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A Spontaneous Deletion Within the Desmoglein 3 Extracellular Domain

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A Spontaneous Deletion Within the Desmoglein 3 Extracellular Domain The American Journal of Pathology, Vol. 185, No. 3, March 2015 ajp.amjpathol.org ANIMAL MODELS A Spontaneous Deletion within the Desmoglein 3 Extracellular Domain of Mice Results in Hypomorphic Protein Expression, Immunodeficiency, and a Wasting Disease Phenotype Evgueni I. Kountikov,* Jonathan C. Poe,* Nancie J. Maclver,y Jeffrey C. Rathmell,z and Thomas F. Tedder* From the Departments of Immunology,* Pediatrics,y and Pharmacology and Cancer Biology,z Duke University Medical Center, Durham, North Carolina Accepted for publication October 23, 2014. Desmoglein 3 is a transmembrane component of desmosome complexes that mediate epidermal cell-to-cell adhesion and tissue integrity. Antibody blockade of desmoglein 3 function in pemphigus vulgaris patients Address correspondence to fi Thomas F. Tedder, Ph.D., leads to skin blistering (acantholysis) and oral mucosa lesions. Desmoglein 3 de ciency in mice leads to a Department of Immunology, phenotype characterized by cyclic alopecia in addition to the dramatic skin and mucocutaneous acan- Duke University Medical tholysis observed in pemphigus patients. In this study, mice that developed an overt squeaky (sqk) Center, Box 3010, Room 353, phenotype were identified with obstructed airways, cyclic hair loss, and severe immunodeficiency subse- Jones Building, Durham, quent to the development of oral lesions and malnutrition. Single-nucleotide polymorphismebased NC 27710. E-mail: thomas. quantitative trait loci mapping revealed a genetic deletion that resulted in expression of a hypomorphic [email protected]. desmoglein 3 protein with a truncation of an extracellular cadherin domain. Because hypomorphic expression of a truncated desmoglein 3 protein led to a spectrum of severe pathology not observed in mice deficient in desmoglein 3, similar human genetic alterations may also disrupt desmosome function and induce a disease course distinct from pathogenesis of pemphigus vulgaris. (Am J Pathol 2015, 185: 617e630; http://dx.doi.org/10.1016/j.ajpath.2014.10.025) Tissues experiencing mechanical stress are held together by Homophilic and heterophilic interactions between the Dsg supramolecular desmosome complexes composed of type I and Dsc proteins lead to the formation of tightly packed transmembrane glycoproteins from the desmoglein (Dsg) and desmosomal complexes.5 desmocollin (Dsc) families of epithelial cadherins.1 The The desmogleins are involved in human disease patho- extracellular protein domains of the desmogleins and des- genesis. Cleavage of the extracellular domain of Dsg1 by mocollins consist of four approximately 110eamino acid Staphylococcus aureus exfoliating toxin results in bullous homologous cadherin domains (EC1 to EC4) and a proximal impetigo in children, manifesting as skin blisters due to extracellular anchor domain. The desmosomal cadherins are detachment (acantholysis) of the outer layer of epidermis.6 differentially expressed in different cellular layers of select Inactivation of either the Dsg2 or Dsc3 gene is embryonic tissues. For example, desmoglein 1 (Dsg1) is expressed at lethal.7,8 The development of circulating IgG autoantibodies high levels in the suprabasal outer layer of skin epidermis against Dsg1 or Dsg3 can result in the human autoimmune (stratified squamous epithelia) and thymus.2,3 Desmoglein 2 blistering disorders pemphigus foliaceus and pemphigus (Dsg2) is expressed ubiquitously in the basal layers of the vulgaris due to reduced desmoglein expression on the cell epidermis and desmosome-enriched cardiac tissues.2,3 Des- surface.9 In patients with pemphigus foliaceus, acantholysis moglein 3 (Dsg3) is primarily expressed by epidermal kera- within the superficial layers of the epidermis results in tinocytes in the basal and immediate suprabasal layers of skin clinical lesions that resemble those observed in lupus and in the basal layer of the mucosal epithelium of the mouth, 2,3 eyes, and trachea. Six Dsg and three Dsc genes are found in Supported by NIH grants AI56363 and U54 AI057157 (T.F.T.). 