The Missense Mutation p

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The Missense Mutation p The Missense Mutation p.R1303Q in Type XVII Collagen Underlies Junctional Epidermolysis Bullosa Resembling Kindler Syndrome Cristina Has, Dimitra Kiritsi, Jemima E. Mellerio, Claus-Werner Franzke, Emma Wedgeworth, Iliana Tantcheva-Poor, Kristin Kernland- Lang, Peter Itin, Michael A. Simpson, Patricia J. Dopping-Hepenstal, Wataru Fujimoto, John A. McGrath, Leena Bruckner-Tuderman Journal of Investigative Dermatology Volume 134, Issue 3, Pages 845-849 (March 2014) DOI: 10.1038/jid.2013.367 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical and skin morphological features of the patients with the COL17A1 mutation c.3908G>A, p.R1303Q. (a) Patient 1 had skin blistering on the lower legs, resolving with scarring, atrophy, and dyspigmentation, and skin atrophy, most prominent over the dorsal aspects of hands and feet. (b) Partial loss of finger and toenails in patient 3. (c) Immunofluorescence staining patterns with antibodies to collagens XVII (mAb-123, gift of P. Marinkovich, Stanford, USA), IV (COL94, Sigma-Aldrich, Poole, UK), and VII (LH7.2, Sigma-Aldrich) (green) in a control and patient 1 demonstrate an irregular, increased deposition of all markers in the papillary dermis of the patient, in contrast to the normal linear pattern. Nuclei are stained with 4′,6-diamidino-2-phenylindole. (d) Transmission electron microscopy images of skin samples of a control and patient 1 are shown. It demonstrates the loss of hemidesmosomes, loss of lamina lucida, obscure anchoring fibers because of amorphous material immediately below the basal cell membrane in the patient. Amorphous material is also present in the papillary dermis (arrows). Insets represent twofold magnifications of the marked areas. Journal of Investigative Dermatology 2014 134, 845-849DOI: (10.1038/jid.2013.367) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Consequences of the collagen XVII gene mutation, c.3908G>A, p.R1303Q. (a) Schematic representation of the collagen XVII molecule with the intracellular endodomain, and the extracellular ectodomain. The collagenous (COL, yellow) and non-collagenous (NC, gray) domains and the position of the amino-acid substitution p.R1303Q (red R>Q) are depicted, as well as epitopes of the domain-specific antibodies used in this study. In the lower panel, the sequence stretch flanking the mutation site spanning amino acids 1215–1398 is shown in detail. Secondary protein structure prediction revealed profound structural modifications in mutant collagen XVII upstream and downstream of the mutation site (indicated by asterisks). (b) Immunofluorescence staining was performed with the following domain-specific antibodies to collagen XVII: Endo2, NC16A, and Hk139 (Nishie et al., 2010), and skin sections from a healthy control, patients 3 and 8, and a patient with junctional EB-other (JEB-o) and loss-of-function mutations leading to absence of collagen XVII. Note apicolateral staining in the basal keratinocytes with the antibody Endo2 in patients 3 and 8, similar to the control skin. Immunostaining patterns with Hk139 and NC16A, which recognize the ectodomain of collagen XVII, demonstrated a broad, irregular distribution below the level of the basement membrane in intact skin of the patients 3 (P3) and 8 (P8) and the presence of the signal at both roof and base of a blister in patient 8. (c) Immunofluorescence staining with an antibody to the laminin γ2 chain (clone GB3) shows broad, irregular distribution below the level of the basement membrane in the intact skin of patient 3. Laminin γ2 immunostaining is present at both roof and floor of the blister in patient 8 and only at the blister floor in a patient with junctional EB-other with COL17A1 loss-of-function mutations. (d) Immunofluorescence staining with an antibody for tenascin C (clone 578, R&D Systems) shows a low expression in control skin but very abundant deposition in the skin of patients 3 and 8. Bars=50 μm, asterisks indicate blisters, and nuclei are stained with 4′,6-diamidino-2-phenylindole. EB, epidermolysis bullosa. Journal of Investigative Dermatology 2014 134, 845-849DOI: (10.1038/jid.2013.367) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions