{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T02:54:29Z","timestamp":1781578469111,"version":"3.54.5"},"reference-count":27,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,9]],"date-time":"2021-01-09T00:00:00Z","timestamp":1610150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FI1767\/3-1"],"award-info":[{"award-number":["FI1767\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.<\/jats:p>","DOI":"10.3390\/genes12010080","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T19:55:56Z","timestamp":1610308556000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-3951","authenticated-orcid":false,"given":"Alrun","family":"Hotz","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Kopp","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Bourrat","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Reference Center for Rare Skin Diseases MAGEC, Saint Louis Hospital AP-HP, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinzenz","family":"Oji","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, M\u00fcnster University Medical Center, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Komlosi","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Giehl","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, University of Munich LMU, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakar","family":"Bouadjar","sequence":"additional","affiliation":[{"name":"Department of Dermatology, CHU of Bab-El-Oued Algiers, Algiers 16008, Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anette","family":"Bygum","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark"},{"name":"Clinical Institute, University of Southern Denmark, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iliana","family":"Tantcheva-Poor","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maritta","family":"Hellstr\u00f6m Pigg","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Has","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Center-University of Freiburg, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Department of Dermatology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan D.","family":"Irvine","sequence":"additional","affiliation":[{"name":"Dermatology, Children\u2019s Health Ireland and Clinical Medicine, Trinity College Dublin, D12 N512 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5024-3623","authenticated-orcid":false,"given":"Regina C.","family":"Betz","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine &amp; University Hospital Bonn, University of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Zambruno","sequence":"additional","affiliation":[{"name":"Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Tadini","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS C\u00e0 Granda Ospedale Maggiore Policlinico, UOSD Pediatria ad Alta Intensit\u00e0 di Cura, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira","family":"S\u00fc\u00dfmuth","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, M\u00fcnster University Medical Center, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Gruber","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-1334","authenticated-orcid":false,"given":"Matthias","family":"Schmuth","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Mazereeuw-Hautier","sequence":"additional","affiliation":[{"name":"Reference Center for Rare Skin Diseases, Dermatology Department, CHU Larrey, Universit\u00e9 Paul Sabatier, 31000 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Jonca","sequence":"additional","affiliation":[{"name":"Department of Epidermis Differentiation and Rheumatoid Autoimmunity, UMR 1056 Inserm University Toulouse, Place du Dr Baylac, H\u00f4pital Purpan, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Guez","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS C\u00e0 Granda Ospedale Maggiore Policlinico, UOSD Pediatria ad Alta Intensit\u00e0 di Cura, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Brena","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS C\u00e0 Granda Ospedale Maggiore Policlinico, UOSD Pediatria ad Alta Intensit\u00e0 di Cura, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Hernandez-Martin","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hospital Infantil Ni\u00f1o Jes\u00fas, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Bolling","sequence":"additional","affiliation":[{"name":"Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katariina","family":"Hannula-Jouppi","sequence":"additional","affiliation":[{"name":"ERN-Skin Center, Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, HUS, 00029 Helsinki, Finland"},{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland and Research Programs Unit, Stem Cells and Metabolism Research Program, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5595-9388","authenticated-orcid":false,"given":"Andreas D.","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2233-8734","authenticated-orcid":false,"given":"Svenja","family":"Alter","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Vahlquist","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences\/Dermatology, Uppsala University, SE-751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8580-8118","authenticated-orcid":false,"given":"Judith","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/jid.2009.346","article-title":"Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients","volume":"130","author":"Vahlquist","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1126\/science.7824952","article-title":"Mutations of keratinocyte transglutaminase in lamellar ichthyosis","volume":"267","author":"Huber","year":"1995","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/hmg\/11.1.107","article-title":"Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) Are Mutated in Non-Bullous Congenital Ichthyosiform Erythroderma (NCIE) Linked to Chromosome 17p13.1","volume":"11","author":"Jobard","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1093\/hmg\/ddh263","article-title":"Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis","volume":"13","author":"Bouadjar","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1093\/hmg\/ddi491","article-title":"Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3","volume":"15","author":"Bouadjar","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1093\/hmg\/ddg235","article-title":"Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2","volume":"12","author":"Audebert","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/ng.1056","article-title":"PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans","volume":"44","author":"Grall","year":"2012","journal-title":"J. Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Radner, F.P.W., Marrakchi, S., Kirchmeier, P., Kim, G.-J., Ribierre, F., Kamoun, B., Abid, L., Leipoldt, M., Turki, H., and Schempp, W. (2013). Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet., 9.","DOI":"10.1371\/annotation\/df5af830-8e1d-495a-a206-f881ed85e7fe"},{"key":"ref_9","first-page":"4484","article-title":"Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis","volume":"25","author":"Shigehara","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1016\/j.ajhg.2017.05.007","article-title":"Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans","volume":"100","author":"Heinz","year":"2017","journal-title":"Am. J. Hum. 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Dermatol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/1\/80\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:09:16Z","timestamp":1760159356000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/1\/80"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,9]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["genes12010080"],"URL":"https:\/\/doi.org\/10.3390\/genes12010080","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,9]]}}}