Unraveling the Role of Desmosomal Proteins

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For the article: http://dx.doi.org/10.1038/jid.2009.357

Unraveling the Role of Desmosomal Proteins Cynthia J. Price1, Julia Tzu1 and Robert S. Kirsner1 Journal of Investigative Dermatology (2010) 130, 916. doi:10.1038/jid.2010.20

Understanding the pathophysiology of various disease processes lends itself to a better understanding of the normal function of tissues. For example, studying autoimmune and infectious blistering diseases has led to significant advances in elucidating the structure and function of the epidermis and the epidermal basement membrane zone (Stanley and Amagai, 2006). Similarly, studies of diseases such as epidermolysis bullosa simplex and epidermolytic hyperkeratosis have helped herald the importance and function of keratin proteins (Leigh and Lane, 1993). Thus, probing the pathophysiology of skin diseases provides insights into the normal structure and function of skin. In a report published in this issue, physicians and investigators teamed together to examine the disease that caused the untimely death of a 14-year-old girl from Finland (Mahoney et al., 2010). The focus of the report is a girl who was born with diffuse blisters of her skin and oral mucous membranes; these blisters gradually diminished until the age of 8, when the blisters resolved. She also suffered from localized palmoplantar keratoderma and exhibited specific features of the hair (sparse, blond, short, and woolly scalp hair), nails (easily detached and dystrophic), and teeth (opacities and enamel defects). She displayed no signs of active cardiac disease and was physically quite active as a dancer and soccer player. Unexpectedly, she died in her sleep at age 14, probably from an arrhythmia. Upon autopsy, she was found to have left and right ventricular cardiomyopathy, and her heart weighed 50% more than a normal healthy heart. In addition, her heart contained fibrosis throughout, and in focal areas of both ventricles this fibrotic tissue replaced cardiac myocytes. Genetically, the patient had a previously undescribed compound heterozygous mutation in the C-terminus of desmoplakin—she had inherited distinct mutations from each of her clinically normal parents. This compound mutation most likely led to her skin defects as well as to her cardiac abnormalities. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to the supplementary material online References Leigh IM, Lane EB (1993) Mutations in the genes for epidermal keratins in epidermolysis bullosa and epidermolytic hyperkeratosis. Arch Dermatol 129:1571–7 Mahoney MG, Sadowski S, Brennan D et al. (2010) Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest Dermatol 130:968–78 Stanley JR, Amagai M (2006) Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. New Engl J Med 355:1800–10

QUESTIONS 1. Describe the structure and function of desmosomes and desmoplakin. 2. What are the diseases that involve desmosomal proteins such as desmoplakin? 3. Describe the patient in the study. 4. Describe the techniques employed to study this patient and her disease. 5. What were the conclusions and implications of this report?

Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA

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916 Journal of Investigative Dermatology (2010), Volume 130

© 2010 The Society for Investigative Dermatology