title: Mutations Affecting Keratin 10 Surface-Exposed Residues Highlight the Structural Basis of Phenotypic Variation in Epidermolytic Ichthyosis.
abstract: 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.
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Haris
authors.initials: H
authors.lastname: Mirza
authors.affiliation: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen PSI, Switzerland.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Brittany G
authors.initials: BG
authors.lastname: Craiglow
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Saraceni
authors.affiliation: St Luke's-Roosevelt Hospital-Mount Sinai Health System, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Torbeck
authors.affiliation: Central Coast Pathology Laboratory, San Louis, California, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Ragsdale
authors.affiliation: The Dermatology Medical Group of Oxnard and Camarillo, Camarillo, California, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Rehder
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Skin and Allergy Hospital, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut, USA; Department of Genetics and Pathology, School of Medicine, Yale University, New Haven, Connecticut, USA. Electronic address: keith.choate@yale.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D005260:Female; D006706:Homeostasis; D006801:Humans; D017488:Hyperkeratosis, Epidermolytic / Q000235:genetics*; D053550:Keratin-10 / Q000737:chemistry / Q000235:genetics*; D008940:Mitotic Index; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
chemical_list: C507493:KRT10 protein, human; D053550:Keratin-10