1. Mutations Affecting Keratin 10 Surface-Exposed Residues Highlight the Structural Basis of Phenotypic Variation in Epidermolytic Ichthyosis 
Haris Mirza, Anil Kumar, Brittany G. Craiglow, Jing Zhou, Corey Saraceni, Richard Torbeck, Bruce Ragsdale, Paul Rehder, Annamari Ranki, Keith A. Choate 
Journal of Investigative Dermatology 
Volume 135, Issue 12, Pages (December 2015)
DOI: /jid
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2. Figure 1
Clinical and histopathological features of mild epidermolytic ichthyosis (EI). (a) Mild EI subject (K101; p.Q434del) shows hyperpigmentation of the upper back with notable fine white scaling and hyperkeratosis around elbows. Similar scaling and hyperkeratosis was also observed around knees and shins (b), as well as ankles and feet (c). (d) and (g) show histology of the wild-type skin. Panels (e) and (h) exhibit histological features of mild EI, highlighting epidermal acanthosis, hyperkeratosis, and hypergranulosis*, with limited cellular degeneration in the uppermost layer of the spinous layer. Panels (f) and (i) show classical EI epidermis of K10 p.R156C, highlighting cytolysis** beginning from the first suprabasal cells layer. Cytolysis was remarkably absent in the suprabasal layer of mild EI epidermis (e and h). Black bars=100μm.
Journal of Investigative Dermatology  , DOI: ( /jid )
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3. Figure 2
Alterations of epidermal intermediate filament network in mild epidermolytic ichthyosis (EI). (a and b) Paraffin-embedded sections of wild-type tissue showed pancytoplasmic keratin 1 (K1) and K10 filaments. Filament retraction and perinuclear K1 and K10 accentuations were observed in p.Q434del, whereas p.R156C showed suprabasal intermediate filament (IF) clumping. (c and d) Compared with wild type, both EI epidermises showed expansion of anti-K14 and -K5 staining to the suprabasal layer, along with suprabasal expression of K6 (e). (f) Expansion of anti-involucrin staining was also observed in both mild and severe EI. Yellow bar=100μm, green and red bars=350μm. Dotted lines represent the dermal–epidermal junction.
Journal of Investigative Dermatology  , DOI: ( /jid )
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4. Figure 3
Apoptosis and proliferation in mild and severe epidermolytic ichthyosis (EI) epidermises. (a) HaCaT cells expressing either wild-type (WT) or p.Q434del or p.R156C mutant (K10). Monolayers were co-stained with anti-K5 and anti-K10. WT co-localizes with K5, whereas p.R156C formed aggregates and disrupted the K5 filaments. p.Q434del formed perinuclear filaments (b) Confluent monolayers of keratinocyte from WT, p.Q434del, and p.R156C subjects were differentiated followed by DAPI staining. More than 50% of the p.R156C cells showed pyknosis, whereas WT and p.Q434del cells showed limited cell death. (c) Differentiating p.QR156C primary keratinocytes showed significantly higher TUNEL-positive cells compared with WT and p.R156C cells (P-values<0.01). (d) Epidermises stained with anti-Ki67 and anti-K14. p.Q434del epidermis showed significantly higher K14+ Ki67+ cells compared with wild-type and p.R156C epidermises (P-value<0.01).
Journal of Investigative Dermatology  , DOI: ( /jid )
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5. Figure 4
Mapping of molecular interactions and keratin 10 (K10) mutations on the K1–K10 2B domain dimer model. (a) Graphical representation of K10 domains with green bars highlighting K10 mutational “hotspots” and red bar represents the portion of K10 α-helix modeled. K1–K10 dimer model highlighting the intermolecular interactions (magenta) between K1 (blue) and K10 (red) residues. (b) Coiled-coil heptad repeat assignments and inter-/intra-chain interactions in K1–K10 dimer. Details of these interactions are summarized in Supplementary Table 1 online (c) Mapping of K10 mutations on the K1–K10 2B dimer with mild mutations in green and severe mutations in red. K10 p.Y449 residue mutation (yellow) results in severe phenotype in mutation K10 p.Y449D or mild phenotype in K10 p.Y449C. Details on interaction and specific mutations are summarized in Table 1.
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6. Figure 5
2B domain dimer models of surface-exposed residue keratin 10 (K10) mutations (a) K10 p.Q434del (K101 and K102) and K1 wild-type dimer model. The model predicted loss of hydrophobic intermolecular interactions between adjoining K10–L435 with K1 coil residues Y465, L468, and M469. (b) K10 p.R441P (K103) and K1 wild-type dimer model. This model predicted loss of an intra-molecular interaction between R441 and E445 residues of K10, leaving the remaining inter- and intra-molecular interactions intact. The crucial intermolecular interactions (magenta) described in Figure 3a remain unaffected by p.Q434del and p.R441P mutations.
Journal of Investigative Dermatology  , DOI: ( /jid )
Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions