Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities

Mỹ G. Mahoney, Sara Sadowski, Donna Brennan, Pekka Pikander, Pekka Saukko, James K Wahl, Heikki Aho, Kristiina Heikinheimo, Leena Bruckner-Tuderman, Andrzej Fertala, Juha Peltonen, Jouni Uitto, Sirkku Peltonen

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)968-978
Number of pages11
JournalJournal of Investigative Dermatology
Volume130
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

Desmoplakins
Enamels
Dental Enamel
Hair
Skin
Phenotype
Mutation
Desmosomal Cadherins
Keratoderma, Palmoplantar, Epidermolytic
Nails
Acantholysis
Mothers
Anchors
Intermediate Filaments
Aspartic Acid
Nonsense Codon
Alanine
Mouth Mucosa
Blister
Electrostatics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. / Mahoney, Mỹ G.; Sadowski, Sara; Brennan, Donna; Pikander, Pekka; Saukko, Pekka; Wahl, James K; Aho, Heikki; Heikinheimo, Kristiina; Bruckner-Tuderman, Leena; Fertala, Andrzej; Peltonen, Juha; Uitto, Jouni; Peltonen, Sirkku.

In: Journal of Investigative Dermatology, Vol. 130, No. 4, 04.2010, p. 968-978.

Research output: Contribution to journalArticle

Mahoney, MG, Sadowski, S, Brennan, D, Pikander, P, Saukko, P, Wahl, JK, Aho, H, Heikinheimo, K, Bruckner-Tuderman, L, Fertala, A, Peltonen, J, Uitto, J & Peltonen, S 2010, 'Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities', Journal of Investigative Dermatology, vol. 130, no. 4, pp. 968-978. https://doi.org/10.1038/jid.2009.357
Mahoney, Mỹ G. ; Sadowski, Sara ; Brennan, Donna ; Pikander, Pekka ; Saukko, Pekka ; Wahl, James K ; Aho, Heikki ; Heikinheimo, Kristiina ; Bruckner-Tuderman, Leena ; Fertala, Andrzej ; Peltonen, Juha ; Uitto, Jouni ; Peltonen, Sirkku. / Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. In: Journal of Investigative Dermatology. 2010 ; Vol. 130, No. 4. pp. 968-978.
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