Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum
calcium ATPase 2 (SERCA2) was linked to
Darier disease more than two decades ago; however, there remain no targeted
therapies for this disorder causing recurrent skin blistering and
infections. Since Atp2a2 knockout mice do not phenocopy its pathology, we established a human tissue model of
Darier disease to elucidate its pathogenesis and identify potential
therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of
Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed
RNA sequencing and proteomic analysis. SERCA2-deficient keratinocytes lacked desmosomal and
cytoskeletal proteins required for epidermal integrity and exhibited excess MAP
kinase signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings with lesions showing
keratin deficiency,
cadherin mis-localization, and ERK hyper-phosphorylation. Dampening ERK activity with
MEK inhibitors rescued adhesive
protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multi-omic analysis with human organotypic epidermis as a pre-clinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified
MEK inhibition as a treatment strategy for
Darier disease.