Identification of a Lethal Form of Epidermolysis Bullosa Simplex Associated with a Homozygous Genetic Mutation in Plectin Maryse Bonduelle, Linda De.

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Identification of a Lethal Form of Epidermolysis Bullosa Simplex Associated with a Homozygous Genetic Mutation in Plectin Maryse Bonduelle, Linda De Raeve Journal of Investigative Dermatology Volume 121, Issue 6, Pages 1344-1348 (December 2003) DOI: 10.1111/j.1523-1747.2003.12639.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Altered expression of plectin in the EBS patients. Immunofluorescence analysis of frozen sections of involved skin samples obtained from proband 2 (a, c, e, g) and fetal skin specimens obtained from an unrelated control (b, d, f, h) using mAb HD121 (a, b) specific to human plectin, 1A8C (c, d) to the cytoplasmic domain of collagen type XVII, GoH3 (e, f) to integrin α6, and CKB1 (g, h) to cytokeratin 14. The upper panels (horizontal sections) show that, in the proband, immunoreactivity of plectin is absent in the skin annexes, whereas immunoreactivity to collagen type XVII and integrin α6 shows slight attenuation of the fluorescent signal compared to a healthy control. Immunoreactivity to cytokeratin 14 was normal. In the patient, vertical sections demonstrate that the floor of the blisters is not reactive to mAb HD121 (a) and has a residual immune reactivity (arrows) to 1A8C and GoH3 (c, e, respectively) compared to the wild-type control (b, d, f). Absent immunoreactivity of the involved skin to cytokeratin 14 confirms that the cleavage plane of the blister lies within the ventral aspect of the basal keratinocytes (g). Scale bars: 50 μm. Journal of Investigative Dermatology 2003 121, 1344-1348DOI: (10.1111/j.1523-1747.2003.12639.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Identification of genetic mutation 2727del14. (A) The PCR products from the amplification of gDNA including the intron-exon boundaries of exons 20–22 were electrophoresed on a 1% agarose gel together with DNA molecular weight markers (m). Compared to a wild-type control (C), the probands' mother (M) and proband (p) are homozygous for a 113 bp deletion within intron 20, whereas the probands' father (F) is heterozygous for this deletion. (B) CSGE heteroduplex analysis of the PCR product spanning exons 21 and 22 revealed a complex pattern of shifts in the migrating bands in the mother (M), father (F), and probands (P1, P2), compared to the control (C). As the parents are consanguineous, and therefore the probands were assumed homozygous for the mutation, CSGE analysis of the probands was done using PCR product solely from the probands (P1, P2), and mixed with an equal quantity of control PCR product (P1+C, P2+C). (C) Direct nucleotide sequencing of the PCR amplification products of the gDNA sequence spanning exon 22 disclosed the homozygous 14 bp deletion (2727del14) in the two probands, and the heterozygosity of both parents for this mutation. (D) Genotyping of the gDNA in the EBS family. Top panel: The intragenic polymorphisms identify the three PLEC1 alleles (1, 2, 3) in the family. The genealogic tree illustrates the Mendelian inheritance of mutation 2727del14 in the carriers (half-filled) and homozygous members (black) of the nuclear EBS family. Bottom panel: Mutation 2727del14 abolishes a DraIII restriction site in exon 22. Digestion of the DNA fragment obtained by PCR amplification of exons 21 and 22 generates two restriction products (523 and 83 bp) of a 606 bp fragment in healthy unrelated controls (lanes Cc (control digested) and Cu, control undigested, respectively) and the heterozygous parents (lanes M, F). The parents harbour an additional undigested 592 bp band amplified from the morbid PLEC1 allele, which is found as a unique band in the homozygous probands (P1 and P2). (E) Localization of mutation 2727del14 in plectin. Plectin comprises an N-terminal actin-binding domain (vertical bars) with a short variable sequence upstream, a globular plakin-like domain (black), a central coiled-coil rod domain (horizontal bars), and a C-terminal intermediate filament-binding domain (empty circles). The position of mutation 2727del14 with respect to the genetic mutations so far associated with EBS-MD and EBS-O (in italics, underlined) is indicated. Journal of Investigative Dermatology 2003 121, 1344-1348DOI: (10.1111/j.1523-1747.2003.12639.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions