Animal Models for Skin Blistering Conditions: Absence of Laminin 5 Causes Hereditary Junctional Mechanobullous Disease in the Belgian Horse Flavia Spirito,

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Animal Models for Skin Blistering Conditions: Absence of Laminin 5 Causes Hereditary Junctional Mechanobullous Disease in the Belgian Horse Flavia Spirito, Alexandra Charlesworth, Jean-Paul Ortonne, Guerrino Meneguzzi Journal of Investigative Dermatology Volume 119, Issue 3, Pages 684-691 (September 2002) DOI: 10.1046/j.1523-1747.2002.01852.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical feature of JEB in Belgian horses. A few days after birth (8 d for the depicted animal) Belgian foals with JEB show extensive erosions over the pressure points of the carpal, tarsal, and femor-tibial joints (a) and exungulation of the hoofs (b). Extensive loss of buccal mucous membrane around the junction of the teeth and gums is detected at birth, as shown in the case of a 24-h-old Belgian newborn (c, e). Erosions are associated with eruption of deciduous incisor teeth (c) and premolar teeth (e), which are irregularly shaped, with serrated edges and pitted enamel. The oral cavity of a wild-type 8-d-old foal shows no eruption of the deciduous incisor teeth (d) and displays normal premolar teeth and buccal mucosa (f). Journal of Investigative Dermatology 2002 119, 684-691DOI: (10.1046/j.1523-1747.2002.01852.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Altered expression of laminin γ2 in horse JEB. Immunofluorescence analysis of frozen sections of tongue epithelia samples obtained from an affected foal (a, c, e, g) and a healthy unrelated control (b, d, f, h) using antibody SE144 (a, b) specific to human laminin γ2, SE85 (c, d) to the human laminin α3 chains, and mAb K140 (e, f) to the human laminin β3 chain. In the JEB foal, immunoreactivity of the laminin γ2 chain is absent, whereas immunoreactivity to the laminin α3 and β3 shows a strong attenuation of the fluorescent signal in the affected animal compared to healthy control. Staining with monoclonal antibody LH7:2 to collagen type VII (g, h) was comparable in both samples. Scale bar: 50 µm. Journal of Investigative Dermatology 2002 119, 684-691DOI: (10.1046/j.1523-1747.2002.01852.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Direct comparison of the primary structure of the horse, human, and mouse laminin γ2 chain. The amino acid sequence of the γ2 polypeptides was aligned using the Clustal W alignment software (Thompson et al, 1994). Identity of the horse (upper line) γ2 chain with the human (middle line) and mouse (lower line) γ2 polypeptides is 87.1% and 82.4%, respectively. Conserved amino acids are framed in black, semiconserved amino acids are boxed in gray, and the nonconserved amino acids are indicated by light boxes. The gaps in the aligned sequences are filled in with a hyphen. The GenBank accession numbers for the human and the mouse γ2 chain are Z15008 and NM_008485, respectively. Journal of Investigative Dermatology 2002 119, 684-691DOI: (10.1046/j.1523-1747.2002.01852.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Identification of genetic mutation 1368insC.(A)Genomic DNA was isolated from peripheral blood and the DNA fragment harbouring mutation 1368insC was PCR amplified. The PCR amplification products were submitted to direct nucleotide sequencing. The homozygous basepair insertion detected in the JEB foal (a) results in a shift of the open reading frame that generates a 58 bp downstream premature termination codon (TGA). Genotyping of the dam (b) and the sire (not shown) disclosed heterozygosity for mutation 1368insC. A wild-type horse genomic DNA was used as a control (c). (B) Mendelian inheritance of mutation 1368insC was assessed by genotyping in an inbred Belgian horse population. Affected foals are indicated by black-filled and numbered symbols, unaffected individuals are indicated by unfilled symbols, and carriers by half-filled symbols. Generations are indicated by roman numerals on the left. Journal of Investigative Dermatology 2002 119, 684-691DOI: (10.1046/j.1523-1747.2002.01852.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions