A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma.

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A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma of the Ichthyosis Hystrix Curth–Macklin Type Elizabeth S. Richardson, Jason B. Lee, Patricia H. Hyde, Gabriele Richard Journal of Investigative Dermatology Volume 126, Issue 1, Pages 79-84 (January 2006) DOI: 10.1038/sj.jid.5700025 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features. (a) Proband with massive, diffuse hyperkeratosis and deep fissures on the soles of both feet. (b) Soles almost completely cleared after treatment with 40% urea cream under occlusion and mechanical filing. Thickened and fissured palms (c) before and (d) after treatment with acitretin. (e) Keratotic plaques over the dorsae of both hands. Keratotic plaques over elbows before (f) and after (g) treatment with acitretin. (h) A punch biopsy from the left palm revealed a papillomatous epidermis with hypergranulosis and marked hyperkeratosis. The insets (bottom) show perinuclear halos (asterisks) and binucleated cells (arrow) in the granular layer. Journal of Investigative Dermatology 2006 126, 79-84DOI: (10.1038/sj.jid.5700025) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Analysis of two different size polymorphisms in KRT1. (a) Agarose gel electrophoresis. For each individual, PCR amplicons in lane (I) encompass a 300bp segment of wild-type DNA spanning across the 21 and 27bp deletions. The products in lane (II) represent a region of KRT1 that includes only the 27bp deletion. Four combinations of the size polymorphisms were detected in controls: control sample 1 (C1) is homozygous wild-type (300bp; 170bp); control 2 (C2) is heterozygous for the 21bp deletion (300bp; 279bp; 170bp); control 3 (C3) is homozygous for the 21bp deletion (279bp; 170bp); control 4 (C4) is heterozygous for the 21bp deletion and the 21bp deletion plus 27bp deletion (300bp; 252bp; 170bp; 143bp). The patient (Pt) is heterozygous for deletions 1556delG, 1656del21, and 1569del27, all on the same mutant allele. (b, c) Schematic depiction of wild-type and mutant K1. (b) The two-dimensional model of the carboxy-terminal tail domain of wild-type K1 protein predicts 10 glycine loops. Black circles highlight those amino-acid residues that are lost owing to size polymorphisms c.1569del27 and c.1656del21. (c) Predicted glycine loop structure in the presence of both deletions. Journal of Investigative Dermatology 2006 126, 79-84DOI: (10.1038/sj.jid.5700025) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Mutation and sequence variants of the KRT1 gene in the proband. (a, b) Sequence analysis of exon 9 of KRT1 in the proband reveals the presence of three different nucleotide deletions – c.1556delG (a), c.1569del27 (a), and c.1656del21 (b) – all on one allele of KRT1 (upper panels). The wild-type allele is shown for comparison in the lower panels. (c) The graphical view illustrates the DNA sequence of both the proband's alleles across the critical region in exon 9 of KRT1. (d) Comparison of the amino-acid sequence of wild-type (WT) and mutant (Mut, underlined) K1 across the V2 domain, indicating also the position of 10 glycine loops (GL1–GL10). (e) The position of the frameshift mutation within the variable (V2) domain of K1 is indicated by the arrow and the resultant aberrant V2 tail is shown in red. Journal of Investigative Dermatology 2006 126, 79-84DOI: (10.1038/sj.jid.5700025) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions