{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:07:25Z","timestamp":1789578445938,"version":"build-2803163510"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T00:00:00Z","timestamp":1746230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100020732","name":"Innovative Research Team of High-level Local Universities in Shanghai","doi-asserted-by":"publisher","award":["SHSMU-ZDCX20211002"],"award-info":[{"award-number":["SHSMU-ZDCX20211002"]}],"id":[{"id":"10.13039\/100020732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["23PJ1408100"],"award-info":[{"award-number":["23PJ1408100"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008233","name":"Shanghai Jiao Tong University School of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008233","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The effectiveness of botulinum toxin A (BoNTA) in the treatment of Hailey-Hailey disease (HHD) has shown heterogeneity in recent studies. However, there is currently no research investigating the underlying mechanism behind the variability in patient response.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To identify potential biomarkers and elucidate the underlying mechanisms of the heterogeneity in efficacy of BoNTA treatment for HHD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Twelve patients with HHD were administered standardized injections of BoNTA, with the primary endpoint being \u2265 75% improvement in Improvement Global Assessment(IGA) from baseline to month 6. A comprehensive multiomics approach, including whole-exome sequencing (WES), bulk RNA sequencing (RNAseq), single-cell RNAseq and immunohistochemistry (IHC) was used to investigate potential mechanisms underlying the heterogeneity of therapeutic efficacy. Additionally, an in vitro experiment was conducted to validate cellular responses to BoNTA, providing further insights into the biologic mechanisms involved.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Ten of 12 patients (83%) achieved the primary endpoint with BoNTA treatment, while 2 patients (17%) showed no response at month 6. WES did not find a significant association between the type of mutation in ATP2C1 in patients with HHD and their response to BoNTA treatment. Transcriptomic analysis and IHC of baseline skin lesions revealed an overactivated store-operated calcium entry (SOCE) pathway involving genes such as ITPKC and ORAI1 in keratinocytes, accompanied by activation of the NOD-like-receptor containing a pyrin domain 1 (NLRP1)\/interleukin (IL)-18\/IL-1\u03b2 inflammatory cascade in BoNTA-resistant patients. We confirmed that loss of ATP2C1 triggered inflammatory responses in HaCaT cells in vitro. BoNTA demonstrated potential anti-inflammatory effects as a calcium antagonist, while upregulation of ORAI1\/SOCE contributed to a diminished response to BoNTA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>BoNTA treatment in HHD exhibits interindividual variability. Although the type of ATP2C1 mutation has no direct association with patients\u2019 response, combined transcriptomic analysis and IHC indicate that upregulation of the ORAI1\/SOCE pathway may contribute to treatment resistance and serve as biomarkers to predict patient responsiveness.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bjd\/ljaf112","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T09:14:19Z","timestamp":1746263659000},"page":"147-156","source":"Crossref","is-referenced-by-count":3,"title":["Exome and transcriptome analysis link calcium channel pathway aberrations to botulinum toxin A resistance in Hailey-Hailey disease"],"prefix":"10.1093","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3265-1046","authenticated-orcid":false,"given":"Yongyong","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]},{"name":"Shanghai Jiao Tong University School of Nursing , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3061-9456","authenticated-orcid":false,"given":"Hailun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 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