The Molecular Revolution in Cutaneous Biology: Identification of Skin Disease Genes

Boyden, Lynn M.; Choate, Keith

doi:10.1016/j.jid.2016.11.019

Cited by 4 publications

(1 citation statement)

References 51 publications

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“…Though advances in gene sequencing have facilitated the diagnosis of rare inherited disorders and enhanced our understanding of their pathogenic mechanisms ( 1 – 3 ), most genetic skin diseases lack proven, rational molecular therapies ( 4 , 5 ). Mutation of the ATP2A2 gene, which encodes sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2), causes Darier disease (DD) ( 6 , 7 ), a dermatologic disorder characterized by aberrant epidermal differentiation and impaired keratinocyte adhesion via desmosomes ( 8 , 9 ), which manifests as recurrent skin blisters, erosions, and infections ( 10 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Zaver¹,

Sarkar²,

Egolf³

et al. 2023

JCI Insight

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Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than 2 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 proteomics analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAPK signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings, with lesions showing keratin deficiency, cadherin mislocalization, and ERK hyperphosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multiomic analysis with human organotypic epidermis as a preclinical 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.

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