title: The expression of epidermal lipoxygenases and transglutaminase-1 is perturbed by NIPAL4 mutations: indications of a common metabolic pathway essential for skin barrier homeostasis.
abstract: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin barrier diseases due inter alia to mutations in transglutaminase-1 (TGM1), in lipoxygenases (LOXs) of the hepoxilin pathway, and in ichthyin, a putative Mg(2+) transporter encoded by the NIPAL4 gene. In search of a common pathogenic pathway for ARCI, we investigated the epidermal expression of TGM1, 12R-LOX, eLOX-3, and ichthyin in skin biopsies from four healthy controls and nine patients with ARCI. In healthy skin, TGM1, ichthyin, and the LOX enzymes were predominantly expressed in the upper epidermis where colocalization signals could also be demonstrated by in situ proximity ligation assay. In patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. In contrast, patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. Treatment of these patients with a retinoid-mimetic drug, liarozole, normalized the expression of 12R-LOX and attenuated the colocalization signal. Altogether, our data indicate that ichthyin and TGM1 are functionally closely related in the lipid processing and that this metabolic pathway can be modified by retinoids.
authors.affiliation: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Loriè
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Freiburg, Freiburg, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Vahlquist
authors.affiliation: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden. Electronic address: hans.torma@medsci.uu.se.
authors.forename: Hans
authors.initials: H
authors.lastname: Törmä
mesh_terms: D000328:Adult; D001706:Biopsy; D002463:Cell Membrane Permeability / Q000502:physiology*; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007057:Ichthyosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D058945:Lipoxygenases / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012176:Retinoids / Q000627:therapeutic use; D012879:Skin Physiological Phenomena; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: C499859:NIPAL4 protein, human; D011956:Receptors, Cell Surface; D012176:Retinoids; D058945:Lipoxygenases; D011503:Transglutaminases; C105804:transglutaminase 1