Genomic Amplification of the Human Plakophilin 1 Gene and Detection of a New Mutation in Ectodermal Dysplasia/Skin Fragility Syndrome Neil V. Whittock,

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Genomic Amplification of the Human Plakophilin 1 Gene and Detection of a New Mutation in Ectodermal Dysplasia/Skin Fragility Syndrome Neil V. Whittock, Robin A.J. Eady, John A. McGrath Journal of Investigative Dermatology Volume 115, Issue 3, Pages 368-374 (September 2000) DOI: 10.1046/j.1523-1747.2000.00082.x Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical examination shows signs of abnormal keratinocyte adhesion and differentiation. Several peripherally spreading, circinate scaly plaques can be seen on the patient's legs. There are no bullae but the marginal skin is tender and slightly edematous. There is some spontaneous healing at the center of the lesions. Acral hyperkeratosis and a fissure on the heel are evident. Journal of Investigative Dermatology 2000 115, 368-374DOI: (10.1046/j.1523-1747.2000.00082.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 PCR amplification of genomic DNA establishes the intron–exon organization of PKP1. (a) Exons are represented by vertical boxes, introns by horizontal lines. The gene consists of 15 exons, 63–2920 bp in size, spanning approximately 50 kb of genomic DNA. Exon 6a is represented as an open box as it is not part of the plakophilin 1a transcript. The positions of the translation–initiation codon (ATG) in exon 1 and of the termination codon (TAA) in exon 13 are indicated. The homozygous mutation discovered in this study (1233–2 A→T) is indicated by the arrow. (b) Exons 1–4 of PKP1 encode the amino terminus and exons 5–13 encode the armadillo repeat units. Journal of Investigative Dermatology 2000 115, 368-374DOI: (10.1046/j.1523-1747.2000.00082.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Agarose gel electrophoresis demonstrating amplification of the entire coding region of PKP1. PCR amplification of exons 1–13 and flanking introns using genomic DNA as template with the primer pairs as shown in Table 3. The lanes M contain ØX174 HaeIII molecular weight markers. Journal of Investigative Dermatology 2000 115, 368-374DOI: (10.1046/j.1523-1747.2000.00082.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Transmission electron microscopy reveals poorly formed desmosomes and an abnormal keratin filament network. In this biopsy taken from normal appearing skin on the thigh at the periphery of a circinate lesion, few, small desmosomes are present. The most striking feature is the compacted, perinuclear arrangement of keratin filaments and the loss of attachment of the keratin filament network to the cell periphery. Scale bar: 1 μm. Journal of Investigative Dermatology 2000 115, 368-374DOI: (10.1046/j.1523-1747.2000.00082.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Light microscopic immunogold-silver enhancement labeling demonstrates complete ablation of plakophilin 1. There is no specific labeling with anti-PKP1 antibody of plastic embedded perilesional epidermis of the patient (a). A few large silver granules seen on the section testify to a long-lasting amplification. The counterstained semithin section in (b), shows the topography of the acanthotic epidermis labeled in (a). Under the same experimental conditions, the anti-PKP1 antibody labeled normal human epidermis in an intercellular punctate pattern (c). The patient's PKP1 unreactive epidermis showed normal expression of plakoglobin (d). Note that the epidermis in the patient's skin is thicker than the control skin (compare a, b and d with c). Scale bar: 20 μm. Journal of Investigative Dermatology 2000 115, 368-374DOI: (10.1046/j.1523-1747.2000.00082.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Nucleotide sequencing reveals a homozygous acceptor splice site mutation in plakophilin 1. Characterization of the 1233–2 A→T mutation in the family studied. (a) Direct nucleotide sequencing of the PCR product spanning exon 7 for the proband reveals a homozygous A→T transition in the - 2 position of the acceptor splice site (indicated by the arrow). (b) Pedigree of the family: the affected proband, III-1, is indicated by the arrow. Carrier status for the family members I-1, II-1, III-2, and III-3 was determined by direct sequencing of the exon 7 PCR product. None of the carriers demonstrated any phenotypic abnormalities. Journal of Investigative Dermatology 2000 115, 368-374DOI: (10.1046/j.1523-1747.2000.00082.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions