Structural and Functional Consequences of Loricrin Mutations in Human Loricrin Keratoderma (Vohwinkel Syndrome with Ichthyosis) Matthias Schmuth, Joachim.

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Structural and Functional Consequences of Loricrin Mutations in Human Loricrin Keratoderma (Vohwinkel Syndrome with Ichthyosis) Matthias Schmuth, Joachim W. Fluhr, Debra C. Crumrine, Yoshikazu Uchida, Jean-Pierre Hachem, Martin Behne, David G. Moskowitz, Angela M. Christiano, Kenneth R. Feingold, Peter M. Elias Journal of Investigative Dermatology Volume 122, Issue 4, Pages 909-922 (April 2004) DOI: 10.1111/j.0022-202X.2004.22431.x Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Loricrin keratoderma skin displays functional abnormalities. (A) Transepidermal water loss (TEWL) was measured using a Tewameter (TM210; Courage & Khazaka, Cologene, Germany) over (i) the wrist area (honeycomb-like changes) (n=11); (ii) lower forearm (fine-scaling ichthyosis) (n=11), and the corresponding skin areas of normal control subjects (n=6). (B) Skin hydration was assessed as stratum corneum (SC) capacitance, measured with a corneometer (TM825; Courage & Khazaka). (C) Skin surface pH was measured with a Skin-pH-Meter (PH900; Courage & Khazaka). (D) SC cohesion was assessed as quotient of protein per D-Squame stripping. Data shown represent mean±SEM. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Accelerated barrier recovery kinetics accelerate in loricrin keratoderma. Barrier recovery was assessed as % change in transepidermal water loss 3 and 6 h after acute barrier disruption of lorcrin keratoderma severely affected (distal, n=8) versus mildly affected (proximal, n=2) skin sites by tape stripping, and normal control skin sites. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Skin fragility localizes to outer granular layer. Cleavage plane in mechanically induced fracture of patient sample passes both between and across cells of the outer granular layer (stratum granulosum, SG). (A) Dark-field view of thick section; (B) hematoxylin & eosin; (C) toluidine blue stained semi-thin preparation; (D) OsO4 post-fixed ultrathin section at level of outer SG. Scale bars: A=100 μm; B, C=10 μm; D=0.5 μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Increased permeability occurs primarily via extracellular pathway. (A–C) Despite evidence of keratinocyte fragility, water-soluble, electron-dense tracer (colloidal lanthanum) enters the stratum corneum (SC) via extracellular domains (arrows). Some corneocytes in lower SC demonstrate (curved arrows) evidence of fragility, shown by leakage of tracer into cytosol (B, open arrows). (A, B) OsO4 post-fixation. Scale bars: A+B=1 μm; C=0.5 μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Cornified envelopes (CEs) in lower stratum corneum (SC) are attenuated in loricrin keratoderma. (A, C) Note thin, CE (solid arrows), with frequent discontinuities (C, open arrows) in lower SC in loricrin keratoderma biopsies versus CE with normal dimensions in control SC (B, solid arrows). (A) Open arrow shows normal CLE in loricrin keratoderma. Delayed lipid processing is also evident in lower SC of loricrin keratoderma biopsies (A, C, asterisks). (A, B) RuO4 post-fixation; (C) OsO4 post-fixation. Scale bar=0.25μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Normal quantities, but abnormal organization of extracellular lamellae in loricrin keratoderma. (A) Normal stratum corneum (SC), with typical extracellular lamellar bilayers (arrows). (B, C) Attenuated cornified envelope (CE) are again evident throughout the lower SC. Although extensive extracellular arrays are present in loricrin keratoderma, these bilayers are loosely organized and often fragmented (asterisks) in comparison to normal SC (A, arrows). Findings are comparable, but more exaggerated in severely (B) than in less severely involved (C) skin sites. (B, inset) Note CE of near-normal thickness in outer SC of loricrin keratoderma. Delayed lipid processing (D, solid arrows) can be seen again, and some entombed lamellar bodies are evident (B–D, double arrows). In contrast, cornified-bound lipid envelope are normal regardless of disease severity (C, D, open arrows). (A–D) RuO4 post-fixation. Scale bar=0.25μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Cornified envelopes are attenuated in lower layers of loricrin keratoderma stratum corneum (SC). Cornified envelope thickness was determined at 0.5 cm intervals in the lower SC of at least 30 randomly obtained micrographs from each biopsy. Values shown represent mean±SEM. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Lamellar body secretion is largely unimpaired in loricrin keratoderma. (A, B) Acid lipase is used as a surrogate cytochemical maker for lamellar body hydrolase content and secretion. In granular layer (stratum granulosum, SG) enzyme activity localizes to lamellar body contents (A, solid arrow). In stratum corneum (SC) most enzyme activity localizes to extracellular domains (A, B, open arrows). OsO4 post-fixation. Scale bar=0.35μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 9 Accelerated lamellar body (LB) production, with premature LB secretion, accounts for normalization of barrier recovery in loricrin keratoderma. (A–D) Three and six hours after tape stripping (TS-3,6), note abundant secreted LB contents deep in granular layer (B, D, arrowheads). Extracellular bilayer quantities are increased in many foci (A, arrows), and there is no evidence of a delay in lipid processing (C, arrows). (A, C) RuO4 post-fixation; (B, D) OsO4 post-fixation. Scale bars: A–C=0.25 μm; D=0.5 μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 10 Calcium in stratum corneum (SC) correlates with normalization of cornified envelope (CE) in loricrin keratoderma. (A) Cytochemical localization of Ca2+ in SC of loricrin keratoderma. Long arrow indicates putative, outward movement of water and Ca2+ (OSC=outer SC). Note Ca2+ within corneocyte cytosol in lower SC (LSC), but predominantly membrane/extracellular localization in OSC. (B) Typical Ca2+ distribution in unaffected control (co-epidermis, with little Ca2+ ion evident in SC). OsO4 post-fixation. Scale bar=0.5 μm. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 11 Theoretical basis for different scaffold abnormalities in loricrin keratoderma versus lamellar ichthyosis (LI). (A) In loricrin keratoderma (1), mutant loricrin does not incorporate into cornified envelope (CE), but other CE precursors incorporate progressively into CE due to persistence of Ca2+, as well as ongoing transglutaminase-1 activity. In LI (2), such compensation cannot occur because of decreased transglutaminase-1 activity. Journal of Investigative Dermatology 2004 122, 909-922DOI: (10.1111/j.0022-202X.2004.22431.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions