Journal Article

Genetics of Darier’s Disease: New Insights into Pathogenic Mechanisms

Ambrosini, Enrico, Taiani, Antonietta, Zamponi, Raffaella, Cesarini, Sofia, Gherli, Andrea, Pagliaro, Luca, Barili, Valeria, Moschella, Barbara, Caramanna, Luca, Cannizzaro, Ilenia Rita, Lagrasta, Costanza Anna Maria, Silini, Enrico Maria, Martorana, Davide, Zanelli, Sara, Luberto, Anita, Montanaro, Anna, Azzoni, Cinzia, Roti, Giovanni, Mozzoni, Paola, Lorusso, Bruno, De Felici Del Giudice, Maria Beatrice, Dominici, Michele Maria, Caggiati, Patrizia, Neri, Iria, Busciglio, Sabrina, Feliciani, Claudio, Uliana, Vera, De Sensi, Erika, Bottarelli, Lorena, Treccani, Mirko, Percesepe, Antonio

2025

Overview

Darier′s disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, which encodes the SERCA2 protein, an endoplasmic reticulum ATPase Ca2+ transporter. These mutations impair the intracellular calcium homeostasis leading to increased protein misfolding, endoplasmic reticulum (ER) stress response, and the activation of the unfolded protein response (UPR), culminating in keratinocyte apoptosis and anomalies in interfollicular epidermal stratification. Clinically, the disease is characterized by the presence of skin lesions with hyperkeratotic papules and an increased susceptibility to inflammatory reactions, bacterial and viral infections. The histological hallmarks include acantholysis, dyskeratosis, and increased apoptotic keratinocytes, referred to as “corp ronds”. The SERCA2b isoform is expressed not only in the epidermis but it is present ubiquitously in all tissues, suggesting that its alteration may have multi-organ effects. The review aims to provide a broad overview of the pathology, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression. Beginning with an examination of the cellular alterations, our work then shifts to exploring their impact in an organ-specific context, providing insights into new potential therapeutic strategies tailored to clinical manifestations.

• Publisher: MDPI AG,MDPI
• Subject: Adenosine triphosphatase / Animals / Apoptosis / ATP2A2 gene / Ca2+-transporting ATPase / Calcium (intracellular) / Calcium (reticular) / Calcium - metabolism / Calcium homeostasis / Cell signaling / Cellular signal transduction / Darier Disease - genetics / Darier Disease - metabolism / Darier Disease - pathology / Dyskeratosis / Endoplasmic reticulum / Endoplasmic Reticulum Stress - genetics / Enzymes / Epidermis / Females / Genetic aspects / Genodermatosis / Genotype & phenotype / Health aspects / Homeostasis / Humans / Infections / Intracellular / Keratinocytes / Microbiota / Mutation / Pathogenesis / Protein folding / Proteins / Review / Risk factors / Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics / Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism / Skin / Skin diseases / Skin lesions / Unfolded Protein Response - genetics / Virus diseases