KRT5 – Epidermolysis bullosa simplex with migratory circinate erythema

Epidermolysis bullosa simplex with migratory circinate erythema (EBS-MCE) is an autosomal dominant skin fragility disorder characterized by migratory blistering lesions that resolve with brownish pigmentation. Two unrelated families harbor a recurrent heterozygous readthrough mutation in the nonhelical tail of keratin 5: c.1649del (p.Gly550fs) (PMID:24104543). Segregation of this variant with disease was observed in both pedigrees (2 probands, 2 families) and no unaffected carriers were reported. Histopathology of an active lesion showed abundant CD4+ and CD8+ T-lymphocyte infiltration at the dermal-epidermal junction and TUNEL-positive keratinocyte apoptosis, implicating cell-mediated immunity in lesion dynamics (PMID:24104543).

In vitro and cellular functional studies of the K5-1649delG mutant demonstrate that removal of the last 41 amino acids and addition of 35 aberrant residues disrupts intermediate filament coassembly with K14. Filaments are shorter, exhibit weak viscoelastic properties under strain, and form cytoplasmic aggregates that colocalize with Hsp70, recapitulating keratinocyte fragility (PMID:15647384). These findings support a dominant-negative mechanism in which aberrant tail interactions perturb keratin network integrity and promote apoptosis at erythematous borders. Key take-home: identification of c.1649del (p.Gly550fs) in KRT5 enables precise diagnosis of EBS-MCE and informs prognosis and potential immunomodulatory interventions.

References

• Acta Dermato-Venereologica • 2014 • T-lymphocytes are directly involved in the clinical expression of migratory circinate erythema in epidermolysis bullosa simplex patients. PMID:24104543
• Molecular Biology of the Cell • 2005 • Defining the properties of the nonhelical tail domain in type II keratin 5: insight from a bullous disease-causing mutation. PMID:15647384

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