Recurrent Mutations in Kindlin-1, a Novel Keratinocyte Focal Contact Protein, in the Autosomal Recessive Skin Fragility and Photosensitivity Disorder,

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Recurrent Mutations in Kindlin-1, a Novel Keratinocyte Focal Contact Protein, in the Autosomal Recessive Skin Fragility and Photosensitivity Disorder, Kindler Syndrome Gabrielle H.S. Ashton Journal of Investigative Dermatology Volume 122, Issue 1, Pages 78-83 (January 2004) DOI: 10.1046/j.0022-202X.2003.22136.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features of Kindler syndrome. (a) Marked poikiloderma on the dorsa of the hands in case 4; (b) atrophy and erythema on the dorsa of the hands in case 14; (c) trauma-induced scars and postinflammatory hyperpigmentation on the lowers limbs in case 6; (d) persistent facial erythema as a sign of photosensitivity in case 6; (e) prominent poikiloderma on the face and neck in case 5; (f) telangiectasiae on the lower lip mucosa in case 6; (g) skin wrinkling and atrophy on the elbow in case 4. Journal of Investigative Dermatology 2004 122, 78-83DOI: (10.1046/j.0022-202X.2003.22136.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Sequencing reveals recurrent nonsense and frameshift mutations in KIND1. (a) Pakistani patients 1–8 show a homozygous insertion of a cytosine at nucleotide 676 in exon 5, denoted 676insC. (b) Omani patients 9 and 10 have a homozygous guanine to adenine substitution at nucleotide 1848 in exon 14 changing a tryptophan residue (TGG) to a stop codon (TGA), denoted W616X. (c) UK Caucasian patients 11–13 are all heterozygous for a guanine to thymine change at nucleotide 910 resulting in glutamic acid (GAA) being converted to a stop codon (TAA) in exon 7, denoted E304X. Each of these cases has a further heterozygous nonsense mutation on the other allele. Illustrated here in patient 11 is a thymine to adenine substitution at nucleotide 905 changing leucine (TTA) to a stop codon (TAA), L302X, depicted by the double arrowhead. (d) Italian patients 14–16 are homozygous for an acceptor splice site mutation, with a substitution of guanine by adenine in intron 7, denoted 958–1G > A. The start of exon 8 is indicated by an open bracket. Journal of Investigative Dermatology 2004 122, 78-83DOI: (10.1046/j.0022-202X.2003.22136.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Schematic diagram showing the positions of all pathogenic mutations found in KIND1 and their positions within the gene. Mutations shown in bold are recurrent mutations, of which those identified in this study are underlined. Mutations in italics are also potential hotspot mutations. Exons (numbered 1–15) are to scale; introns in between are not to scale. Hatched areas denote start of 5′ and 3′ untranslated regions. Journal of Investigative Dermatology 2004 122, 78-83DOI: (10.1046/j.0022-202X.2003.22136.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Immunofluorescence labeling with antikindlin-1 C-terminal antibody. (a) Control skin shows strong epidermal labeling within the basal keratinocytes and along the dermal–epidermal junction. (b) Patient 6, homozygous for the mutation 676insC, shows weak basal keratinocyte staining and broken staining along the dermal–epidermal junction. (c) Patient 11, compound heterozygous for E304X/L302X, shows weak staining throughout the epidermis. (d) Patient 10, homozygous for W616X, shows absence of staining. (e) Patient 16, homozygous for 958–1G > A, shows weak staining throughout the epidermis. (f) Negative control skin labeling. Bar: 40 μm. Journal of Investigative Dermatology 2004 122, 78-83DOI: (10.1046/j.0022-202X.2003.22136.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions