Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.
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.
Mahoney
My G
MG
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Sadowski
Sara
S
Brennan
Donna
D
Pikander
Pekka
P
Saukko
Pekka
P
Wahl
James
J
Aho
Heikki
H
Heikinheimo
Kristiina
K
Bruckner-Tuderman
Leena
L
Fertala
Andrzej
A
Peltonen
Juha
J
Uitto
Jouni
J
Peltonen
Sirkku
S
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
C495294:DSP protein, human; D051180:Desmoplakins