Beyond the skin involvement in Darier disease: A complicated neuropsychiatric phenotype

Pomi, Federica Li; Motolese, Alfonso; Bertino, Lucrezia; Macca, Laura; Arminio, Natalia C; Cardia, Roberta; Vaccaro, Mario; Borgia, Francesco

doi:10.1002/ccr3.4263

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…Since calcium is a major second messenger regulating diverse biological functions including skeletal muscle contraction, cardiac pacing, neurotransmitter release, and apoptosis in many cell types (84, 85), compounds affecting intracellular calcium may have a narrow therapeutic window. In fact, coincidence of neuropsychiatric and cardiac disease with DD (6, 86) implies a role beyond the skin for SERCA2 (87), including in higher-order cognition and behavior (88–90).…”

Section: Discussionmentioning

confidence: 99%

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

Zaver

Sarkar

Egolf

et al. 2023

Preprint

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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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Zaver

Sarkar

Egolf

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Since calcium is a major second messenger regulating diverse biological functions, including skeletal muscle contraction, cardiac pacing, neurotransmitter release, and apoptosis in many cell types ( 87 , 88 ), compounds affecting intracellular calcium may have a narrow therapeutic window. In fact, coincidence of neuropsychiatric and cardiac disease with DD ( 6 , 89 ) implies a role beyond the skin for SERCA2 ( 90 ), including in higher order cognition and behavior ( 91 – 93 ).…”

Section: Discussionmentioning

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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“…Darier disease is a rarehereditary acantholytic dermatosis caused by heterozygous mutations in the ATP2A2 gene which encodes the sarco/endoplasmic reticulum Ca 2+ ATPase isoform 2 (SERCA2), a calcium pump located in the endoplasmic reticulum (ER) membrane that plays a pivotal role in calciumsignalling,dysfunctionof which leads toimpaired processing of junctional proteins resulting in acantholysis and dyskeratosis due to increased apoptosis. ATP2A2gene is highly expressed both in the skin and in the brain 3 . It ischaracterized primarily by malodorous, warty, greasy, yellow to brown, hyperkeratotic papules, on the seborrheic areas of the chest, upper back, forehead, scalp, nasolabial folds, and ears.These lesionscan lead to large crusted plaques.Typical nailabnormalities are characterized by longitudinal white or red lines with ridges and distal V-shaped notches on the nail surface.…”

Section: Discussion:-mentioning

confidence: 99%

A Rare Genodermatosis in a Patient With Neuropsychiatric Disorder

Hemalatha¹,

Lahari²,

Rao³

et al. 2023

IJAR

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Darierdisease(DD)is a rare congenital acantholytic disorder characterised by persistent eruptions of greasy, hyperkeratotic papules in seborrhoeic areas, extremities and rarely in intertriginous areas.Nail abnormalitiesand mucous membraneinvolvement also occurs. A neuropsychiatricdisordercan be present occasionally. We are reporting a rare case of Darier disease in a male child born in a consanguineous marriage coexisting with Attention Deficit Hyperactivity Disorder (ADHD).

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Beyond the skin involvement in Darier disease: A complicated neuropsychiatric phenotype

Abstract: Psichiatric illness such as depression, schizophrenia and cognitive deficiency are frequently associated with the Darier Disease. Physicians should be aware of such association to allow prompt diagnosis and early interventions of potentially life‐threatening psychiatric disorders.

Cited by 4 publications

References 7 publications

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

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

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

A Rare Genodermatosis in a Patient With Neuropsychiatric Disorder

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