dd , caused by mutations in the er ca atpase atp2a2 ( sakuntabhai , et al . , 1999 ) , is an uncommon ( 1:30,000 ) blistering skin disease .
patients with dd suffer from impaired cell - to - cell adhesion , defective keratinocyte differentiation , and non - physiologic keratinocyte apoptosis .
histologically , dd manifests with suprabasal clefting in the epidermis , acantholysis , rounded dyskeratotic keratinocytes (  corps ronds  ) , hyperkeratosis and parakeratotic keratinocytes in the stratum corneum (  grains  ) .
current treatments , such as retinoids , do not ameliorate the underlying defect in er ca sequestration , and are ineffective for many patients .
this report , by savignac et al ( editor , please add reference ) , advances our understanding of dd in several important ways .
first , it illustrates how er stress impairs the formation of both adherens junctions and desmosomes , contributing to dd pathogenesis .
second , it expands our understanding of how er ca signaling may control , not only keratinocyte growth and differentiation , but also keratinocyte cell - to - cell adhesion .
defects in desmoplakin redistribution have been associated with the impaired cell - to - cell adhesion seen in dd ( dhitavat , et al . , 2003 ,
defective desmoplakin redistribution after serca2 ca depletion is mediated by protein kinase c alpha ( pkcalpha ) ( hobbs , et al . , 2011 ) .
pkcalpha also may act on desmoplakin to direct the  hyperadhesive  desmosomal state ( hobbs and green , 2012 ) , rearrange desmosome components during wound healing ( garrod , 2013 ) , and modulate desmosomal susceptibility to autoimmune attack in pemphigus vulgaris ( cirillo , et al . ,
more recently , cell - to - cell adhesion defects in dd also have been associated with defects in e - cadherin redistribution ( celli , a. , et al . , 2011 ) .
because both desmoplakin and e - cadherin have been shown to have signaling as well as structural roles ( kowalczyk and green , 2013 , tu , et al . , 2012 ) , it is likely that interactions among adhesion components involve multiple feedback loops between each other and the serca2-controlled er ca store .
mild and self - limited er stress , due to transient release and refill of er ca stores , is an important physiologic signal for epidermal permeability barrier repair and antimicrobial peptide synthesis ( celli , a. , et al . , 2011 , park , et al . , 2011 ) .
once er ca depletion passes a critical threshold , the er unfolded protein response ( upr ) is triggered , and apoptotic mechanisms are initiated in many cell types ( oakes , et al . , 2003 ) .
this report identifies er stress , induced by er ca depletion due to serca2 dysfunction , as an important contributor to dd pathogenesis .
finally , this report demonstrates that treatment of dd keratinocytes with miglustat improves desmoplakin and e - cadherin redistribution and improves ( although it does not normalize ) cell - to - cell adhesion .
the authors propose that miglustat acts as a chaperone that allows adhesion molecules to escape from the er stress - induced upr , thus enabling them to reach the plasma membrane and form adherens junctions and desmosomes .
miglustat , used clinically for gaucher disease , also acts to inhibit glucosylceramide synthase ( reviewed in venier and igdoura ( venier and igdoura , 2012 ) ) , and an additional potential therapeutic pathway may be through its modulation of the ceramide / sphingolipid pathway previous described in dd pathogenesis ( celli , a , et al . , 2012 ) .
lastly , since glucosylceramide synthesis is required for epidermal permeability maintenance ( jennemann , et al . , 2007 ) , some caution should be used in extrapolating these results from monolayer keratinocytes to a multilayered epidermis or to patients .
as the authors note , however , therapeutic options for dd are limited , and miglustat may be the first in a series of agents that treat dd by facilitating redistribution of adhesion molecules to the plasma membrane .
 darier 's disease ( dd ) is caused by mutations in the endoplasmic reticulum ( er ) ca2 + atpase atp2a2 ( protein serca2 ) . 
 current treatment modalities are ineffective for many patients . 
 this report shows that impaired serca2 function , both in dd keratinocytes and in normal keratinocytes treated with the serca2-inhibitor thapsigargin , depletes er ca2 + stores , leading to constitutive er stress and increased sensitivity to er stressors . 
 er stress , in turn , leads to abnormal cell - to - cell adhesion via impaired redistribution of desmoplakin , desmoglein 3 , desmocollin 3 and e - cadherin to the plasma membrane . 
 this report illustrates how er ca2 + depletion and the resulting er stress are central to the pathogenesis of the disease . 
 additionally , the authors introduce a possible new therapeutic agent , miglustat . 