Identification of molecular and genetic variations underlying skin diseases
- Autores: Andrea Roso Mares
- Directores de la Tesis: Isabel Andújar (dir. tes.), Tania Díaz Corpas (codir. tes.), Bryan K. Sun (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2025
- Idioma: inglés
- Tribunal Calificador de la Tesis: Jose Bañuls Roca (presid.), Luis Sendra Gisbert (secret.), Alba Guijarro Belmar (voc.)
- Programa de doctorado: Programa Oficial de Doctorado en Medicina
- Menciones:
- Internacional
- Calificación: Sobresaliente Cum Laude
- Materias:
- Enlaces
- Resumen
Skin diseases affect up to 70% of the global population, representing a significant burden on healthcare systems worldwide (Hay et al., 2014). Although some conditions have been extensively studied, many remain poorly understood, limiting the development of accurate diagnoses and effective treatments. This shortage of therapies directly affects patients’ quality of life, since the etiological diversity of these conditions—ranging from infectious, oncological, autoimmune, and genetic pathologies—produces distressing symptoms such as itching, pain, irritation, and inflammation. Added to this are psychological and social consequences derived from the visibility of lesions, which often compromise self-esteem, body image, and interpersonal relationships, increasing the risk of anxiety, depression, and social isolation (Verhoeven et al., 2007).
Beyond local symptoms, many diseases present systemic implications and may be associated with more severe conditions, such as metabolic or autoimmune disorders. This complexity highlights the need for a comprehensive approach that addresses both cutaneous manifestations and broader health consequences (Sampaio et al., 2021). It is therefore essential to investigate the molecular and genetic mechanisms underlying these conditions to enable more effective and potentially definitive therapies (Roso-Mares et al., 2024). Within this framework, the central aim of this doctoral thesis is to identify molecular and genetic variations relevant to rare dermatological disorders, contributing new insights to an expanding field.
The first part reviewed the emerging role of non-coding RNAs (ncRNAs) in dermatology, with emphasis on miRNAs and lncRNAs. These regulatory elements contribute to skin biology by modulating proliferation, differentiation, apoptosis, wound healing, and inflammatory responses. Literature analysis showed that ncRNAs act as biomarkers and molecular signatures that can improve diagnosis, predict prognosis, and monitor treatment response. They may also serve as therapeutic targets in contexts such as cancer, inflammatory diseases (psoriasis, atopic dermatitis), fibrotic processes, and abnormal wound healing. A key clinical advantage lies in their detectability in biological fluids, making them valuable non-invasive biomarkers. This review concluded that ncRNAs hold transformative potential in dermatology for advancing knowledge of pathophysiology and developing targeted therapies, although challenges remain regarding specificity, delivery, and clinical tolerability.
The second part focused on an exceptional case that motivated experimental investigation. It involved a patient with an extensive blaschkoid glomuvenous malformation (GVM) associated with polydactyly, a clinical association not previously reported. Genetic analysis revealed a germline mutation in GLMN (c.515C>A, p.Ser172Ter), known for its role in GVM pathophysiology, together with a rare somatic mutation in CCM2L (c.1505G>A, p.Arg502His), found only in affected tissue. This raised the hypothesis that CCM2L might act as a genetic modifier of the disease, influencing severity and phenotypic characteristics.
To test this, functional studies were conducted in HUVECs. The experiments showed that the R502H variant of CCM2L impairs regulation of the MAPK/ERK pathway, causing a significant increase in proliferation. Moreover, combined GLMN and CCM2L alterations produced an additive effect on growth, reinforcing the hypothesis of a functional interaction between both genes in disease pathogenesis.
Taken together, these findings expand the clinical and genetic spectrum of GVMs and suggest a role for CCM2L as a modulator of phenotypic expression in these rare disorders. In this way, the present research contributes an innovative finding on the molecular mechanism involved in a rare genetic disease such as GVM and establishes a solid foundation for future studies aimed at developing new diagnostic and therapeutic strategies.
