Important Discovery Made in AEC and EEC Research

January 10, 2017May 7, 2019 Category: Research Posted by NFED

By Maranke I. Koster, Ph.D. and Peter J. Koch, Ph.D., University of Colorado School of Medicine

Since our last research update, we have been hard at work to understand the basis for skin and eye abnormalities that occur in patients affected by ankyloblepharon-ectodermal defects-clefting (AEC) syndrome and ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome. These two ectodermal dysplasias are caused by mutations in the p63 gene.  In particular, we want to understand how mutant p63 causes fragility and breakdown of the epidermis (outer layer of the skin) and cornea (outer layer of the eye).

To start these studies, we initially needed cells from AEC and EEC patients.  We were very fortunate to find volunteers affected by AEC or EEC who were willing to donate a skin biopsy to our research program. Cells isolated from these biopsies were grown in the lab, and were then converted into induced pluripotent stem cells (iPSC).  We also corrected the p63 mutation in the DNA of these cells using advanced gene-correction tools.

iPSC with and without the p63 mutation were then converted into either skin cells (keratinocytes) or eye cells (corneal cells).  In other words, we have now pairs of cells from the same patients that are absolutely identical except for the presence/absence of the p63 mutation.  By comparing these pairs of cells to each other, we will gain a very detailed understanding of how the p63 mutation causes cell fragility.

Important Discovery

The most important discovery that we have made so far is that normal p63 controls genes that are important for keratinocytes to adhere to each other and to adhere to the underlying dermis. When p63 is mutated, these genes are not appropriately expressed.  As a result, the cells fail to firmly adhere to each other and potentially to the dermis on which they sit.  We believe that this finding might explain the skin erosions that occur in AEC and EEC patients.  We also believe that these processes underlie corneal fragility in patients affected by AEC or EEC.  In the worst case scenario, this corneal fragility sets off a cascade of events that leads to severe vision loss.

Our Next Steps

We now believe that we have identified key genes and proteins that contribute to tissue fragility in AEC and EEC patients.  We are in the process to further define the precise molecular mechanisms by which mutant p63 affects genes and causes skin and cornea fragility.  A new task will be to confirm the results obtained in our iPSC-derived cells in real patient tissue.  Although this is not feasible for the eye, a new set of skin biopsies would allow us to confirm our research findings in skin from AEC/EEC patients.  Ultimately, a complete understanding of the mechanisms underlying AEC and EEC will be essential for designing therapies aimed at restoring the skin and cornea in patients.