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

Defective Calcium Homeostasis Causes Darier's Disease and Hailey-Hailey Disease

In 1993 the gene for Darier's disease was linked to chromosome 12q23-24.1.[7,8] After painstaking research to narrow the region of interest, ATP2A2 was identified as the causative gene in Darier's disease.[9] This gene encodes the type 2 sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2), one of a family of Ca2+-ATPases that catalyse the transport of calcium (Ca2+) from the cytosol into the lumen of the endoplasmic reticulum (Fig. 5).

Figure 5.

Diagram showing the predicted secondary structure of SERCA2. The 10 transmembrane helices anchoring the molecule to the endoplasmic reticulum (ER) membrane are linked by stalk helices to a cytoplasmic headpiece with the ß-strand, phosphorylation and nucleotide binding domains. Both the N- and C-terminal segments of SERCA2a are exposed on the cytoplasmic surface of the ER membrane whereas in SERCA2b an extended tail section enters the lumen of the ER. The active site for ATP hydrolysis is formed in the phosphorylation and nucleotide binding domains. The transmembrane domain containing Ca2+ binding sites forms the channel for transport of Ca2+ into the ER.[37]

The discovery of the genetic basis for Darier's disease raised the possibility that alterations in Ca2+ homeostasis might also underlie Hailey-Hailey disease. Family studies had already linked Hailey-Hailey disease to chromosome 3q21-24,[10,11,12] but now a candidate gene encoding another Ca2+-ATPase was noted in the critical region and eventually mutations in this gene, ATP2C1, were identified in affected individuals.[13,14]ATP2C1 encodes the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (SPCA1) that is found in the Golgi apparatus.[15] SPCA1 is thought to be localized predominantly in the trans face of the Golgi apparatus[15](Fig. 6). This pump supplies the Golgi apparatus, and possibly other more distal components of the secretory pathway, with both Ca2+ and Mn2+.

Figure 6.

Simplified view of a keratinocyte showing the localization of SERCA2 and SPCA1. Proteins synthesized in association with the endoplasmic reticulum membrane are transported to the Golgi apparatus for further processing before being targeted to various destinations. The Golgi apparatus consists of flattened cisternae with two distinct faces. Proteins enter at the cis face close to the endoplasmic reticulum but exit from the trans face. SERCA2 is found in association with the endoplasmic reticulum membrane, while SPCA1 is found linked to the Golgi apparatus, where it seems to be associated primarily with the membranes of the trans or exit face.[15]

Missense, frameshift, splice site and nonsense mutations have been found scattered throughout the coding regions of these genes, disrupting functional domains of the encoded proteins in both Darier's disease[16,17,18,19,20,21,22,23] and Hailey-Hailey disease.[14,24,25,26,27] No clear correlations have been established between phenotype and genotype in either disease. Mutations have not been identified in a minority of patients with classical disease, but we have no evidence that other genes are involved and these results do not exclude changes in the promoter, 5' or 3' untranslated regions, intronic branch sites or extragenic regulatory elements of the genes.

It has been hypothesized that haploinsufficiency is responsible for the dominant phenotypes in these diseases, i.e. one correct copy of the gene in keratinocytes is insufficient to encode adequate levels of the protein pump for normal function. Nonsense or frameshift insertion/deletions lead to premature termination codons and the predicted effect of such mutations is an absence or significant reduction in the level of mutant protein expression as a consequence of nonsense-mediated mRNA decay. Truncated proteins may also be targeted for endoplasmic reticulum-associated degradation. Mutant genes may have other effects that contribute to variation in phenotype.