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Studying Kindler Syndrome in a zebrafish model system (Sonnenberg 4)

Project lead Arnoud Sonnenberg
Organisation The Netherlands Cancer Institute (NKI), Amsterdam, THE NETHERLANDS
Project budget GBP 101,998.00
Start date / Duration 01. Nov 2011 / 24 months
Funder(s) / Co-Funder(s) DEBRA UK, EB MSAP/EBEP Recommended
Research area Cellular therapy

Project details

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.

Strategic relevance

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.”

What did this project achieve?

In this project, the research team has studied the functions of kindlin-1 using kindlin-1-mutant zebrafish. The mutant zebrafish develop cell-matrix and cell-cell adhesion defects in the basal epidermis leading to progressive fin rupturing, which therefore is designated, rupturing-of-fins (rof). Similar defects were observed in the epidermis of Kindler syndrome patients carrying germline mutations in KIND1. Mutational analysis and rescue experiments in zebrafish embryos revealed that the F3 domain of Kindlin-1 containing the major integrin-binding site is essential for its function in vivo, and that Kindlin-2 can compensate for the loss of Kindlin-1.

The fin phenotype of rof/kindlin-1 mutants resembles that of badfin mutants, carrying a loss-of-function mutation in the gene encoding Integrin α3. Genetic interaction studies revealed that Integrin α3β1 and Kindlin-1 cooperate to avoid trauma-induced epidermal defects. A similar interaction was observed between Kindlin-1 and Integrin-linked kinase (ILK). However, Kindlin-1 and Ilk surprisingly do not act in a synergistic but in a parallel fashion.

Studies performed with a keratinocyte cell line derived from a Kindler patient revealed that despite the presence of endogenous kindlin-2, the cells exhibited reduced integrin function including reduced cell adhesion and spreading. These defects could be rescued by expression of wild-type kindlin-1, but not by a β1-binding defective mutant, indicating that the interaction between kindlin-1 and β1 is required for proper maintenance of integrin adhesive function. Our finding that the surface levels of β1 integrins are strongly reduced in KS keratinocytes suggests that the association between kindlin-1 and β1 is required for stable expression of integrins at the cell surface. One mechanism by which kindlin-1 may exert this effect is by preventing the binding of β1 to endocytotic adaptor proteins involved in clathrin-dependent endocytosis of integrins. Furthermore, kindlin-1 may facilitate the sorting of those integrins that are internalized into a recycling compartment from which they can directly return to the plasma membrane in stead of becoming degraded by lysosomes. Reduced expression of integrins at the surface of KS keratinocytes may be one of several factors that contribute to the defects in cell-matrix adhesion observed in KS patients.

More on DEBRA UK's website.


Kindler Syndrome
skin cells
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