INVESTIGATING THE MOLECULAR MECHANISMS UNDERLYING SKIN FRAGILITY IN TP63-LINKED ECTODERMAL DYSPLASIAS

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Jessica A Gugger (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome and ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome are two rare autosomal dominant disorders caused by heterozygous mutations occurring in the TP63 gene. Individuals with AEC and EEC experience abnormal development of ectodermally-derived tissues such as hair, nails, teeth and most notably skin. Further, AEC patients as well as a subgroup of EEC patients experience severe skin erosions, which puts them at high risk of developing life-threatening infections. Currently, symptomatic care is the only available therapy to individuals with AEC or EEC. To develop novel therapeutic strategies, the underlying molecular mechanisms responsible for AEC and EEC must be understood. We hypothesize that the skin fragility experienced by individuals with AEC and EEC is linked to abnormal expression of genes involved in hemidesmosomal and desmosomal cell adhesion as well as in keratinocyte differentiation. The rationale for this hypothesis is based on preliminary data generated by the Koch and Koster laboratories suggesting defects in these keratinocyte properties. Further, previous work from others demonstrates that defects in keratinocyte adhesion and proper keratinocyte differentiation can lead to skin blistering disorders with symptoms similar to those observed in AEC and EEC. To test this hypothesis, we analyzed gene and protein expression of hemidesmosomal, desmosomal, and differentiation-associated components in keratinocytes derived from AEC and EEC patient induced pluripotent stem cells (iPSCs). Using qRT-PCR and Western blot analyses, we found that gene and protein expression of hemidesmosomal, desmosomal, and differentiation markers were abnormally expressed in iPSC-derived keratinocytes of AEC and EEC patients. Based on our findings, we conclude that skin fragility in AEC patients is caused, at least in part, by reduced expression of hemidesmosomal components. In EEC, the skin fragility is likely caused by another mechanism. Our data suggest defects in keratinocyte terminal differentiation in EEC keratinocytes. These data provide novel insights into the cause of skin fragility in AEC and EEC and may lead to the identification of new therapeutic targets.

Additional Information

Publication

Thesis

Language: English

Date: 2023

Subjects

induced pluripotent stem cells;ectodermal dysplasia;skin fragility;keratinocytes;hemidesmosomes

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