title: The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to cholesterol metabolic enzymes.
abstract: Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone-4 (MK-4, vitamin K(2) ), but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK-4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177-mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two-hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate-binding cleft and substrate-binding overlaps with GGPP binding, an MK-4 substrate, suggesting potential competition between these metabolites. Impaired MK-4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggest a role for endogenous MK-4 in maintaining cornea health and visual acuity.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA. nickersonml@mail.nih.gov
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Allen D
authors.initials: AD
authors.lastname: Bosley
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Weiss
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Kostiha
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hirota
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
authors.forename: Dominic
authors.initials: D
authors.lastname: Esposito
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Ludger
authors.initials: L
authors.lastname: Wessjohann
authors.forename: Scott G
authors.initials: SG
authors.lastname: Morham
authors.forename: Thorkell
authors.initials: T
authors.lastname: Andresson
authors.forename: Howard S
authors.initials: HS
authors.lastname: Kruth
authors.forename: Toshio
authors.initials: T
authors.lastname: Okano
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002784:Cholesterol / Q000378:metabolism*; D003315:Cornea / Q000201:enzymology; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D004122:Dimethylallyltranstransferase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005387:Finland; D014644:Genetic Variation; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D007564:Japan; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D014421:Turkey; D024482:Vitamin K 2 / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D024482:Vitamin K 2; C030814:menatetrenone; D018698:Glutamic Acid; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1; D004122:Dimethylallyltranstransferase; C425464:UBIAD1 protein, human; D005998:Glycine