Mislocalization of Adherens Junction- Associated Proteins in a Patient with Darier Disease

Main Article Content

George D Glinos
Irena Pastar
Marjana Tomic-Canic
Rivka C Stone

Keywords

Darier Disease, adherens junction, SERCA2, ATP2A2, immunofluorescence, E-cadherin, alpha-catenin, beta-catenin, vinculin

Abstract

Darier disease (DD) is an autosomal dominant keratinizing genodermatosis that manifests clinically with red-brown pruritic papules in a seborrheic distribution often in association with palmoplantar pits and dystrophic nail changes. It is caused by mutation in ATP2A2 which encodes a sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2) pump that regulates calcium flux. Consequent alteration of intracellular calcium homeostasis is thought to impair trafficking of cellular adhesion proteins and to lead to aberrant keratinocyte differentiation, contributing to the characteristic histopathologic features of acantholysis and dyskeratosis in DD, though the precise mechanisms are incompletely understood. Previous studies have identified defective localization of desmosomal attachment proteins in skin biopsies and cultured keratinocytes from DD patients, but reports of effects on adherens junction proteins (including calcium-dependent E-cadherin) are conflicting. Here we describe a case of DD presenting with characteristic clinical and histologic features in which we performed immunofluorescence staining of four adherens junction-associated proteins (E-cadherin, α-catenin, β-catenin, and vinculin). In lesional (acantholytic) DD skin, we identified loss of distinctive bright membranous staining that was present at the periphery of keratinocytes throughout the epidermis in the healthy skin of a matched donor. Perilesional (non-acantholytic) portions of DD skin partially recapitulated the normal phenotype. Our findings support a role for SERCA2 dysfunction in impaired assembly of adherens junctions, which together with defective desmosomes contribute to acantholysis in DD.

References

Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27(1):40-50.

Savignac M, Edir A, Simon M, Hovnanian A. Darier disease : a disease model of impaired calcium homeostasis in the skin. Biochim Biophys Acta. 2011;1813(5):1111-1117.

Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 2016;43(3):275-279.

Elias PM, Ahn SK, Denda M, et al. Modulations in epidermal calcium regulate the expression of differentiation-specific markers. J Invest Dermatol. 2002;119(5):1128-1136.

Hakuno M, Shimizu H, Akiyama M, et al. Dissociation of intra- and extracellular domains of desmosomal cadherins and E-cadherin in Hailey-Hailey disease and Darier's disease. Br J Dermatol. 2000;142(4):702-711.

Savignac M, Simon M, Edir A, Guibbal L, Hovnanian A. SERCA2 dysfunction in Darier disease causes endoplasmic reticulum stress and impaired cell-to-cell adhesion strength: rescue by Miglustat. J Invest Dermatol. 2014;134(7):1961-1970.

Burge SM, Garrod DR. An immunohistological study of desmosomes in Darier's disease and Hailey-Hailey disease. Br J Dermatol. 1991;124(3):242-251.

Raiko L, Leinonen P, Hagg PM, Peltonen J, Oikarinen A, Peltonen S. Tight junctions in Hailey-Hailey and Darier's diseases. Dermatol Reports. 2009;1(1):e1.

Wheelock MJ, Johnson KR. Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol. 2003;19:207-235.