Raymond Group – Modelling monogenic human skin diseases

EBS research

EBS patients suffer from skin fragility due to impaired resistance to mechanical stress, resulting in painful, lifelong blisters from birth.

Our research focuses on mutations in KLHL24, recently identified as a cause of EBS. Unlike most EBS-associated mutations that affect structural proteins, KLHL24 encodes a protein involved in the ubiquitin-proteasome system, which regulates protein degradation. The mutated KLHL24 protein is thought to be more stable, suggesting that excessive degradation of its targeted substrates underlies disease development. Clinically, KLHL24-related EBS presents with denuded skin at birth, burn-like scars, skin atrophy, and nail defects. Patients also face a high risk of developing life-threatening dilated cardiomyopathy. The underlying disease mechanisms remain poorly understood, and identifying KLHL24 targets in affected tissues is essential for developing targeted therapies. 

We generated hiPSCs from four patients with KLHL24 mutations and used gene editing to create isogenic corrected lines (Ramovs et al., 2021; Pachis, Ramovs et al., 2024). While 2D cultures of patient-derived keratinocytes and fibroblasts show minimal defects, 3D SOs recapitulate key clinical features. Given the cardiac risk, we are extending our research to identify relevant targets in the heart.  

XPA research

XP patients experience severe photosensitivity and a significantly increased risk of developing skin cancers due to UV light exposure. Mutations in the XPA gene impair the Nucleotide Excision Repair pathway, resulting in an inability to repair bulky DNA lesions, particularly those caused by to UV radiation or chemotherapeutic agents such as cisplatin. Currently, there is no curative treatment for XPA, and patients must maintain strict sun protection. Additionally, they face a high risk of neurodegeneration. 

We have developed a high-throughput screening (HTS) assay to identify compounds that may prevent the cutaneous and neurodegenerative manifestations of XPA. This effort follows a drug repurposing approach. In parallel, we are developing a preclinical model of solar UVB-induced photodamage using 3D SOs both with and without XPA mutations (Widyastuti et al., 2024). This model will be used to evaluate the efficacy of compounds identified through the HTS.  

Epidermal stress research

We are studying a genetic mouse model in which epidermal stress—characterized by altered protein turnover—induces chronic inflammation, leading to epidermal hyperplasia, dermal infiltration of immune cells, and lymphatic vessel enlargement. This model recapitulates a disease condition resembling atopic dermatitis. Our aim is to decipher how protein stress in the epidermis influences skin immunity and to assess the relevance of this mechanism to various non-inherited immune-mediated skin diseases.