Transient Bullous Dermolysis of the Newborn Associated with Compound Heterozygosity for Recessive and Dominant COL7A1 Mutations Nadja Hammami-Hauasli,

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Transient Bullous Dermolysis of the Newborn Associated with Compound Heterozygosity for Recessive and Dominant COL7A1 Mutations Nadja Hammami-Hauasli, Michael Raghunath, Leena Bruckner-Tuderman Journal of Investigative Dermatology Volume 111, Issue 6, Pages 1214-1219 (December 1998) DOI: 10.1046/j.1523-1747.1998.00394.x Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Morphology of TBDN skin at birth and at the age of 14 mo. (a) At birth, EM revealed dermo–epidermal separation below the lamina densa of the basement membrane. Diffuse fibril-like structures (arrows) are attached to the lamina densa at the blister roof. The asterisk marks the blister cavity. The blister floor consists of dermal matrix without basement membrane or anchoring fibrils. (b) Epidermal keratinocytes contain characteristic vacuoles with filamentous material and electron-dense granules and rods. (c) Collagen VII IF staining of a postnatal skin biopsy with the antibody NC2–10 recognizing the carboxyterminus of the triple-helical domain and the NC-2 domain. The dermo–epidermal junction (arrowheads) was very weakly stained. In contrast, several layers of epidermal keratinocytes showed striking accumulation of collagen VII. The same staining pattern was obtained with different domain-specific antibodies to the NC-1, triple-helical, and the NC-2 domains of procollagen VII (not shown). (d) A skin sample obtained at the age of 14 mo, after significant clinical improvement of the blistering, showed strong basement membrane staining of collagen VII, but only a weak intraepidermal staining with the NC2–10 antibody. Journal of Investigative Dermatology 1998 111, 1214-1219DOI: (10.1046/j.1523-1747.1998.00394.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Identification of mutations G1519D and G2251E in COL7A1. (A) Pedigree, the black areas indicate the presence of the recessive paternal mutation and the schaded areas the presence of the dominant maternal mutation; (B) conformation sensitive gel electrophoresis revealed heteroduplex bands in the PCR products spanning exon 44 of individuals 1 and 2, and in the PCR products including exon 86 of probands 1 and 3; (C) direct sequencing of the PCR products disclosed a heterozygous G→A transition in exon 44 in patient 1 and her unaffected father 2. This sequence alteration led to the glycine substitution G1519D. The paternal mutation created aBamHI site, with cleavage of the 461 bp PCR product into two fragments of 357 bp and 104 bp (lower panel). The dominant maternal mutation was a heterozygous G→A transition in exon 86 (forward and reverse sequence is shown). The mutation led to the glycine substitution G2251E, and was detected in the propositus, 1, her mother, 3, and her great-grandmother, 4. The maternal mutation was verified by the loss of aBsiYI site that led to appearance of an additional 189 bp fragment (lower panel). Journal of Investigative Dermatology 1998 111, 1214-1219DOI: (10.1046/j.1523-1747.1998.00394.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 TBDN keratinocytes accumulate procollagen VIIin vitro. Analyses of single optical sections (0.6 μm) as obtained by confocal laser scanning after double immunolabeling of normal keratinocytes (a, b) and TBDN keratinocytes (c–h). Double immunostaining of normal keratinocytes and TBDN cells for procollagen VII (a, c) and the lysosomal marker cathepsin D (b, d) showed fine granular cytoplasmic staining for procollagen VII (a) and the lysosomal marker cathepsin D (b) in normal keratinocytes. In contrast, marked accumulation of procollagen VII in TBDN keratinocytes appeared as perinuclear patches (c). Cathepsin D did not colocalize with procollagen VII in TBDN cells (d), excluding significant distribution of the accumulated material in the lysosomes of TBDN cells. Double immunostaining of TBDN keratinocytes for procollagen VII (e, f) and the RER marker protein disulfide isomerase (g, h) demonstrated colocalization of the signals. The colocalization of procollagen VII and protein disulfide isomerase indicates accumulation of procollagen VII within the lumen of the RER of the TBDN keratinocytes.Scale bars: 10 μm. Journal of Investigative Dermatology 1998 111, 1214-1219DOI: (10.1046/j.1523-1747.1998.00394.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 TBDN keratinocytes accumulate procollagen VIIin vitro. Immunoblotting of procollagen VII from keratinocyte cultured from control and TBDN skin. Cell extracts (two left lanes) and the culture medium (two right lanes) were immunoblotted with antibodies to procollagen VII. In TBDN cultures, more procollagen VII and a higher relative cell/medium ratio of procollagen VII was seen than in controls. Co, control keratinocytes; Pat, TBDN proband. Journal of Investigative Dermatology 1998 111, 1214-1219DOI: (10.1046/j.1523-1747.1998.00394.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions