What is the role of calcium regulation in the pathophysiology of keratosis follicularis (Darier disease)?

Updated: Jul 31, 2018
  • Author: Pui-Yan Kwok, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Answer

Some studies of keratosis follicularis (Darier disease) have suggested that alterations in calcium regulation may affect the synthesis, folding, or trafficking of desmosomal proteins. [25] In particular, studies have revealed that keratosis follicularis (Darier disease) keratinocytes displayed abnormal trafficking of the desmosomal protein desmoplakin and abnormal expression of cytokeratins 10 and 14. [26, 27] A recent study shows that SERCA2-controlled Ca²+ -dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway. [28]

Alternatively, another hypothesis, based on a canine model of keratosis follicularis (Darier disease), is that keratosis follicularis (Darier disease) calcium dysregulation leads to impaired control of cell cycle checkpoints, leading to increased epidermal sensitivity to skin trauma and subsequent keratinocyte apoptosis.

Two particular ATP receptors have been reported to abnormally localize in vivo in keratosis follicularis(Darier disease) and are speculated to play a role in apoptosis as well as abnormal calcium signaling. [27] More recently, Darier keratinocytes were found to display a constitutive endoplasmic reticulum stress response, with immature adherens junctions and desmosomes, which results in decreased intercellular adhesion strength. [29]

Remarkably, an orphan drug, the α-glucosidase inhibitor miglustat, restores mature adherens junctions and desmosomes in Darier keratinocytes and increases adhesion strength. The observation that miglustat is able to restore proper localization to the plasma membrane of nonmutated proteins retained in the endoplasmic reticulum supports a misfolding mechanism. [29]


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