title: Roles of the 15-kDa selenoprotein (Sep15) in redox homeostasis and cataract development revealed by the analysis of Sep 15 knockout mice.
abstract: The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Kasaikina
authors.forename: Dmitri E
authors.initials: DE
authors.lastname: Fomenko
authors.forename: Vyacheslav M
authors.initials: VM
authors.lastname: Labunskyy
authors.forename: Salil A
authors.initials: SA
authors.lastname: Lachke
authors.forename: Wenya
authors.initials: W
authors.lastname: Qiu
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Moncaster
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Mark W
authors.initials: MW
authors.lastname: Wojnarowicz
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Natarajan
authors.forename: Mikalai
authors.initials: M
authors.lastname: Malinouski
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
authors.forename: Petra A
authors.initials: PA
authors.lastname: Tsuji
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
authors.forename: Marjorie F
authors.initials: MF
authors.lastname: Lou
authors.forename: Lee E
authors.initials: LE
authors.lastname: Goldstein
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002386:Cataract / Q000378:metabolism* / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D008970:Molecular Weight; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051149:Selenoprotein P / Q000378:metabolism; D051140:Selenoproteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D050505:Mutant Proteins; D012333:RNA, Messenger; C495239:Selenof protein, mouse; D051149:Selenoprotein P; D051140:Selenoproteins