results confirm that PDRM12 is essential for the development of pain-sensing neurons, and neatly explain why it causes pain insensitivity when mutated. Whereas people with a mutation in SCN9A or SCN11A have pain fibres that don’t send signals, those carrying a PDRM12 mutation fail to develop pain fibres altogether. |
| Pain is a major global health problem that affects a significant proportion of the world’s population, and has an estimated annual cost of at least $560 billion in the U.S. alone. Management of chronic pain – defined as any pain lasting longer than 3 months – can be especially difficult, as it often presents itself with no underlying physical cause. | |
| These new findings open up promising avenues for understanding pain, and suggests that it may be possible to develop new analgesics that target PRDM12 and provide relief by epigenetic “reprogramming” of over-active pain neurons. | |
| Reference | Reference |
| Chen, Y. –C., et al. (2015). Transcriptional regulator PRDM12 is essential for human pain perception. Nat. Genet. doi: 10.1038/ng.3308. | Chen, Y. –C., et al. (2015). Transcriptional regulator PRDM12 is essential for human pain perception. Nat. Genet. doi: 10.1038/ng.3308. |