Microscopic view of skin cells with a highlighted gene mutation, symbolizing research into P63-associated disorders.

Unlocking the Secrets of P63-Associated Disorders: How New Research Offers Hope for Skin Health

Soraya Malik in Health & Wellness August 2025 • 4 min read.

"A Deep Dive into the Genetic Mechanisms Behind Rare Syndromes and Potential Breakthroughs in Treatment."

The p53 family member p63 plays a vital role in gene expression within stratified epithelia, which includes the epidermis. One of its major functions is sustaining mechanical resistance by positively regulating several epidermal genes involved in cell-matrix adhesion and cell-cell adhesion. When p63 is deficient, it can lead to severe defects in stratified epithelia and their derivatives, impacting overall health.

Heterozygous mutations in the p63 gene in humans can lead to at least five rare, related syndromes with overlapping features. These include ectodermal dysplasia, cleft lip/palate, and limb malformations. Among these disorders, one notable condition is Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC). This syndrome is often characterized by central reduction defects of the hands and feet, associated with cleft lip and/or palate, and is frequently caused by mutations in the DNA-binding domain that disrupt p63's binding ability.

In contrast, Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome presents with severe skin symptoms such as congenital erythroderma, skin fragility, atrophy, palmo-plantar hyperkeratosis, and extensive, long-lasting erosive lesions. The mechanisms behind AEC skin erosions are not fully understood, standard care focuses on minimizing trauma and preventing infections.

How Does Mutant p63 Lead to Skin Problems?

Microscopic view of skin cells with a highlighted gene mutation, symbolizing research into P63-associated disorders.

To understand the molecular basis of AEC syndrome, researchers generated a knock-in mouse model that expresses a mutation in the leucine 514 to phenylalanine (L514F). This mutation is significant because leucine 514 is highly conserved and found mutated in phenylalanine, valine, or serine in AEC patients. The AEC mouse model closely resembles the human disorder, presenting with cleft palate, skin atrophy, hair and tooth defects, but without ectrodactyly.

Key findings from studying this model include:

Skin atrophy and delayed wound healing are linked to a reduced number of epidermal stem cells.
This reduction is caused by compromised fibroblast growth factor receptor signaling and downregulation of Fgfr2 and Fgfr3, which are p63 target genes.
A defective stem cell compartment is also observed in human skin affected by AEC syndrome.
Desmosomes, essential cell junctions for mechanical resistance in the epidermis, are weakened in AEC syndrome.
This is due to reduced gene expression of p63 direct target genes like Dsc3, Dsg1, and Dsp.

These findings suggest that reduced mechanical resistance may be due, at least in part, to reduced cell adhesion. To further investigate skin erosions, which are typical in AEC syndrome, a novel conditional mouse model was created. In this model, mutant p63 L514F is expressed in the skin starting from late development, bypassing the issue of cleft palate. Consistent with the human phenotype, these AEC mice develop skin erosions, crusting, and scaling, alongside reduced mechanical strength, acantholysis, and cytolysis of the basal layer.

The Role of TSLP in Skin Inflammation and Autoimmunity

Skin erosions trigger local and systemic inflammatory responses that depend on TSLP, an IL-7-like cytokine. TSLP is produced by keratinocytes and released in response to epidermal barrier failure. In human and mouse skin, TSLP is highly expressed in acute and chronic lesions associated with atopic dermatitis and Netherton syndrome. TSLP has wide-ranging effects on cell lineages, including immune cells, and drives Th2-mediated inflammation. In AEC mice, Tslp circulates in the blood, causing expansion of pre-B cells and leading to an autoimmune B-cell proliferative disorder. Ablating Tslp in the epidermis of AEC mice reduces skin and systemic inflammation, rescues B-cell differentiation, and reduces mortality.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.jisp.2018.10.004, Alternate LINK

Title: Functional And Mechanistic Insights Into The Pathogenesis Of P63-Associated Disorders

Subject: Cell Biology

Journal: Journal of Investigative Dermatology Symposium Proceedings

Publisher: Elsevier BV

Authors: Maria Rosaria Mollo, Luisa Cirillo, Claudia Russo, Dario Antonini, Caterina Missero

Published: 2018-12-01

Everything You Need To Know

What is the role of p63 in maintaining skin health?

