Keratin Variants in Pyoderma Gangrenosum: Pathogenetic Insights from a Whole-Exome Sequencing-Based Bioinformatic Analysis.

Abstract

Pyoderma gangrenosum (PG) is an inflammatory skin disorder that belongs to the group of neutrophilic dermatoses. Clinically, it is typified by cutaneous ulcers with distinctive erythematoviolaceous borders and may occur alone or in association with other inflammatory, autoinflammatory, or neoplastic conditions. Although its pathophysiology remains incompletely understood, mounting evidence points toward a predisposing genetic background and dysregulation of both the innate and adaptive immune responses, with follicular or epidermal structures as putative initial targets. To investigate the genetic factors associated with PG susceptibility and severity (arbitrarily defined as unilesional or multilesional), whole-exome sequencing was performed on 11 unrelated patients with PG. Eight strains carried at least 1 variant of the keratin-encoding gene, including keratin (K)18 gene K18, K20, K23, K32, and K33B. Strikingly, a recurrent variant (rs77999286) of the K18 gene was identified in 5 of 6 patients with multilesional PG and 1 of 5 of those with unilesional PG. AlphaFold modeling and mutation analysis revealed the destabilizing effect of the K18 rs77999286 variant on protein structure. Furthermore, immunohistochemistry revealed undetectable K18 staining in lesional skin compared with that in healthy control skin. Overall, these findings suggest that keratin variants may play a role in PG pathogenesis and indicate that the K18 rs77999286 variant is a potential genetic factor linked to multilesional disease.