{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:17:24Z","timestamp":1778199444426,"version":"3.51.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373459"],"award-info":[{"award-number":["82373459"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373500"],"award-info":[{"award-number":["82373500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Premature diffuse familial sebaceous hyperplasia (PDFSH) constitutes a distinct clinical variant of sebaceous hyperplasia, characterized by three hallmark features: early disease onset; characteristic sparing of the perioral and periocular regions; and a positive family history. To date, the pathogenic gene underlying PDFSH has remained unidentified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To identify the underlying genetic cause and pathogenesis of three familial cases of autosomal dominant PDFSH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole-exome sequencing was performed in two unrelated families with autosomal dominant PDFSH. In an additional patient, using Sanger sequencing, the identified candidate gene was further screened for variants. The ultrastructure of sebaceous glands was analysed by transmission electron microscopy. Immunofluorescence staining was done to assess lipid peroxidation levels in sebaceous glands. Functional analyses included quantification of the NADPH\/NADP+ ratio, and glutathione and reactive oxygen species (ROS) levels. Flow cytometry with C11-BODIPY and propidium iodide staining was performed to assess lipid peroxidation and cell viability, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a missense variant c.2063T&amp;gt;G (p.Leu688Trp) in NNT in all affected members across the three families with PDFSH. Patient-derived keratinocytes and nicotinamide nucleotide transhydrogenase (NNT)-knockdown SZ95 sebocytes overexpressing mutant NNT exhibited enhanced antioxidant capacity, as shown by an elevated NADPH\/NADP+ ratio, increased glutathione levels and decreased production of ROS vs. controls. Ultrastructural analysis revealed a decreased proportion of mitochondria with cristae disorganization; immunofluorescence staining showed reduced levels of lipid peroxidation in the patients\u2019 sebaceous glands, suggesting decreased susceptibility to ferroptosis. In\u00a0vitro experiments confirmed that the NNT c.2063T&amp;gt;G variant protects SZ95 sebocytes from ferroptosis by mitigating oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified a gain-of-function variant [c.2063T&amp;gt;G (p.Leu688Trp)] in NNT underlying PDFSH. This genetic variant enhances the antioxidant capacity of NNT, while attenuating intracellularly accumulated ROS levels, and reduces sebaceous glands\u2019 susceptibility to ferroptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bjd\/ljaf294","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:49:56Z","timestamp":1753271396000},"page":"1182-1191","source":"Crossref","is-referenced-by-count":2,"title":["Gain-of-function variant in\n                    <i>NNT<\/i>\n                    causes premature diffuse familial sebaceous hyperplasia"],"prefix":"10.1093","volume":"193","author":[{"given":"Lina","family":"Liang","sequence":"first","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, West China Hospital, Sichuan University , Chengdu ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4553-2871","authenticated-orcid":false,"given":"Yonghu","family":"Sun","sequence":"additional","affiliation":[{"name":"Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences , Jinan, Shandong ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sha","family":"Peng","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1646-2608","authenticated-orcid":false,"given":"Christos C","family":"Zouboulis","sequence":"additional","affiliation":[{"name":"Departments of Dermatology, Venereology, Allergology and Immunology, Staedtisches Klinikum Dessau, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg , Dessau ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir M","family":"Hossini","sequence":"additional","affiliation":[{"name":"Departments of Dermatology, Venereology, Allergology and Immunology, Staedtisches Klinikum Dessau, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg , Dessau ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Dermatology, Guangzhou Dermatology Hospital , Guangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5414-1472","authenticated-orcid":false,"given":"Huijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9323-2035","authenticated-orcid":false,"given":"Zhimiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"2025111813164776100_ljaf294-B1","doi-asserted-by":"crossref","first-page":"909694","DOI":"10.3389\/fcell.2022.909694","article-title":"Aging in the sebaceous gland","volume":"10","author":"Hou","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"2025111813164776100_ljaf294-B2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1046\/j.1365-2133.2003.05397.x","article-title":"Ciclosporin A-induced sebaceous gland hyperplasia","volume":"149","author":"Boschnakow","year":"2003","journal-title":"Br J Dermatol"},{"key":"2025111813164776100_ljaf294-B3","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S0151-9638(05)79279-6","article-title":"Hyperplasies