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Meta-Analysis of Mutations in ALOX12B Or ALOXE3 Identified in A G C A T T A C G G C A T genes Article Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients Alrun Hotz 1 , Julia Kopp 1, Emmanuelle Bourrat 2, Vinzenz Oji 3, Katalin Komlosi 1, Kathrin Giehl 4, Bakar Bouadjar 5, Anette Bygum 6,7,8, Iliana Tantcheva-Poor 9, Maritta Hellström Pigg 10, Cristina Has 11, Zhou Yang 1,12, Alan D. Irvine 13, Regina C. Betz 14 , Giovanna Zambruno 15, Gianluca Tadini 16, Kira Süßmuth 3, Robert Gruber 17, Matthias Schmuth 17 , Juliette Mazereeuw-Hautier 18, Natalie Jonca 19, Sophie Guez 16, Michela Brena 16, Angela Hernandez-Martin 20, Peter van den Akker 21, Maria C. Bolling 22, Katariina Hannula-Jouppi 23,24, Andreas D. Zimmer 1 , Svenja Alter 1, Anders Vahlquist 25 and Judith Fischer 1,* 1 Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; [email protected] (A.H.); [email protected] (J.K.); [email protected] (K.K.); [email protected] (Z.Y.); [email protected] (A.D.Z.); [email protected] (S.A.) 2 Department of Dermatology, Reference Center for Rare Skin Diseases MAGEC, Saint Louis Hospital AP-HP, 75010 Paris, France; [email protected] 3 Department of Dermatology and Venereology, Münster University Medical Center, 48149 Münster, Germany; [email protected] (V.O.); [email protected] (K.S.) 4 Department of Dermatology and Allergy, University of Munich LMU, 80337 Munich, Germany; [email protected] 5 Department of Dermatology, CHU of Bab-El-Oued Algiers, Algiers 16008, Algeria; [email protected] 6 Department of Dermatology, Odense University Hospital, 5000 Odense, Denmark; [email protected] 7 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark 8 Clinical Institute, University of Southern Denmark, 5000 Odense, Denmark 9 Department of Dermatology, University of Cologne, 50937 Cologne, Germany; [email protected] Citation: Hotz, A.; Kopp, J.; Bourrat, 10 Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden; E.; Oji, V.; Komlosi, K.; Giehl, K.; [email protected] 11 Bouadjar, B.; Bygum, A.; Department of Dermatology, Medical Center-University of Freiburg, University of Freiburg, 79104 Freiburg, Tantcheva-Poor, I.; Hellström Pigg, Germany; [email protected] 12 Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for M.; et al. Meta-Analysis of Mutations Children’s Health, Beijing 100045, China in ALOX12B or ALOXE3 Identified in 13 Dermatology, Children’s Health Ireland and Clinical Medicine, Trinity College Dublin, D12 N512 Dublin, a Large Cohort of 224 Patients. Genes Ireland; [email protected] 2021, 12, 80. https://doi.org/ 14 Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, 10.3390/genes12010080 53127 Bonn, Germany; [email protected] 15 Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, Received: 23 December 2020 IRCCS, 00165 Rome, Italy; [email protected] 16 Accepted: 6 January 2021 Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UOSD Pediatria ad Alta Intensità di Cura, Published: 9 January 2021 20122 Milan, Italy; [email protected] (G.T.); [email protected] (S.G.); [email protected] (M.B.) 17 Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, 6020 Innsbruck, Publisher’s Note: MDPI stays neu- Austria; [email protected] (R.G.); [email protected] (M.S.) tral with regard to jurisdictional clai- 18 Reference Center for Rare Skin Diseases, Dermatology Department, CHU Larrey, Université Paul Sabatier, ms in published maps and institutio- 31000 Toulouse, France; [email protected] nal affiliations. 19 Department of Epidermis Differentiation and Rheumatoid Autoimmunity, UMR 1056 Inserm University Toulouse, Place du Dr Baylac, Hôpital Purpan, 31059 Toulouse, France; [email protected] 20 Department of Dermatology, Hospital Infantil Niño Jesús, 28009 Madrid, Spain; [email protected] 21 Department of Genetics, University Medical Center Groningen, University of Groningen, 9700RB Groningen, Copyright: © 2021 by the authors. Li- The Netherlands; [email protected] censee MDPI, Basel, Switzerland. 