Compound Heterozygous Desmoplakin Mutations Result in a Phenotype with a Combination of Myocardial, Skin, Hair, and Enamel Abnormalities My G. Mahoney,

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Compound Heterozygous Desmoplakin Mutations Result in a Phenotype with a Combination of Myocardial, Skin, Hair, and Enamel Abnormalities My G. Mahoney, Sara Sadowski, Donna Brennan, Pekka Pikander, Pekka Saukko, James Wahl, Heikki Aho, Kristiina Heikinheimo, Leena Bruckner-Tuderman, Andrzej Fertala, Juha Peltonen, Jouni Uitto, Sirkku Peltonen Journal of Investigative Dermatology Volume 130, Issue 4, Pages 968-978 (April 2010) DOI: 10.1038/jid.2009.357 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical manifestations of the patient with novel mutations in the desmoplakin (DP) gene. (a) Palmoplantar keratoderma, hyperkeratosis, and erosion on a site of a blister; (b) dystrophic second and fifth toenails; (c) sparse and woolly scalp hair; (d) and enamel dysplasia and horizontal ridging of the teeth. Journal of Investigative Dermatology 2010 130, 968-978DOI: (10.1038/jid.2009.357) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Morphological analysis shows keratinocyte disadhesion. (a) Periodic acid-Schiff staining of the affected skin and (b and c) transmission electron microscopy of the affected oral mucosa. Orthokeratotic hyperkeratosis (arrows), acanthosis in the mid- and lower epidermal layers, and widened intercellular spaces in the upper epidermal layers. The remaining desmosomes appear intact. Inset, in panel c, intact desmosome. Bars=100μm (a), 2μm (b), and 0.5μm (c). Journal of Investigative Dermatology 2010 130, 968-978DOI: (10.1038/jid.2009.357) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Immunohistochemical staining of the epidermis and oral epithelium using a panel of desmoplakin (DP)-specific antibodies (Abs). (a) Schematic diagram of DP depicts regions of antibody recognition. (b) All antibodies showed cell surface staining throughout the normal adult epidermis (upper panel). In patient's skin, the multiclonal epitope antibody (DP mix) shows significant but disrupted staining of DP in the skin, whereas the C-terminal antibody 10F6 does not detect appreciable levels of DP. Two different antibodies (2C8 and 2A8) detecting parts of the C-terminal domain of DP show clear reduction in patient's oral mucosa compared with normal oral epithelium. Typical cell–cell border staining of desmoglein 1 (Dsg1) and plakoglobin (PG) (c) is observed in both control and patient's skin. Staining for β-catenin in formalin-fixed, paraffin-embedded patient's skin is reduced when compared with that of control epidermis (possibly because of formalin fixation). However, β-catenin expression does not seem to be altered in patient's oral mucosa when compared with that of the control section. Bar=50μm. Journal of Investigative Dermatology 2010 130, 968-978DOI: (10.1038/jid.2009.357) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Widespread right and left ventricular cardiomyopathy. Masson's trichrome staining of the (a) right and (b–d) left ventricles showing loss of cardiomyocytes (pink/red) with replacement by fibrous tissue (blue/gray/green). Degenerating cardiomyocytes embedded in extensive deposits of collagenous connective tissue and fat tissue (c), with dense “pycnotic” nuclei, suggestive of apoptosis (arrows in d), as compared with the slender and spindle-shaped nuclei in normal cells (arrowheads in d). Connexin 43 containing gap junctions in normal heart (e) and in the patient's right ventricle (f). (g) In the patient's left ventricle, the expression of connexin 43 was clearly reduced. Immunostaining of normal heart (h, top panels) and patient's myocardial sample (h, lower panels) for desmosomal proteins using antibodies to desmoplakin (DP) (DP mix), PG (11E4), and desmoglein 2 (Dsg2) (Rb5) shows disorganization of intercalated disks in the patient's sample, whereas the expression levels of desmosomal components do not show significant differences. Blue: DAPI-stained nuclei. Bars=0.5mm (a and b), 50μm (c), 20μm (d), 100μm (e–g), and 25μm (h). Journal of Investigative Dermatology 2010 130, 968-978DOI: (10.1038/jid.2009.357) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Novel compound heterozygous mutations in desmoplakin (DP) gene. Nucleotide sequencing of PCR-amplified genomic DNA of the patient, father, mother, and control corresponding to exon 24 of the DP gene (a). Arrows indicate the positions of identified mutations. Pedigree of the family with novel compound heterozygous mutations (b). Father and all three offspring harbor a c.6310delA mutation, whereas only the deceased proband inherited the maternal mutation, p.A2655D (b). A schematic structure of DP showing three functional domains: plakophilin/plakoglobin-binding domain (plakin), central rod domain, and intermediate filament-binding plakin repeat domain (PRD). Arrows indicate mutation sites. Predicted paternal and maternal DP proteins based on sequence analysis; the sites of mutations indicated in red (c). Western analysis of normal human skin and paternal skin using two different DP antibodies shows classical DP doublets and truncation of DP (d). Molecular analysis of the electrostatic potential (EP) of the surface of the wild-type (WT) and mutant fragments (e). The EP range for WT is (+)227.9/(-)247.7, whereas that of the mutant is (+)216.9/(-)269.4. Color-coded panel indicates differences in the EP and lipophilic potential (LP): red, highly positive EP; blue, highly negative EP; brown, highly hydrophobic; and blue, highly hydrophilic. Journal of Investigative Dermatology 2010 130, 968-978DOI: (10.1038/jid.2009.357) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions