Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.

Abstract

The cytoplasmic plaque protein desmoplakin (DP), which is located in desmosomes, plays a major role in epithelial and muscle cell adhesion by linking the transmembrane cadherins to the cytoplasmic intermediate filament network. Mutations of DP may cause striate palmoplantar keratoderma, arrhythmogenic right ventricular dysplasia, skin fragility/woolly hair syndrome, Naxos-like disease, and Carvajal syndrome. DP must be indispensable, because DP-/- mice are early abortive. Here, we report a patient with severe fragility of skin and mucous membranes caused by genetic truncation of the DP tail. The new phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. The phenotype also comprised universal alopecia, neonatal teeth, and nail loss. Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes. Immunofluorescence staining of DP showed a distinct punctate intercellular pattern in the patient's skin. Protein analysis revealed expression of truncated DP polypeptides. Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively. Aberrant mRNA transcripts that predict premature termination of translation with loss of the three intermediate filament-binding subdomains in the DP tail were detected by RT-PCR. The new dramatic phenotype, which we named "lethal acantholytic epidermolysis bullosa," underscores the paramount role of DP in epidermal integrity.

• Authors: Marcel F Jonkman, Anna M G Pasmooij, Suzanne G M A Pasmans, Maarten P van den Berg, Henk J Ter Horst, Albertus Timmer, Hendri H Pas
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 77 Issue 4 Pg. 653-60 (Oct 2005) ISSN: 0002-9297 [Print] United States
• PMID: 16175511 (Publication Type: Case Reports, Journal Article)

Chemical References

• Cytoskeletal Proteins
• DSP protein, human
• Desmoplakins

Topics

• Acantholysis (genetics)
• Cytoskeletal Proteins (genetics)
• Desmoplakins
• Desmosomes (ultrastructure)
• Epidermolysis Bullosa (genetics)
• Fatal Outcome
• Fluorescent Antibody Technique
• Genes, Lethal
• Humans
• Infant, Newborn
• Male
• Microscopy, Electron
• Molecular Sequence Data
• Mutation
• Reverse Transcriptase Polymerase Chain Reaction