title: Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.
abstract: Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: My G
authors.initials: MG
authors.lastname: Mahoney
authors.forename: Sara
authors.initials: S
authors.lastname: Sadowski
authors.forename: Donna
authors.initials: D
authors.lastname: Brennan
authors.forename: Pekka
authors.initials: P
authors.lastname: Pikander
authors.forename: Pekka
authors.initials: P
authors.lastname: Saukko
authors.forename: James
authors.initials: J
authors.lastname: Wahl
authors.forename: Heikki
authors.initials: H
authors.lastname: Aho
authors.forename: Kristiina
authors.initials: K
authors.lastname: Heikinheimo
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fertala
authors.forename: Juha
authors.initials: J
authors.lastname: Peltonen
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Sirkku
authors.initials: S
authors.lastname: Peltonen
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D003743:Dental Enamel / Q000002:abnormalities; D051180:Desmoplakins / Q000737:chemistry / Q000235:genetics*; D003896:Desmosomes / Q000473:pathology / Q000502:physiology; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D006197:Hair / Q000002:abnormalities; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D053546:Keratoderma, Palmoplantar, Epidermolytic / Q000235:genetics* / Q000473:pathology; D009061:Mouth Mucosa / Q000473:pathology / Q000502:physiology; D020125:Mutation, Missense; D009260:Nail Diseases / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012868:Skin Abnormalities / Q000235:genetics* / Q000473:pathology; D014071:Tooth Abnormalities / Q000235:genetics* / Q000473:pathology
chemical_list: C495294:DSP protein, human; D051180:Desmoplakins