Epidermolysis Bullosa Simplex Associated with Pyloric Atresia Is a Novel Clinical Subtype Caused by Mutations in the Plectin Gene (PLEC1) Hiroyuki Nakamura,

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Epidermolysis Bullosa Simplex Associated with Pyloric Atresia Is a Novel Clinical Subtype Caused by Mutations in the Plectin Gene (PLEC1) Hiroyuki Nakamura, Daisuke Sawamura, Maki Goto, Hideki Nakamura, James R. McMillan, Susam Park, Sumio Kono, Shiro Hasegawa, Son'e Paku, Tomohiko Nakamura, Yoshihumi Ogiso, Hiroshi Shimizu The Journal of Molecular Diagnostics Volume 7, Issue 1, Pages 28-35 (February 2005) DOI: 10.1016/S1525-1578(10)60005-0 Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 1 Clinical, X-ray, and ultrastructural findings of proband 1 in pedigree 1. A: Sharply demarcated erosions and ulcers on the trunk, genitalia, and lower extremity. B: Marked ulcers on the lower extremities. C: A single abdominal bubble of gas in an abdominal X-ray of proband 1. D and E: The same clinical manifestation of his elder brother. F: Electron microscopy of the skin from proband 1 shows tissue separation occurring at the base of the basal keratinocytes (stars). Keratin filaments are sparse and thin and not well associated with the hemidesmosome (HD) inner plaque (full arrowheads). Reduced numbers of hypoplastic HDs are recognized (triangles) and occasional HDs can be observed associated with thin bundles of keratin filaments within the basal keratinocyte (open arrow). The lamina densa (LD) and lamina lucida (LL) are present in the papillary dermis. Bar, 500 nm. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 2 Clinical and ultrastructural findings of proband 2 in pedigree 2. A: Clearly demarcated blisters and ulcers on the scalp, abdomen, and extremities. B: Ulcers on the left arm. C: Localized erosions on the scalp. D: Ulcers on the left leg. E: Electron microscopy of the skin shows basal cell debris including flat electron densities (representing remnant hemidesmosome outer plaques (arrows) can be seen at the base of the intraepidermal split (asterisk). Bar, 1 μm. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 3 Immunofluorescence using antibodies against basement membrane zone components. Staining using HD1–121, K15, 10F6, and 5B3 monoclonal antibodies (mAbs) for plectin were markedly attenuated in the proband 1 and completely loss in the proband 2. Immunostaining for other proteins including α6 and β4 integrins, laminin 5, type VII and IV collagens were normal in both probands and controls. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 4 Mutation detection in pedigree 1. The proband harbored a G→A transition at position c.1344 in exon 12 within an intron-exon border (middle-right panel). He also possessed a heterozygous transition 913C→T (exon 9), leading to the substitution of glutamine 305 with a nonsense codon (Q305X). HphI digestion of the 428-bp fragment with and without the 1344G->A mutation product resulted in single band of 428 bp and double bands of 221 and 207 bp, respectively (left panel). The 387-bp PCR fragment containing the Q305X mutation was not digested by PstI whereas the digestion of the fragment without the mutation showed two bands of 240 and 147 bp (right panel). The 1344G→A mutation was paternal and the Q305X mutation was maternal. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 5 Mutation detection in pedigree 2. The proband 2 harbored a homozygous transition 3565C→T (exon 27) at codon 1189 producing a nonsense codon instead of arginine (R1189X) (middle panel). She also harbored a heterozygous C→T (c.7612) substitution (exon 32) in codon 2538, replacing glutamine with a nonsense codon (Q2538X). The R1189X mutation caused the generation of site for the Tsp45I restriction enzyme. The 771-bp PCR product with the mutation was digested by Tsp45I resulting in 424-bp and 347-bp bands (left panel). Since no proper restriction enzyme site was found around the Q2538X mutation, we changed one base of the PCR primer from the original sequence to create a site for AluI (see Materials and Methods). The digestion of 225-bp PCR product with Q2538X produced 70-bp band (right panel). The father and the mother are heterozygous for R1189X and Q2538X mutations, respectively. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 6 Detection of uniparental isodisomy. Comparison of 8 intragenic polymorphisms around the homozygous R1189 mutation showed that the father and the mother were heterozygous for 2 of 8 and 6 of 8 markers. The mutation R1189X and intron 28/10648 T→A were informative for the absence of a maternal allele in the proband. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 7 Database showing the position of mutations in PLEC1. Each functional domain is shown in the schematic model of plectin structure. The cDNA and the amino acids of the protein are numbered based on the previous sequence information (GenBank Accession No. AH003623).17 Amino-terminal actin binding domain, amino-terminal globular domain, β4 integrin binding sites, rod domain, and carboxyl-terminal globular domain are shown. The Journal of Molecular Diagnostics 2005 7, 28-35DOI: (10.1016/S1525-1578(10)60005-0) Copyright © 2005 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions