Studying Kindler Syndrome in a model system

Contents:

• Project information
• Lay summary

Investigator: Arnoud Sonnenberg, Head of Division of Cell Biology

Institution: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Grant: £101,998 (01/11/11-31/10/13)

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. The research group showed that 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 in human skin cells.

What is important about this research?

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.

Investigator biography Dr. Arnoud Sonnenberg is Head of the Division of Cell Biology at the Netherlands Cancer Institute in Amsterdam and Professor at the University of Leiden. His primary interest is to understand the importance of integrins in regulating adhesion and chemical signals important for proliferation and differentiation. He is particularly interested in those integrins whose absence in affected individuals causes junctional epidermolysis bullosa and that play a role in skin cancer. Dr. Sonnenberg worked at the Salk Institute and Scripps Clinic & Research Foundation in San Diego and after obtaining his PhD from the University of Amsterdam, established his research group in Leiden.