s\u00e9bac\u00e9es profuses du visage induites par la ciclosporine","volume":"132","author":"Engel","year":"2005","journal-title":"Ann Dermatol Venereol"},{"key":"2025111813164776100_ljaf294-B4","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1080\/000155598442917","article-title":"Isotretinoin for sebaceous skin lesions in Muir-Torre syndrome: a case report","volume":"78","author":"Marcusson","year":"1998","journal-title":"Acta Derm Venereol"},{"key":"2025111813164776100_ljaf294-B5","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/S0190-9622(97)70345-1","article-title":"Familial presenile sebaceous gland hyperplasia","volume":"36","author":"Boonchai","year":"1997","journal-title":"J Am Acad Dermatol"},{"key":"2025111813164776100_ljaf294-B6","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1111\/1346-8138.13416","article-title":"Presenile diffuse familial sebaceous hyperplasia successfully treated with low-dose isotretinoin: a report of two cases and review of the published work","volume":"43","author":"Liu","year":"2016","journal-title":"J Dermatol"},{"key":"2025111813164776100_ljaf294-B7","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1159\/000246601","article-title":"Hypohidrotic ectodermal dysplasia with recurrent otitis and sebaceous gland hypertrophy of the face","volume":"191","author":"Piletta","year":"1995","journal-title":"Dermatology"},{"key":"2025111813164776100_ljaf294-B8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj2540001","article-title":"Physiological roles of nicotinamide nucleotide transhydrogenase","volume":"254","author":"Hoek","year":"1988","journal-title":"Biochem J"},{"key":"2025111813164776100_ljaf294-B9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41586-019-1519-2","article-title":"Structure and mechanism of mitochondrial proton-translocating transhydrogenase","volume":"573","author":"Kampjut","year":"2019","journal-title":"Nature"},{"key":"2025111813164776100_ljaf294-B10","doi-asserted-by":"crossref","first-page":"e20191689","DOI":"10.1084\/jem.20191689","article-title":"Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function","volume":"217","author":"Ward","year":"2020","journal-title":"J Exp Med"},{"key":"2025111813164776100_ljaf294-B11","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","article-title":"Ferroptosis: molecular mechanisms and health implications","volume":"31","author":"Tang","year":"2020","journal-title":"Cell Res"},{"key":"2025111813164776100_ljaf294-B12","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.freeradbiomed.2009.12.022","article-title":"Reactive oxygen species, cellular redox systems, and apoptosis","volume":"48","author":"Circu","year":"2010","journal-title":"Free Radic Biol Med"},{"key":"2025111813164776100_ljaf294-B13","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/ng.2299","article-title":"Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency","volume":"44","author":"Meimaridou","year":"2012","journal-title":"Nat Genet"},{"key":"2025111813164776100_ljaf294-B14","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1210\/clinem\/dgac705","article-title":"Nicotinamide nucleotide transhydrogenase is essential for adrenal steroidogenesis: clinical and in vitro lessons","volume":"108","author":"Bodoni","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2025111813164776100_ljaf294-B15","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.redox.2018.07.017","article-title":"Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer","volume":"18","author":"Li","year":"2018","journal-title":"Redox Biol"},{"key":"2025111813164776100_ljaf294-B16","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1038\/s41418-021-00859-z","article-title":"Organelle-specific regulation of ferroptosis","volume":"28","author":"Chen","year":"2021","journal-title":"Cell Death Differ"},{"key":"2025111813164776100_ljaf294-B17","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41580-024-00703-5","article-title":"The cell biology of ferroptosis","volume":"25","author":"Dixon","year":"2024","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2025111813164776100_ljaf294-B18","doi-asserted-by":"crossref","first-page":"1426477","DOI":"10.3389\/fbioe.2024.1426477","article-title":"Unveiling the mechanism of photothermal therapy in acne management: targeting sebaceous gland ferroptosis via umbilical cord mesenchymal stem cell membrane-encapsulated Au-Ag-PDA","volume":"12","author":"Wu","year":"2024","journal-title":"Front Bioeng Biotechnol"},{"key":"2025111813164776100_ljaf294-B19","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1046\/j.1523-1747.1999.00771.x","article-title":"Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95)","volume":"113","author":"Zouboulis","year":"1999","journal-title":"J Invest Dermatol"},{"key":"2025111813164776100_ljaf294-B20","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1016\/j.molcel.2023.05.011","article-title":"IL-1\u03b2-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance","volume":"83","author":"Han","year":"2023","journal-title":"Mol Cell"},{"key":"2025111813164776100_ljaf294-B21","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/s41419-023-06045-y","article-title":"The diversified role of