EBS patient cells with null mutations in the K14 gene
© 2011 Society for Investigative Dermatology
Patients with epidermolysis bullosa simplex (EBS) have overly delicate skin that blisters easily. Their skin cells become extremely sensitive to the external environment and might burst in response to stress. Birgit Lane from the A*STAR Institute of Medical Biology and co-workers from the University of Dundee in the UK and University of Groningen in the Netherlands have now found that gene therapy could help restore the skin’s normal resistance to physical damage.
EBS is caused by mutations in the genes that encode the proteins keratin 5 and keratin 14 (K14). These proteins assemble into filament structures that help to keep epithelial cells in the skin strongly linked together and therefore durable against friction and other stressors. Most of the EBS-causing keratin mutations cause weakness in the keratin network, which can collapse and form aggregates upon mild physical trauma. Previous work by this group has shown that the skin cells of EBS patients carrying these ‘dominant negative’ (DN) mutations have an enhanced response to various stressors, such as exposure to heat or stretching.
‘Null’ mutations that cause the complete lack of a keratin protein in EBS patients’ skin cells have also been reported. Lane and her co-workers examined the stress responses of cells with a total lack of K14 (see image), and found that their reaction to stress could, in some cases, be quite different from the cells carrying a DN mutation.
For example, heat stress caused the DN mutant cells to form keratin aggregates, but these aggregates did not appear in the K14-null cells after exposure to the same type of stress. Both cell types had a faster than normal activation of stress-related signaling pathways in response to conditions that caused cell swelling or recreated the effect of a skin wound, suggesting that stress responses are more easily triggered in both types of EBS patient cells compared with normal cells. However, the DN cells’ response to any type of stress was significantly higher than the keratin-null cells. “The total lack of K14 can therefore be less detrimental than a DN mutation in the keratin gene,” explains Mariella D’Alessandro from the research team.
Strikingly, the researchers showed that adding back the gene that encodes K14 protein into the K14-null cells can reduce the overactive response to physical stresses. These findings suggest that the introduction of healthy genes into EBS patients lacking K14 could make their skin more resilient to friction and other stressors and may therefore represent a potential therapeutic approach in the treatment of EBS.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology.
