Aoi Nakano, Hajime Nakano, Sal LaForgia, Leena Pulkkinen, Jouni Uitto

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Papillon–Lefèvre Syndrome: Mutations and Polymorphisms in the Cathepsin C Gene Aoi Nakano, Hajime Nakano, Sal LaForgia, Leena Pulkkinen, Jouni Uitto Journal of Investigative Dermatology Volume 116, Issue 2, Pages 339-343 (February 2001) DOI: 10.1046/j.1523-1747.2001.01244.x Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pedigrees of Family 1 and Family 2 with Papillon–Lefèvre syndrome. The solid symbols refer to affected individuals, whereas the half-solid symbols refer to clinically unaffected individuals shown to be heterozygous carriers of a mutation. The open symbols refer to clinically unaffected individuals. DNA from individuals indicated by a number under their symbol were studied for mutations in the CTSC gene. Note that the parents of the affected individuals in the two families are related. Journal of Investigative Dermatology 2001 116, 339-343DOI: (10.1046/j.1523-1747.2001.01244.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical findings in Family 2. The palms and soles of individual II-3 at the age of 21 y (a, b) show severe erythema and hyperkeratosis. There was evidence of development of pseudoainhums on the fingers (arrowhead in panel a). The 24-y-old sister had well-defined erythematous plaques on her elbows and knees (c, d). Panozamic X-ray of the teeth of individual II-3 at the age of 21 y (e) shows general alveolar and tooth resorption (arrows). Journal of Investigative Dermatology 2001 116, 339-343DOI: (10.1046/j.1523-1747.2001.01244.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Histopathologic findings in a skin biopsy from the knee of individual II-3 of Family 2 at the age of 5 y. Note acanthosis and hyperkeratosis with follicular hyperkeratosis, parakeratosis, and perivascular inflammatory cell infiltrates (scale bar: 300 μm; hematoxylin and eosin stain). Journal of Investigative Dermatology 2001 116, 339-343DOI: (10.1046/j.1523-1747.2001.01244.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Identification and verification of the homozygous missense mutation in Family 1. Direct nucleotide sequencing of the PCR product spanning exon 1 revealed a homozygous 116G→C in the affected individuals (I-2, I-3, I-4, and I-5) (top panel), whereas an unaffected child (II-1) of the patient I-4 was heterozygous for this nucleotide change (middle panel), compared with the normal sequence also found in an unaffected brother (I-1) (lower panel). The mutation was designated W39S. Verification of the mutation by digestion with MnlI (bottom panel). The mutation created a new restriction enzyme site for MnlI, which cuts the 338 bp PCR product in the case of the normal allele to 161 bp, 114 bp, 37 bp, 19 bp, and 7 bp bands, and in case of the mutant allele to 114 bp, 81 bp, 80 bp, 37 bp, 19 bp, and 7 bp bands (the smaller bands are not visible). MW, molecular weight markers φX174/HaeIII; C, control. Journal of Investigative Dermatology 2001 116, 339-343DOI: (10.1046/j.1523-1747.2001.01244.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Schematic illustration of the cathepsin C polypeptide, deduced from cDNA, with domain organization, and positions of all CTSC mutations disclosed thus far in patients with PLS. The premature termination codon and the putative splice site mutation are shown above the molecule, whereas missense mutations are shown below. The mutations disclosed in this study are shown in bold. The amino acid positions at the domain borders are indicated above the polypeptide. Journal of Investigative Dermatology 2001 116, 339-343DOI: (10.1046/j.1523-1747.2001.01244.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Conservation of peptide segments encoded by exon 7 of the CTSC gene. The partial human sequences are compared with those in other vertebrates indicated, as well as in Schistosoma japonicum (SchJp) and mansoni (SchMa). The conserved amino acids are boxed, and the positions of missense and nonsense mutations are indicated by arrows. The dashed lines indicated additional sequences not shown. A similar comparison of sequences encoded by exons 1–6 is presented elsewhere (Hart et al. 2000a). Journal of Investigative Dermatology 2001 116, 339-343DOI: (10.1046/j.1523-1747.2001.01244.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions