A Novel Mutation in the L12 Domain of Keratin 5 in the Köbner Variant of Epidermolysis Bullosa Simplex Philippa Galligan, Pawel Listwan, Gregory M. Siller,

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A Novel Mutation in the L12 Domain of Keratin 5 in the Köbner Variant of Epidermolysis Bullosa Simplex Philippa Galligan, Pawel Listwan, Gregory M. Siller, Joseph A. Rothnagel Journal of Investigative Dermatology Volume 111, Issue 3, Pages 524-527 (September 1998) DOI: 10.1046/j.1523-1747.1998.00308.x Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Sequence analysis of the L12 domain of K5 in EBS-K patients and unaffected family members. (a) Sequence of the normal K5 alleles obtained from an unaffected family member. (b) Direct genome sequencing of the proband (individual III.2 in Figure 2) who is heterozygous for the mutant allele. The affected individual contains a T to C mutation (indicated by the arrow) in codon 323, resulting in the expression of alanine at position 7 of the L12 domain. The sequence shown begins at the first codon of the L12 domain. Journal of Investigative Dermatology 1998 111, 524-527DOI: (10.1046/j.1523-1747.1998.00308.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Restriction enzyme analysis of codon 323 showing cosegregation of the mutation with affected individuals. The L12 region of K5 was amplified and the 280 bp product digested with Msp A1 I. The T to C transition identified in the proband creates a Msp A1 I site in the mutant allele and results in 197 bp and 83 bp fragments after digestion. Wild-type alleles remain uncut. Solid symbols denote affected individuals, open symbols unaffected individuals; males are represented by squares and females by circles. The arrow indicates the proband (individual III.2). Journal of Investigative Dermatology 1998 111, 524-527DOI: (10.1046/j.1523-1747.1998.00308.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Sequence comparison of the L12 linker peptide showing conservation of the valine residue at position 7. The delineation of the L12 region is as determined byConway & Parry (1988). EBSmut indicates the disease-associated mutations found in this study (V7A) and in other studies (Rugg et al.1993;Chan et al.1994;Matsuki et al.1995). The SwissProt accession numbers are: K5-P13647; K1-P04264; K2e-P35908; K2p-Q01546; K3-P12035; K4-P19013; K6a-P02538; K7-P08729; K8-P05786; XK8 Xenopus laevis-P04266; FK8 Carassius auratus-P18520; Wool(7c) Ovis aries-P15241; Vimentin-P08670; Desmin-P17661; GFAP-P14136; Hagfishγ polymer-Q90502. Journal of Investigative Dermatology 1998 111, 524-527DOI: (10.1046/j.1523-1747.1998.00308.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Secondary structure analysis of the L12 linker peptide. The Chou and Fasman algorithm of the peptide analysis tool (PEPPLOT) of ANGIS (http://www.angis.su.oz.au/) was used to calculate the affect of the alanine substitution at position seven. The graphs show the propensity for α-helix (red curve) and β-sheet (blue curve) formation for the normal L12 sequence (a) and the mutant L12 sequence (b). Both curves are the average of a residue-specific attribute over a window of four residues. The threshold value for the continuation of a given structure is arbitrarily set at 1.0. Journal of Investigative Dermatology 1998 111, 524-527DOI: (10.1046/j.1523-1747.1998.00308.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions