Calcium Pumps and Keratinocytes: Lessons From Darier's Disease and Hailey-Hailey Disease

J. Dhitavat; R.J. Fairclough; A. Hovnanian; S.M. Burge


The British Journal of Dermatology. 2004;150(5) 

In This Article

Summary and Introduction


Darier's disease and Hailey-Hailey disease are autosomal dominantly inherited skin disorders in which desmosomal adhesion between keratinocytes is abnormal. ATP2A2 and ATP2C1 have been identified as the causative genes for Darier's disease and Hailey-Hailey disease, respectively. ATP2A2 encodes the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) pump, while ATP2C1 encodes a secretory pathway Ca2+/Mn2+-ATPase (SPCA1) found in the Golgi apparatus. We review recent work into the function of these pumps in human keratinocytes and discuss how mutations in these genes might cause these diseases by altering the formation or stability of desmosomes.


Darier's disease is an autosomal dominantly inherited skin disorder characterized by malodorous warty papules and plaques (Fig. 1), palmoplantar pits and distinctive nail abnormalities.[1] Skin fragility with painful erosions dominates the picture in some patients (Fig. 2). Histological features include focal separation between suprabasal epidermal cells (acantholysis), suprabasal clefting and a distinctive dyskeratosis (Fig. 3). The clinical and histological features of Darier's disease overlap with those of Hailey-Hailey disease (familial benign chronic pemphigus), an autosomal dominantly inherited skin disorder that manifests as uncomfortable erosions or vegetating lesions at sites of friction[2](Fig. 4). Ultrastructural studies and immunohistology have suggested that loss of cell-to-cell adhesion in these diseases might be due to a failure in the formation or stability of desmosomes.[3,4,5,6]

Figure 1.

Keratotic papules in Darier's disease.

Figure 2.

Skin fragility and painful erosions dominate the clinical picture in some patients with Darier's disease.

Figure 3.

Skin biopsy from Darier's disease reveals a characteristic dyskeratosis with suprabasal acantholysis secondary to breakdown of the desmosome adhesion junctions. The epidermis shows hyperproliferative budding beneath the dyskeratotic plug.

Figure 4.

Painful erosions in the flexures characterize Hailey-Hailey disease. The skin is more fragile than in Darier's disease. Flexural skin may become rather thickened and papillomatous, but patients do not develop the hyperkeratotic papules that are seen in Darier's disease.