{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:20:23Z","timestamp":1790742023256,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T00:00:00Z","timestamp":1576195200000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG014713"],"award-info":[{"award-number":["R01AG014713"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH060009"],"award-info":[{"award-number":["R01MH060009"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03AR063271"],"award-info":[{"award-number":["R03AR063271"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15EB019704"],"award-info":[{"award-number":["R15EB019704"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["NSF1455613"],"award-info":[{"award-number":["NSF1455613"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disorder characterized clinically with acne-like lesions in apocrine gland\u2013bearing skin, follicular occlusion and recurrent inflammation. Thirty-four unique mutations in patients with HS have been found in three genes encoding the \u03b3-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and in POGLUT1, an endoplasmic reticulum O-glucosyltransferase involved in Notch signaling. We have carried out a system review and have performed a functional analysis of the 34 unique reported HS-linked mutations in NCSTN, PSEN1, PSENEN and POGLUT1. We have also examined the effects of the HS-linked PSEN1-P242LfsX11 mutation on cytokine and chemokine expression in macrophages. Mutations in NCSTN are predicted to cause loss of function, to result in loss of transmembrane (TM) domain, to affect NCSTN substrate recruitment sites, to cause loss or creation of new ligand binging sites and to alter post-translational modifications and disulfide bonds. PSEN1-P242LfsX11 occurs at the opposite side of TM5 from Alzheimer\u2019s disease\u2013linked PSEN1 mutations. All of the PSENEN mutations occur on TM regions that are predicted to disrupt membrane function. POGLUT1 mutations lead to an early termination of protein synthesis and are predicted to affect ligand binding function. In addition, PSEN1-P242LfsX11 mediates cytokine and chemokine expression and prolongs tumor necrosis factor \u03b1 production on the inflammatory processes in THP-1 cells and phorbol-12-myristate-13-acetate\u2013differentiated macrophages in response to lipopolysaccharide stimulation. These in silico analyses are instructive for functional studies of the HS-linked mutations. The PSEN1-P242LfsX11 mutation mediates cytokine and chemokine expression in macrophages.<\/jats:p>","DOI":"10.1093\/hmg\/ddy414","type":"journal-article","created":{"date-parts":[[2018,12,12]],"date-time":"2018-12-12T20:11:41Z","timestamp":1544645501000},"page":"1173-1182","source":"Crossref","is-referenced-by-count":37,"title":["Analysis of hidradenitis suppurativa\u2013linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages"],"prefix":"10.1093","volume":"28","author":[{"given":"Airong","family":"Li","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Peng","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M","family":"Taiclet","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph E","family":"Tanzi","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,12,13]]},"reference":[{"key":"2020030521310640900_ref1","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1001\/jamadermatol.2017.0201","article-title":"Sex- and age-adjusted population analysis of prevalence estimates for hidradenitis suppurativa in the United States","volume":"153","author":"Garg","year":"2017","journal-title":"JAMA Dermatol."},{"key":"2020030521310640900_ref2","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jaad.2008.11.911","article-title":"Hidradenitis suppurativa: a comprehensive review","volume":"60","author":"Alikhan","year":"2009","journal-title":"J. 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Clin."},{"key":"2020030521310640900_ref5","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1126\/science.1196284","article-title":"Gamma-secretase gene mutations in familial acne inversa","volume":"330","author":"Wang","year":"2010","journal-title":"Science"},{"key":"2020030521310640900_ref6","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/bjd.16264","article-title":"Novel POFUT1 mutation associated with hidradenitis suppurativa\u2013Dowling\u2013Degos disease firm up a role for Notch signalling in the pathogenesis of this disorder","volume":"178","author":"Gonzalez-Villanueva","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"2020030521310640900_ref7","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1001\/archdermatol.2011.315","article-title":"Hidradenitis suppurativa: the role of deficient cutaneous innate immunity","volume":"148","author":"Dreno","year":"2012","journal-title":"Arch. Dermatol."},{"key":"2020030521310640900_ref8","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1093\/bfgp\/elu017","article-title":"RNA regulatory networks in animals and plants: a long noncoding RNA perspective","volume":"14","author":"Bai","year":"2015","journal-title":"Brief Funct. Genomics"},{"key":"2020030521310640900_ref9","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1038\/jid.2012.162","article-title":"Mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa)","volume":"132","author":"Pink","year":"2012","journal-title":"J. Invest. Dermatol."},{"key":"2020030521310640900_ref10","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/jid.2011.62","article-title":"Confirmation by exome sequencing of the pathogenic role of NCSTN mutations in acne inversa (hidradenitis suppurativa)","volume":"131","author":"Liu","year":"2011","journal-title":"J. Invest. 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