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Here we report three patients with PG from two unrelated kindreds with homozygous R57C mutation of the linear deubiquitinase OTULIN. The patients have isolated, pediatric-onset, OTULIN-related PG (ORP). In contrast to OTULIN-related autoinflammatory syndrome (ORAS), caused by mutations affecting the catalytic domain, R57C affects the PUB-interacting motif with distinct biochemical, immunological and clinical consequences. OTULIN-R57C is catalytically active but is unable to bind the linear ubiquitin assembly complex (LUBAC). Patient monocytes show heightened expression of\n                    <jats:italic>IL1B<\/jats:italic>\n                    , and OTULIN-R57C fails to suppress inflammasome activity. Patients have elevated levels of TNF, and their dermal fibroblasts show heightened susceptibility to TNF-dependent cell death. Homozygosity for OTULIN-R57C leads to accumulation of linear ubiquitin and LUBAC autoubiquitination in patients\u2019 dermal fibroblasts, consistent with pathogenic LUBAC activity. These findings identify a genetic etiology of isolated PG of childhood. We propose a multifactorial mechanism of ORP, including myeloid IL-1\u03b2 production and TNF-driven death of skin-resident cells, suggesting that blockade of IL-1\u03b2 or TNF are therapeutic options in PG.\n                  <\/jats:p>","DOI":"10.1038\/s41590-026-02568-6","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T09:03:13Z","timestamp":1781514193000},"page":"1619-1632","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pyoderma gangrenosum caused by the molecular uncoupling of OTULIN catalytic activity and LUBAC binding"],"prefix":"10.1038","volume":"27","author":[{"given":"Barathram","family":"Swaminathan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3722-4302","authenticated-orcid":false,"given":"Hwi M.","family":"Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagar","family":"Bhattad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyothi","family":"Janardhanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1696-8310","authenticated-orcid":false,"given":"Gerardo","family":"Mej\u00eda Baltodano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Mariskanish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7619-7892","authenticated-orcid":false,"given":"Shamel","family":"Basaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisette M.","family":"Scheepmaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamud","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5240-3555","authenticated-orcid":false,"given":"Bertrand","family":"Boisson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Laurent","family":"Casanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivona","family":"Aksentijevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5981-7259","authenticated-orcid":false,"given":"Andr\u00e1s N.","family":"Spaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-4368","authenticated-orcid":false,"given":"Janet G.","family":"Markle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"2568_CR1","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/s41576-023-00656-z","volume":"25","author":"YT Akalu","year":"2024","unstructured":"Akalu, Y. T. & Bogunovic, D. Inborn errors of immunity: an expanding universe of disease and genetic architecture. Nat. Rev. Genet. 25, 184\u2013195 (2024).","journal-title":"Nat. Rev. Genet."},{"key":"2568_CR2","doi-asserted-by":"publisher","unstructured":"Casanova, J.-L. Human immunity. J. Hum. Immun. https:\/\/doi.org\/10.70962\/jhi.20250001 (2025).","DOI":"10.70962\/jhi.20250001"},{"key":"2568_CR3","doi-asserted-by":"publisher","first-page":"e14388","DOI":"10.1111\/iwj.14388","volume":"21","author":"GN Pathak","year":"2024","unstructured":"Pathak, G. N., Pathak, S. S., Truong, T. M., Tan, I. J. & Rao, B. K. Pyoderma gangrenosum in underrepresented patient populations: An All of Us database analysis. Int. Wound J. 21, e14388 (2024).","journal-title":"Int. Wound J."},{"key":"2568_CR4","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.jaad.2019.08.001","volume":"83","author":"A Xu","year":"2020","unstructured":"Xu, A., Balgobind, A., Strunk, A., Garg, A. & Alloo, A. 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