mitochondria in ferroptosis in cancer","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis"},{"key":"2025111813164776100_ljaf294-B22","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1016\/j.freeradbiomed.2005.02.012","article-title":"A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress","volume":"38","author":"Arkblad","year":"2005","journal-title":"Free Radical Biol Med"},{"key":"2025111813164776100_ljaf294-B23","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.bbabio.2011.12.004","article-title":"Silencing of nicotinamide nucleotide transhydrogenase impairs cellular redox homeostasis and energy metabolism in PC12 cells","volume":"1817","author":"Yin","year":"2012","journal-title":"Biochim Biophys Acta"},{"key":"2025111813164776100_ljaf294-B24","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1136\/jmedgenet-2015-103078","article-title":"Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress","volume":"52","author":"Weinberg-Shukron","year":"2015","journal-title":"J Med Genet"},{"key":"2025111813164776100_ljaf294-B25","doi-asserted-by":"crossref","first-page":"33670","DOI":"10.1074\/jbc.M204170200","article-title":"The proton channel of the energy-transducing nicotinamide nucleotide transhydrogenase of Escherichia coli","volume":"277","author":"Yamaguchi","year":"2002","journal-title":"J Biol Chem"},{"key":"2025111813164776100_ljaf294-B26","doi-asserted-by":"crossref","first-page":"6575","DOI":"10.1021\/bi034172v","article-title":"Roles of individual amino acids in helix 14 of the membrane domain of proton-translocating transhydrogenase from Escherichia coli as deduced from cysteine mutagenesis","volume":"42","author":"Karlsson","year":"2003","journal-title":"Biochemistry"},{"key":"2025111813164776100_ljaf294-B27","doi-asserted-by":"crossref","first-page":"45333","DOI":"10.1074\/jbc.M308236200","article-title":"Essential glycine in the proton channel of Escherichia coli transhydrogenase","volume":"278","author":"Yamaguchi","year":"2003","journal-title":"J Biol Chem"},{"key":"2025111813164776100_ljaf294-B28","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/anie.200390319","article-title":"Interactions with aromatic rings in chemical and biological recognition","volume":"42","author":"Meyer","year":"2003","journal-title":"Angew Chem Int Ed Engl"},{"key":"2025111813164776100_ljaf294-B29","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1073\/pnas.1722038115","article-title":"Structure of full-length human TRPM4","volume":"115","author":"Duan","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025111813164776100_ljaf294-B30","doi-asserted-by":"crossref","first-page":"e2307776121","DOI":"10.1073\/pnas.2307776121","article-title":"A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction","volume":"121","author":"Clatot","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025111813164776100_ljaf294-B31","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s00204-023-03476-6","article-title":"ROS-induced lipid peroxidation modulates cell death outcome: mechanisms behind apoptosis, autophagy, and ferroptosis","volume":"97","author":"Wang","year":"2023","journal-title":"Arch Toxicol"},{"key":"2025111813164776100_ljaf294-B32","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jphotobiol.2015.12.014","article-title":"Infrared and skin: friend or foe","volume":"155","author":"Barolet","year":"2016","journal-title":"J Photochem Photobiol B"},{"key":"2025111813164776100_ljaf294-B33","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jid.2019.06.150","article-title":"Holocrine secretion occurs outside the tight junction barrier in multicellular glands: lessons from Claudin-1-deficient mice","volume":"140","author":"Atsugi","year":"2020","journal-title":"J Invest Dermatol"},{"key":"2025111813164776100_ljaf294-B34","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/1523-1747.ep12676780","article-title":"Enzymes of carbohydrate metabolism in \u00adnormal human sebaceous glands","volume":"62","author":"Im","year":"1974","journal-title":"J Invest Dermatol"},{"key":"2025111813164776100_ljaf294-B35","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1111\/1523-1747.ep12259988","article-title":"Quantitative histochemistry of nicotinamide adenine nucleotides in human skin","volume":"55","author":"Im","year":"1970","journal-title":"J Invest Dermatol"}],"container-title":["British Journal of Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bjd\/advance-article-pdf\/doi\/10.1093\/bjd\/ljaf294\/63843877\/ljaf294.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/193\/6\/1182\/63843877\/ljaf294.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/193\/6\/1182\/63843877\/ljaf294.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T18:16:58Z","timestamp":1763489818000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bjd\/article\/193\/6\/1182\/8212129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,25]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,7,25]]},"published-print":{"date-parts":[[2025,11,18]]}},"URL":"https:\/\/doi.org\/10.1093\/bjd\/ljaf294","relation":{},"ISSN":["0007-0963","1365-2133"],"issn-type":[{"value":"0007-0963","type":"print"},{"value":"1365-2133","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,7,25]]}}}