title: Defects in Stratum Corneum Desquamation Are the Predominant Effect of Impaired ABCA12 Function in a Novel Mouse Model of Harlequin Ichthyosis.
abstract: Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease.
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-0418-7872
authors.initials: M
authors.lastname: Ferreyros
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Dermatology, School of Medicine, University of California San Francisco, and Veterans Affairs Medical Center, San Francisco, CA, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.affiliation: Department of Dermatology, School of Medicine, University of California San Francisco, and Veterans Affairs Medical Center, San Francisco, CA, United States of America.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Crumrine
authors.affiliation: Department of Pathology and Dermatology, Stony Brook University School of Medicine, Stony Brook, NY, United States of America.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Dermatology, School of Medicine, University of California San Francisco, and Veterans Affairs Medical Center, San Francisco, CA, United States of America.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Department of Dermatology, School of Medicine, University of California San Francisco, and Veterans Affairs Medical Center, San Francisco, CA, United States of America.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
authors.affiliation: Service de Dermatologie et Vénéréologie, Hôpital de Beaumont, Université de Lausanne, Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Trevor
authors.initials: T
authors.lastname: Williams
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Enrique C
authors.initials: EC
authors.lastname: Torchia
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002518:Ceramides / Q000378:metabolism; D002874:Chromosome Mapping; D003896:Desmosomes / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005091:Exons; D005808:Genes, Recessive; D005963:Glucosylceramides / Q000378:metabolism; D017490:Ichthyosis, Lamellar / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D007610:Kallikreins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010539:Permeability; D010641:Phenotype; D017422:Sequence Analysis, DNA; D012867:Skin / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D016038:Skin Transplantation
chemical_list: D018528:ATP-Binding Cassette Transporters; C532573:Abca12 protein, mouse; D002518:Ceramides; D005963:Glucosylceramides; D007610:Kallikreins