Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominant genodermatosis characterized by reticulate skin pigmentation, palmoplantar keratoderma, and dental anomalies, caused by pathogenic mutations in the KRT14 or KRT5 genes. Protheragen provides NFJS drug development solutions with insights from NFJS's molecular basis to therapeutic strategy, underlining its preclinical drug development use.
Introduction to Naegeli-Franceschetti-Jadassohn Syndrome
The estimated prevalence is 1:200,000. NFJS has recently been linked to the dysregulated apoptosis pathways and mitochondrial dysfunction that are thought to act as secondary contributors to disease progression. Mutations on KRT14 or KRT5 genes which encode for keratin 14 and 5 proteins important in anchoring the epidermis leads to these epidermal mutations. These changes result in keratinocyte fragility, abnormal pigmentation, and hyperkeratosis due to disruption of intermediate filament assembly.
Pathogenesis of Naegeli-Franceschetti-Jadassohn Syndrome
Characterized by skin erosions, palmoplantar keratoderma, and reticulate pigmentation, Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is accompanied by the mutations KRT14/KRT5, which disrupt keratin filament assembly, leading to cytoskeletal fragility of keratinocytes. Dysfunction of melanocytes is worsened by oxidative stress on the mitochondrion and impaired transport of melanosomes, increasing the distinctive abnormal pigmentation. Other systemic ectodermal anomalies give rise to dental defects, hypohidrosis, and hyperhidrosis due to abnormal epithelial-mesenchymal signaling and blocked sweat gland duct hyperkeratosis.
Fig.1 Common clinical features of NFJ syndrome. (Shah
et al., 2025)
Therapeutics Development for Naegeli-Franceschetti-Jadassohn Syndrome
| Therapeutic Strategy |
Therapeutic Target |
Key Findings/Mechanism |
Development Stage |
| KRT14 Gene Replacement Therapy |
KRT14 Gene Mutation |
Restoration of epidermal keratinocyte function through adeno-associated viral delivery of the KRT14 gene corrects its defects. |
Preclinical |
| Small Molecule Drug Intervention |
KRT14 Protein Misfolding |
Some compounds have been found to stabilize the KRT14 protein and decrease aggregation pathologically. |
Preclinical |
| EGFR Inhibitors |
EGFR Signaling Pathway |
There is good evidence of improvement in keratinocyte multiplication and differentiation. |
Preclinical |
| RNA Interference Therapy |
Mutant KRT14 mRNA |
During gene expression, the mRNA is cut off to lessen the amount of protein abnormal KRT14 that is made. |
Preclinical |
| Proteasome Inhibitors |
Protein Degradation Pathways |
Enhance clearance of misfolded KRT14 proteins to mitigate cellular toxicity. |
Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers full service to develop treatment methods for rare skin disorders like Naegeli-Franceschetti-Jadassohn syndrome. Every step of the research project is supported by therapeutic and disease model development research from our specialized scientists, dermatologists, and geneticists.
Therapeutic Development Platforms for Naegeli-Franceschetti-Jadassohn Syndrome
Disease Model Development for Naegeli-Franceschetti-Jadassohn Syndrome
Protheragen designs 2D cell models and 3D skin models to study the molecular pathologies of NFJS. Our models replicate hallmark NFJS phenotypes such as epidermal fragility, palmoplantar hyperkeratosis, and reticulate pigmentation. These animal models serve as robust platforms to validate drug candidates targeting keratin stabilization, oxidative stress, and epithelial-mesenchymal signaling.
- Patient-Derived NFJS Keratinocytes
- KRT14-KO HaCaT
- iPSC-Derived Keratinocytes
- NFJS Skin Organoids
- Krt14 p.Arg125His Knock-In Mice
- Keratin 5 Conditional Knockout Mice
- krt14 Knockout Zebrafish
- krt14 Knockout Mice
Protheragen focuses on the pre-clinical phase of unusual skin conditions such as Naegeli-Franceschetti-Jadassohn Syndrome. Their specialist skills extend from target selection to drug safety evaluation and DMPK services. Our proprietary models of disease and integrated platforms accelerate preclinical validation and mitigate risk to development of therapeutic candidates. Contact us to accelerate your rare disease drug development pipeline.
References
- Burger, B., et al. "Naegeli-Franceschetti-Jadassohn Syndrome and Dermatopathia Pigmentosa Reticularis: Intrafamilial Overlap of Phenotypes in Patients with the Same Krt14 Frameshift Variant." Br J Dermatol 181.4 (2019): 864-66.
- Shah, H. H., et al. "Naegeli-Franceschetti-Jadassohn Syndrome: A Systematic Review of Case Studies." Front Med (Lausanne) 12 (2025): 1453172.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
