Mutations Affecting Keratin 10 Surface-Exposed Residues Highlight the Structural Basis of Phenotypic Variation in Epidermolytic Ichthyosis.

Epidermolytic ichthyosis (EI) due to KRT10 mutations is a rare, typically autosomal dominant, disorder characterized by generalized erythema and cutaneous blistering at birth followed by hyperkeratosis and less frequent blistering later in life. We identified two KRT10 mutations p.Q434del and p.R441P in subjects presenting with a mild EI phenotype. Both occur within the mutational "hot spot" of the keratin 10 (K10) 2B rod domain, adjacent to severe EI-associated mutations. p.Q434del and p.R441P formed collapsed K10 fibers rather than aggregates characteristic of severe EI KRT10 mutations such as p.R156C. Upon differentiation, keratinocytes from p.Q434del showed significantly lower apoptosis (P-value<0.01) compared with p.R156C as assessed by the TUNEL assay. Conversely, the mitotic index of the p.Q434del epidermis was significantly higher compared with that of p.R156C (P-value<0.01) as estimated by the Ki67 assay. Structural basis of EI phenotype variation was investigated by homology-based modeling of wild-type and mutant K1-K10 dimers. Both mild EI mutations were found to affect the surface-exposed residues of the K10 alpha helix coiled-coil and caused localized disorganization of the K1-K10 heterodimer. In contrast, adjacent severe EI mutations disrupt key intermolecular dimer interactions. Our findings provide structural insights into phenotypic variation in EI due to KRT10 mutations.