Journal Club I

Last week, I presented a Nature 2006 paper at Basic Sciences Journal Club on a gene mutation which confers an inability to experience pain. It's a pretty fascinating paper, demonstrating a remarkable journey from a very rare phenotype to identifying the gene and confirming that the mutated protein is likely to cause the presentation of the disease. The paper spends some time describing these patients: they have never felt any pain on any part of their body at any time. It's pretty crazy. They have normal sense of light touch, vibration, temperature, proprioception (where their limbs are), and tickle. But the lack of pain sensation means they never learn what things are harmful to them; one of the people studied was a boy who did street theater where he stuck knives into his arms and walked on burning coals. So lack of pain is really not a gift, but a danger to these people.

They identified several families with this phenotype and mapped the disease gene through positional cloning with microsatellite markers. They finally identified SCN9A as the mutated gene in these patients. SCN9A encodes an alpha subunit of a voltage-gated sodium channel found at the ends of nociceptive (pain-sensing) neurons. Sodium channels often start action potentials, signals which communicate to the brain. It makes sense that if you had nonfunctional sodium channels at the ends of pain-sensing neurons, you wouldn't feel any pain.

The authors then confirmed this by doing in vitro studies with voltage-clamping to show that indeed, these mutations led to nonfunctional sodium channels. Although this was expected, I spent some time going over the technique and interpretation of patch-clamping and voltage-clamping. In the end, the authors had demonstrated that mutations in this sodium channel leading to nonfunctional proteins causes this very strange phenotype of insensitivity (or indifference) to pain.

(Cox, JJ et al. "An SCN9A channelopathy causes congenital inability to experience pain." Nature Vol 444, 14 December 2006, p.894-898)