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

Calcium Pumps, Proliferation and Differentiation

Acantholysis in Darier's disease and Hailey-Hailey disease is associated with varying degrees of dyskeratosis and papillomatosis. Perhaps this is not surprising when one realizes that desmosome formation is critical for cell growth, cell differentiation and formation of the cornified cell envelope.[68,69] Mutations in desmoplakins and desmoglein 1 cause keratodermas rather than skin fragility[4,69,70] and in mice, knockout or misexpression of desmosomal cadherins influences epidermal differentiation.[71,72]

Loss of desmosomal adhesion triggers anoikis, a type of apoptosis characterized by cell detachment, in keratinocytes in Darier's disease and Hailey-Hailey disease.[73] Apoptosis may be secondary to changes in Ca2+ transport activity. In support of this hypothesis is the finding that inhibition of SERCA pumps with thapsigargin triggers apoptosis in a variety of epithelial cells.[74]

No animal model is available for Hailey-Hailey disease, but SERCA2 knockout is lethal in mice and studies of SERCA2± mice have revealed major differences in the effect of SERCA2 dysfunction in humans and mice. The ATP2A2 gene encodes the cardiac sarcoplasmic reticulum pump (SERCA2a). SERCA2± mice do not develop Darier-like skin lesions, but do have mild impairment of cardiac contractility and relaxation.[46,75] Studies of cardiac function in patients with Darier's disease have revealed normal cardiac performance with a normal increase in systolic function and contractility during exercise.[76,77] Reductions in SERCA2a protein activity have been implicated in the pathogenesis of the failing human heart, but these data from Darier's disease suggest that reduced SERCA2a activity plays a secondary role in heart failure. Other systems involved in intracellular Ca2+ homeostasis in cardiac muscle in humans seem able to compensate for deficiencies in the sarcoplasmic reticulum pump.

Perhaps of more relevance to Darier's disease is the observation that aged SERCA2± mice develop papillomas and squamous cell carcinomas.[78] Although SERCA2 haploinsufficiency does not appear to increase the incidence of squamous cell skin cancer in Darier's disease, deficiencies in SERCA2 activity do alter keratinocyte proliferation and differentiation. In both Darier's disease and Hailey-Hailey disease patients develop malodorous hypertrophic plaques, but hyperkeratosis and dyskeratosis are more marked in Darier's disease. These changes may be secondary to the abnormality in desmosomes, but as discussed above SERCA2 and SPCA1 pumps also contribute to the production of cytosolic Ca2+ oscillations involved in signalling.47,79,[80] Abnormal Ca2+ oscillations may alter the phosphorylation of target proteins as well as the regulation of genes influencing keratinocyte growth and differentiation.