Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

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Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy Fatima Rouan, Leena Pulkkinen, Sal LaForgia, Patrice Hyde, Gabriele Richard, Jouni Uitto Journal of Investigative Dermatology Volume 114, Issue 2, Pages 381-387 (February 2000) DOI: 10.1046/j.1523-1747.2000.00880.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Histopathology of a skin biopsy shows tissue separation at the dermal–epidermal junction in the proband of family 1. PAS stain; original magnification, ×90. Journal of Investigative Dermatology 2000 114, 381-387DOI: (10.1046/j.1523-1747.2000.00880.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Transmission electron microscopy demonstrates intracellular tissue cleavage in the skin of patient 1. (A) Dermal–epidermal separation with intact basal lamina in the floor of the blister; (B, C) higher magnification of areas outlined in (A) reveals attachment of intracellular material, including cytoplasmic vesicles in (B) and mitochondria (M) in (C) adjacent to the basal lamina (arrows). The hemidesmosomes appear hypoplastic (arrowheads). Journal of Investigative Dermatology 2000 114, 381-387DOI: (10.1046/j.1523-1747.2000.00880.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Immunofluorescence staining of a skin biopsy from the proband Family 1. Immuno-fluorescence with a monoclonal antibody 121 (HD1) revealed negative staining at the dermal BMZ in the patient’s skin (A), whereas control skin revealed bright linear staining at the dermal–epidermal junction (B). Staining of parallel sections with antibodies recognizing β4 (C, D) or α6 (E, F) integrin subunits showed similar linear BMZ staining in both the patient and control skin (left and right panels, respectively). Journal of Investigative Dermatology 2000 114, 381-387DOI: (10.1046/j.1523-1747.2000.00880.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Identification of nonsense mutations in family 1. (A) The proband (II-I) was a 6-mo-old male with clinically unaffected parents. (B) Protein truncation test, when applied to exons 32 and 33, revealed two extra bands, 43 kDa and 67 kDa in size, respectively, whereas a normal control (C) prominently displayed the expected polypeptide of 81 kDa. (C) Sequencing of the regions predicted to contain mutations leading to truncation of the plectin polypeptide revealed a G-to-T transversion mutation within exon 32 (left panel) in one allele at position 6064, which lead to substitution of a glutamic acid codon by a stop codon (E2005X). This mutation was also detected in the mother’s DNA (not shown). Note also the presence of a silent G-to-A polymorphism (Ala→Ala) at position 6060, the patient (upper panel) being a heterozygote (G/A), whereas the normal control (lower panel) was homozygous for an A. Sequencing of exon 33 (right panel) revealed an A-to-T transversion in position 13429; this resulted in substitution of a codon for lysine by a stop codon (K4460X). (D) The K4460X mutation in the proband (II-1) was confirmed by restriction enzyme digestion. The mutation created a new restriction site for BfaI that resulted in digestion of the 524 bp PCR product to 396 and 128 bp fragments. The corresponding PCR products representing maternal (I-2) and paternal (I-1) DNA remained undigested, similar to control DNA (C). Journal of Investigative Dermatology 2000 114, 381-387DOI: (10.1046/j.1523-1747.2000.00880.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Detection of deletion mutations in family 2. (A) The proband (II-I) was a 5-mo-old female with clinically unaffected parents. (B) PCR amplification of exon 23 and flanking intronic sequences resulted in a product that showed on agarose gel two bands in the proband (II-1) and her mother (I-2), whereas the father’s DNA product showed a single band only (I-1). (C) PTT analysis of exon 32 (32-I) revealed a 43 kDa band in the case of the proband in addition to the expected 67 kDa band. (D) Heteroduplex analysis of the PCR products shown in (B) confirmed, by conformation sensitive gel electrophoresis (CSGE), the presence of sequence variants in the proband’s and mother’s DNA, whereas the father’s DNA revealed a homoduplex band only. (E) Sequencing of the region containing the putative stop codon mutation in exon 32, as shown in (C), revealed deletion of a G in comparison with normal sequence (5083delG) (left panel). Direct sequencing of the PCR products suggesting the presence of sequence variants in exon 23, as shown in (B) and (D), revealed a 21 bp deletion that spans the intron 22/exon 23 junction (-9 to +12) (right panel). Journal of Investigative Dermatology 2000 114, 381-387DOI: (10.1046/j.1523-1747.2000.00880.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Summary of plectin mutations in EB-MD. Schematic representation of the plectin domain organization, and positions of the plectin mutations in patients with EB-MD, as described in this study (cases 1 and 2; bold) and reported in the literature (see Table 1). Journal of Investigative Dermatology 2000 114, 381-387DOI: (10.1046/j.1523-1747.2000.00880.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions