title: Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice.
abstract: Elongase of very long chain fatty acids-4 (ELOVL4) is the only mammalian enzyme known to synthesize C28-C36 fatty acids. In humans, ELOVL4 mutations cause Stargardt disease-3 (STGD3), a juvenile dominant macular degeneration. Heterozygous Stgd3 mice that carry a pathogenic mutation in the mouse Elovl4 gene demonstrate reduced levels of retinal C28-C36 acyl phosphatidylcholines (PC) and epidermal C28-C36 acylceramides. Homozygous Stgd3 mice die shortly after birth with signs of disrupted skin barrier function. In this study, we report generation of transgenic (Tg) mice with targeted Elovl4 expression driven by an epidermal-specific involucrin promoter. In homozygous Stgd3 mice, this transgene reinstates both epidermal Elovl4 expression and synthesis of two missing epidermal lipid groups: C28-C36 acylceramides and (O-linoleoyl)-omega-hydroxy C28-C36 fatty acids. Transgene expression also restores skin barrier function and rescues the neonatal lethality of homozygous Stgd3 mice. These studies establish the critical requirement for epidermal C28-C36 fatty acid synthesis for animal viability. In addition to the skin, Elovl4 is also expressed in other tissues, including the retina, brain, and testes. Thus, these mice will facilitate future studies to define the roles of C28-C36 fatty acids in the Elovl4-expressing tissues.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390. Electronic address: Anne.Mcmahon@utsouthwestern.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: McMahon
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Butovich
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kedzierski
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002518:Ceramides / Q000235:genetics / Q000378:metabolism*; D025063:Chromosome Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D018703:Founder Effect; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000151:congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010539:Permeability; D010713:Phosphatidylcholines / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D014048:Tolonium Chloride / Q000032:analysis / Q000493:pharmacokinetics; D014162:Transfection; D019076:Transgenes
chemical_list: D002518:Ceramides; C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D005227:Fatty Acids; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D011498:Protein Precursors; D014048:Tolonium Chloride; C032253:involucrin