22 Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, This article is an open access article University of Groningen, 9700RB Groningen, The Netherlands; [email protected] 23 distributed under the terms and con- ERN-Skin Center, Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, 00029 HUS Helsinki, Finland; Katariina.Hannula-Jouppi@hus.fi ditions of the Creative Commons At- 24 Folkhälsan Research Center, Helsinki, Finland and Research Programs Unit, Stem Cells and Metabolism tribution (CC BY) license (https:// Research Program, University of Helsinki, 00290 Helsinki, Finland creativecommons.org/licenses/by/ 4.0/). Genes 2021, 12, 80. https://doi.org/10.3390/genes12010080 https://www.mdpi.com/journal/genes Genes 2021, 12, 80 2 of 11 25 Department of Medical Sciences/Dermatology, Uppsala University, SE-751 85 Uppsala, Sweden; [email protected] * Correspondence: judith.fi[email protected] Abstract: 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. Keywords: ALOX12B; ALOXE3; ARCI; ichthyosis 1. Introduction Autosomal recessive congenital ichthyosis (ARCI) comprises a clinically and genet- ically heterogeneous group of rare disorders of cornification characterized by hyperker- atosis, scaling of the body, and a variable degree of erythroderma. ARCI is subclassified into lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), and harlequin ichthyosis (HI). Patients with LI often present with large, dark plate-like scales and with minimal erythema, whereas patients with CIE usually show variable erythroderma and generalized fine white scaling. Some patients show overlapping phenotypes of LI and CIE. HI represents the most severe form of ARCI and is a potentially life-threatening condition. CIE is typically on the milder end of the spectrum. Neonates with ARCI are often born with a collodion membrane, a parchment-like membrane covering the whole body surface. This membrane is shed within 1–3 weeks and is followed by presentation of an underlying LI or CIE. In some cases, either no or only mild signs of ichthyosis persist after the neonatal or infant period. This condition has been named self-improving collodion ichthyosis (SICI) and is often associated with mutations in ALOX12B and ALOXE3 [1]. To date, mutations in ten genes have been identified to cause ARCI: TGM1 (MIM 190195) [2], ALOX12B (MIM 603741) [3], ALOXE3 (MIM 607206) [3], NIPAL4/ICHTHYIN (MIM 609383) [4], CYP4F22 (MIM 611495) [5], ABCA12 (MIM 607800) [6], PNPLA1 (MIM 612121) [7], CERS3 (MIM 615276) [8], SDR9C7 (MIM 609769) [9], and SULT2B1 (MIM 604125) [10]. Mutations in TGM1 are the most common cause for ARCI, followed by mutations in the two lipoxygenase genes, ALOX12B and ALOXE3 [11]. In this report we focus on the spectrum, the type, and the position of mutations in both ALOX12B and ALOXE3 genes. ARCI is associated with impaired skin barrier function, which is mainly caused by the inability of mutated keratinocytes to produce or to secrete the skin lipids that are required for the formation of the cornified cell envelope and for the extracellular lipid layers in the stratum corneum [12]. ALOX12B and ALOXE3 encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis- type lipoxygenase-3 (eLOX3), respectively. Lipoxygenases (LOXs) are a family of nonheme, Genes 2021, 12, 80 3 of 11 iron-containing dioxygenases. LOXs catalyze the oxygenation of polyunsaturated fatty acid substrates that contain (Z,Z)-1,4-pentiadiene structures [13]. Deficiency of 12R-LOX and eLOX3 disrupts
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