The p63 protein, a member of the p53 family, is crucial for maintaining skin health. It functions within the stratified epithelia, particularly the epidermis, where it regulates gene expression. A key role of p63 is to support mechanical resistance in the skin. It achieves this by positively regulating epidermal genes involved in cell-matrix adhesion and cell-cell adhesion. Adequate p63 function is essential, and its deficiency can lead to severe defects in stratified epithelia and related structures, thereby affecting overall health. This is crucial for processes like wound healing and the integrity of the skin barrier.

What are the key characteristics of Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC) and how does it differ from Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome?

EEC syndrome is characterized by central reduction defects in the hands and feet, along with cleft lip and/or palate. This condition often arises from mutations in the DNA-binding domain of the p63 gene, which disrupts p63's ability to bind. In contrast, AEC syndrome presents with severe skin symptoms, including congenital erythroderma, skin fragility, atrophy, palmo-plantar hyperkeratosis, and extensive, long-lasting erosive lesions. While EEC primarily affects limb development and facial features, AEC predominantly impacts skin integrity and barrier function. Both are linked to p63 mutations, but the specific mutations and resulting clinical presentations differ significantly. For instance, in the AEC syndrome, the mutation L514F in the p63 gene can lead to skin erosions, while EEC frequently involves mutations that disrupt p63's DNA-binding capabilities.

How does the L514F mutation in p63 lead to skin problems, and what are the underlying mechanisms?

The L514F mutation in p63, found in AEC patients, disrupts the normal function of p63, leading to various skin problems. This mutation results in skin atrophy and delayed wound healing due to a reduced number of epidermal stem cells. This reduction is caused by compromised fibroblast growth factor receptor signaling and downregulation of Fgfr2 and Fgfr3, which are p63 target genes. Additionally, desmosomes, essential cell junctions for mechanical resistance, are weakened, leading to reduced cell adhesion. The skin erosions, a hallmark of AEC syndrome, are also caused by reduced mechanical strength, acantholysis, and cytolysis of the basal layer, further highlighting the critical role of p63 in maintaining skin structure and integrity.

What role does TSLP play in the skin inflammation and autoimmunity observed in Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) mice?

TSLP, an IL-7-like cytokine, plays a critical role in the inflammatory and autoimmune responses seen in AEC mice. Skin erosions trigger local and systemic inflammatory responses that depend on TSLP. TSLP is produced by keratinocytes in response to epidermal barrier failure. In AEC mice, TSLP circulates in the blood, causing the expansion of pre-B cells and leading to an autoimmune B-cell proliferative disorder. When TSLP is ablated in the epidermis of AEC mice, the skin and systemic inflammation is reduced. The B-cell differentiation is also rescued and mortality is reduced. This indicates that TSLP is a key driver of the inflammatory and autoimmune aspects of AEC syndrome.

How can understanding p63-associated disorders lead to potential breakthroughs in treatment for conditions like AEC syndrome?

Understanding p63-associated disorders provides several avenues for potential breakthroughs in treating conditions like AEC syndrome. Research into the genetic mechanisms, such as the impact of the L514F mutation, reveals the specific pathways disrupted, like fibroblast growth factor receptor signaling and desmosome function. By identifying these mechanisms, researchers can explore targeted therapies. For example, understanding the role of TSLP in inflammation opens the door for treatments that inhibit TSLP or its downstream effects. Furthermore, the development of novel conditional mouse models allows for studying treatments' effects on specific issues, like skin erosions, without the confounding issues of the cleft palate. The identification of p63 target genes provides opportunities for gene therapies or small-molecule drugs that can restore the normal function of these genes. Therefore, a deeper understanding of the disorder can offer targeted treatments.