4 mice, with four Dsg and three Dsc genes in humans. Disclosures: None declared. Copyright ª 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2014.10.025 Kountikov et al erythematosus and seborrheic dermatitis patients. Pemphigus using SNPBrowser software version 2.0 (Applied Biosystems, foliaceus patients experience no oral involvement and have Carlsbad, CA). The probes were used to identify crossovers no associated mortality. By contrast, patients with pemphigus among 510 F2 mouse DNA samples using an ABI 7900HT vulgaris experience acantholysis within the deep basilar and PRC machine and SDS software version 2.3 (Applied Bio- parabasilar portions of the epidermis, which results in lesions systems). Additional internal SNPs for fine mapping were that may resemble toxic epidermal necrolysis. With identified using the SNP database dbSNP build 138 (Short pemphigus vulgaris, there is significant oral and skin Genetic Variations, http://www.ncbi.nlm.nih.gov/projects/SNP, involvement and untreated patients experience considerable last accessed October 23, 2014) and Mouse Genome Infor- mortality. matics (Mouse SNP Query Form, http://www.informatics.jax. Although mutations in the human Dsg3 gene have not org/javawi2/servlet/WIFetch?pageZsnpQF, last accessed been described, gene inactivation in Dsg3À/À mice leads to October 23, 2014) databases. The genotype of each SNP was fragility of the skin and oral mucous membranes, analogous determined after amplicon sequencing (Duke Cancer Center to those found in pemphigus vulgaris patients,10 along with DNA Analysis Facility) as single-nucleotide (homozygous runting and progressive hair loss.11 Two independent B6:B6) or double-nucleotide (heterozygous B6:129) peaks. spontaneous mutations within mouse chromosome 18 affecting exons encoding the Dsg3 cytoplasmic domain also Immunofluorescence Staining and Analysis ablate protein expression and lead to a Dsg3À/À pheno- type.10,12,13 Herein, a spontaneous gene mutation was Immunofluorescence staining was as described.14 The identified in mice that develop an overt squeaky (sqk) following antibodies (Abs) were used: fluorescein iso- phenotype with cyclic hair loss, obstructed airways, and thiocyanatee, phosphatidylethanolamine-, phosphatidyletha- severe immunodeficiency subsequent to the development of nolamine-cyanine 7e, or allophycocyanin-conjugated oral lesions and malnutrition. This phenotype was mapped monoclonal Abs to mouse CD93 (clone AA4.1), B220 to a partial exon deletion in the Dsg3 gene that results in (30-F11), CD4 (RM4-5), and CD8 (53-6.7) (BioLegend, hypomorphic expression of a truncated Dsg3 protein, which San Diego, CA); and anti-IgM Ab (goat; Southern Biotech, leads to a severe spectrum of pathology not observed in Birmingham, AL). Single-cell splenocytes and thymocytes À À Dsg3 / mice. were prepared by macerating spleens or thymuses between frosted ends of glass slides (Gold Seal; VWR International, fl Materials and Methods Radnor, PA). Bone marrow cells were ushed from femurs and resuspended in phosphate-buffered saline. Cells were Mouse SNP Genotyping and QTL Analysis washed with phosphate-buffered saline containing 1% fetal bovine serum. Red blood cells were removed by lysis before C57BL/6 (B6) and 129S1 (129) mice (The Jackson Labo- single-cell leukocyte suspensions (106 cells) were stained at ratories, Bar Harbor, ME) were maintained in specific 4C using predetermined optimal concentrations of pathogen-free housing. Vanilla-flavored Ensure Plus nutri- fluorochrome-conjugated Abs for 20 minutes. Multicolor tion shake (Abbott Laboratories, Abbott Park, RI) was used immunofluorescence analysis of cell surface molecule to supplement solid food for select experiments. Mice were expression used a BD FACSCanto II (BD Biosciences, euthanized if a predetermined level of distress was reached Franklin Lakes, NJ). Background staining levels were before natural death. All procedures were approved by the determined using nonreactive isotype-matched, fluoro- Duke University (Durham, NC) Institutional Animal Care chrome-conjugated control monoclonal Abs (BioLegend and Use Committee. and Southern Biotech). B6 mice with the sqk phenotype were crossed with 129 wild-type (WT) mice to generate heterozygous F1 progeny. PCR Analysis The F1 mice were intercrossed using sister-brother mating pairs to produce F2 progeny, which were monitored for Total RNA was extracted from tissues using TRIzol reagent emergence of the sqk phenotype after the age of 3 weeks. (Life Technologies, Carlsbad, CA), according to the manu- Purified genomic DNA from tail snips of 74 F2 mice was facturer’s instructions. cDNA was synthesized from sample used for genome-wide genotyping of 222 single-nucleotide RNA using random or oligo-d(T)25 primers and SuperScript polymorphism (SNPs) that are distinct between the B6 and III Reverse Transcriptase (Life Technologies), according to 129 mouse genomes. Genotyping (Duke University Geno- the manufacturer’s protocols. Primer pairs that generated typing Facility) used an Illumina BeadArray platform (Illu- overlapping 500- to 800-bp amplicons were used to amplify mina, San Diego, CA). Quantitative trait loci (QTL) mapping the entire coding sequence of Dsg3 transcripts. Sequencing was performed by calculating logarithm of odds (LOD) revealed a deletion within Dsg3sqk/sqk cDNAs that were scores for each SNP using permutation test and J-QTL amplified using the following primers: 50-TACCTACCG- regression analysis
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