Getting Under The Skin of p63

December 2007
By Hans van Bokhoven, PhD, Department of Human Genetics, University Medical Centre Nijmegen

In our laboratory, we try to resolve the exact genetic p63 defect in patients with an ectodermal dysplasia syndrome and we try to gain more insight into the mechanisms by which these mutations cause disease. The identification of new p63 mutations sometimes provides unexpected results and new insights into p63 function.

Part of the complexity of p63 function is due to the fact that the p63 gene carries the instructions for the production of at least six different proteins, the functional executors in living cells and the body. These six proteins are different in their head and tail structures, but the middle body is identical for all of them. For this reason, it is often impossible to figure out whether p63 mutations disrupt the function of multiple p63 proteins or just a specific one.

So far, all mutations in AEC syndrome and Rapp-Hodgkin syndrome (RHS) were located in the same domain within a tail of the p63 protein that is common to only two different p63 proteins. We recently have identified p63 mutations in three AEC/RHS families, which are located in the head domain that is common to three different p63 proteins. Strikingly, combination of these data reveals that there is only one specific p63 protein that is disrupted by all AEC/RHS mutations. Therefore, we now know exactly which protein is responsible for the disease phenotype.

Another part of our research is dedicated to gain more insight into the normal role of p63 in ectodermal development and the disrupted mechanisms that lead to a disease phenotype. For that, we are using specialized epithelial cells from human skin, denoted keratinocytes. Keratinocytes, can be isolated from a small piece of donor skin (from patients or control individuals) and grown in cell cultures in the laboratory as these cells have properties of stem cells that allow them to grow and divide. In our group, we are using the keratinocytes for skin reconstitution experiments to determine which steps in this process require p63. In addition, we use DNA microarray technology to elucidate the molecular and cellular pathways that involve p63.

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