Studying Kindler Syndrome in a zebrafish model system (Sonnenberg 4)Completed
|The Netherlands Cancer Institute (NKI), Amsterdam, THE NETHERLANDS
|Start date / Duration
|01. Nov 2011 / 24 months
|Funder(s) / Co-Funder(s)
|DEBRA UK, MSAP/EBEP Recommended
Short lay summary
Kindler Syndrome (KS), named after the first person to describe it, Theresa Kindler, is a type of EB in which the skin of babies and children is fragile, sensitive to light and prone to blisters in response to trauma. As the patient ages, abnormal pigmentation develops in the skin, spider and thread veins occur, and the skin becomes thinner making it vulnerable to damage. There can also be problems with the lining of the mouth, progressive hair loss, gastro-intestinal disturbances and occasionally skin tumours.
KS is caused by mutations in a gene called KIND1 which normally controls the production of the protein kindlin-1. One role of kindlin-1 is to activate or stimulate other molecules called integrins which lie at the heart of many cellular processes, e.g. the “integrity” or well-being of the skin cells. In KS it is difficult to understand which aspect of integrin function is at fault in the skin cells.
In this study, the research group had to separately study different aspects of the problem: one part of the study was aimed at investigating whether another related protein, kindlin-2, could compensate for the loss of kindlin-1: the second part was to investigate whether “recycling” of integrins in KS occurs normally.
They used a laboratory ‘model’ that provides a good imitation of KS. A small type of tropical zebrafish lacking kindlin-1 experiences fin ruptures and blistering, equivalent to the skin blistering of KS patients. The research group showed that the fish developed normal fins after kindlin-2 was given to the embryo, meaning kindlin-2 could compensate for the loss of kindlin-1, yet natural levels of kindlin-2 present in KS patients are not enough to compensate for the absence of kindlin-1. They then found that when kindlin-1 was missing a particular part of the molecule that binds to the integrins, the protein did not function properly either in fish or human skin cells.
This research has answered an important question: kindlin-1 loss in KS skin cells means that integrins are not activated or recycled properly which gives rise to poor structure and fragility of the skin, however the natural levels of kindlin-2 are insufficient to overcome this problem. This information is invaluable as researchers continue to try and understand the genetic defects in KS.
“The results of this DEBRA research have increased our understanding of the molecular mechanisms underlying Kindler Syndrome, which may lead to the development of new therapeutic strategies for this disease.”