A Novel Keratin 5 Mutation (K5V186L) in a Family with EBS-K: a Conservative Substitution Can Lead to Development of Different Disease Phenotypes Mirjana.

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A Novel Keratin 5 Mutation (K5V186L) in a Family with EBS-K: a Conservative Substitution Can Lead to Development of Different Disease Phenotypes Mirjana Liovic, Jure Stojan, Paul E. Bowden, Daniel Gibbs, Anders Vahlquist, E. Birgitte Lane, Radovan Komel Journal of Investigative Dermatology Volume 116, Issue 6, Pages 964-969 (June 2001) DOI: 10.1046/j.1523-1747.2001.01334.x Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 The EBS-K case with the K5V186L mutation. (A) Family pedigree. Affected family members are present in all three generations. Family members investigated in this study are marked with a star. Clinical features of the father's hand (B) and his 2 y old daughter's foot, buttocks, and perineum (C–E) showing blisters of varying sizes and the red halo surrounding them. Journal of Investigative Dermatology 2001 116, 964-969DOI: (10.1046/j.1523-1747.2001.01334.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Identification and confirmation of K5V186L mutation in a patient with EBS-K. (A) The index case was found to have a heterozygous point mutation in KRT5 at codon 186 (GTG to TTG, lower panel), thus converting valine 186 into leucine (V186L) at position 18 in the 1A helix (1A:V18L). A normal sequence is shown in the upper panel. (B) mismatch-allele-specificPCR followed by digestion with HhaI was performed for the EBS-1 sample and 50 control samples. Gel electrophoresis (5% polyacrylamide gel) revealed that the EBS-1 sample (lane 2) gave two fragments, the uncut original (≈ 560 bp) and the digested fragment (≈ 530 bp). Normal samples generated only the smaller fragment (≈530 bp) representing the normal allele (only two controls are shown, lanes 3 and 4). The molecular weight marker (pBR322/HaeIII) is in lane 1 (Std). Journal of Investigative Dermatology 2001 116, 964-969DOI: (10.1046/j.1523-1747.2001.01334.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 PE13300 epithelial lens cells microinjected with K5 and K14 constructs. (A–C) Cells fixed and stained (rabbit anti-K5, BL18, as primary, and fluorescein isothiocyanate tagged goat-anti-rabbit as secondary antibody) at the 16 h postmicroinjection time point. (A) Cells microinjected with K5V186L/K14 WT; (B) K5 WT/K14V133L and (C) K5 WT/K14 WT cDNA constructs. (D–F) Cells fixed and stained at the 72 h postmicroinjection time point. (D) Cells were microinjected with K5V186L/K14 WT; (E) K5 WT/K14V133L; and (F) K5 WT/K14 WT cDNA constructs. At 16 h postmicroinjection there is a time delay in network assembly in K5V186L/K14 WT cells (A), as well as filaments are thinner in appearance. Instead, the K5 WT/K14V133L cells (B) have fully formed filaments at the same time point, but they tend more to bundle in contrast to the web-like appearance of the WT. The bundling is even more pronounced at the 72 h time point, but in both cases where cells express mutant keratins (D,E) compared with the WT ones (F). Furthermore, the two 1A:V18L mutations in K5 and K14 may indirectly also affect the cell morphology. Scale bar: 10 µm. Journal of Investigative Dermatology 2001 116, 964-969DOI: (10.1046/j.1523-1747.2001.01334.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Space-filling model of K5/K14 1A region. The N-terminal end of the 1A domain is at the top of the figure; K5 on left, K14 on right. Residues at “d” position are colored green. Asn25 at position “a” in K5 1A is colored magenta, adjacent to the respective residue in K14 in orange. The salt bridge between Glu22 of K5 1A (left strand) and Lys17 of K14 1A (right strand) is in yellow, whereas both V18 residues (in K5 and K14 1A) are in red and lie immediately under the salt bridge. The figure was generated with CHARMM and LIGHT programs (seeBrooks et al, 1983). Journal of Investigative Dermatology 2001 116, 964-969DOI: (10.1046/j.1523-1747.2001.01334.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Computer-generated model of K5/K14 1A regions as helix representations. The K5 strand is in yellow and the K14 in blue. The residues involved are shown as space-filling in the end-on views (below): WT (left), K5 1A:V18L mutation (center) and K14 1A:V18L mutation (right). Both mutations, in conjunction with the two salt bridges (see Figure 4), clearly produce major bending of the predicted structure. The K5 mutant, however, causes far greater distortion of the coiled-coil molecule than the corresponding K14 one, correlating with the greater disease severity. Journal of Investigative Dermatology 2001 116, 964-969DOI: (10.1046/j.1523-1747.2001.01334.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions