Authors
Robert M Harmon, Erin F McCarthy, Annette Krol, Aashutosh Shetti, Jonas Braun, Rosemary J DiDominicis, Lisa Godsel, Ziyou Ren, Bethany E Perez White, Eran Cohen-Barak, Roni Dodiuk-Gad, Johann E Gudjonsson, Amy S Paller, Cory L Simpson, Samuel Weinberg, Russell Dahl, Yogesh Goyal, Murali Prakriya, Kathleen J Green
Published in
Science advances. Volume 12. Issue 32. Pages eaee1599. Aug 07, 2026. Epub Aug 05, 2026.
Abstract
Congenital pathogenic gene variants may not elicit symptoms until later in life, highlighting the importance of identifying extra-genetic factors influencing the onset and severity of heritable diseases. We explored this in Darier disease (DD or ATP2A2-nEDD), an autosomal dominant skin disorder arising from heterozygous ATP2A2 variants leading to haploinsufficiency of the endoplasmic reticulum (ER) calcium pump, SERCA2. Metabolic analysis of epidermal keratinocytes from confirmed patients with DD revealed abnormalities in the pentose phosphate pathway responsible for regenerating antioxidants like glutathione, accompanied by diminished free glutathione and increased glutathione-based, oxidative modifications of SERCA2. Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.
PMID:
42555718
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.
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