title: UBIAD1 mutation alters a mitochondrial prenyltransferase to cause Schnyder corneal dystrophy.
abstract: BACKGROUND
  Mutations in a novel gene, UBIAD1, were recently found to cause the autosomal dominant eye disease Schnyder corneal dystrophy (SCD). SCD is characterized by an abnormal deposition of cholesterol and phospholipids in the cornea resulting in progressive corneal opacification and visual loss. We characterized lesions in the UBIAD1 gene in new SCD families and examined protein homology, localization, and structure.
  
  
  RESULTS
  We characterized five novel mutations in the UBIAD1 gene in ten SCD families, including a first SCD family of Native American ethnicity. Examination of protein homology revealed that SCD altered amino acids which were highly conserved across species. Cell lines were established from patients including keratocytes obtained after corneal transplant surgery and lymphoblastoid cell lines from Epstein-Barr virus immortalized peripheral blood mononuclear cells. These were used to determine the subcellular localization of mutant and wild type protein, and to examine cholesterol metabolite ratios. Immunohistochemistry using antibodies specific for UBIAD1 protein in keratocytes revealed that both wild type and N102S protein were localized sub-cellularly to mitochondria. Analysis of cholesterol metabolites in patient cell line extracts showed no significant alteration in the presence of mutant protein indicating a potentially novel function of the UBIAD1 protein in cholesterol biochemistry. Molecular modeling was used to develop a model of human UBIAD1 protein in a membrane and revealed potentially critical roles for amino acids mutated in SCD. Potential primary and secondary substrate binding sites were identified and docking simulations indicated likely substrates including prenyl and phenolic molecules.
  
  
  CONCLUSIONS
  Accumulating evidence from the SCD familial mutation spectrum, protein homology across species, and molecular modeling suggest that protein function is likely down-regulated by SCD mutations. Mitochondrial UBIAD1 protein appears to have a highly conserved function that, at least in humans, is involved in cholesterol metabolism in a novel manner.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA. nickersonml@mail.nih.gov
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Kostiha
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
authors.forename: William
authors.initials: W
authors.lastname: Fredericks
authors.forename: Ke-Ping
authors.initials: KP
authors.lastname: Xu
authors.forename: Fu-Shin
authors.initials: FS
authors.lastname: Yu
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: James
authors.initials: J
authors.lastname: Chodosh
authors.forename: Marc
authors.initials: M
authors.lastname: Goldberg
authors.forename: Da Wen
authors.initials: DW
authors.lastname: Lu
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamada
authors.forename: Timo M
authors.initials: TM
authors.lastname: Tervo
authors.forename: Richard
authors.initials: R
authors.lastname: Grutzmacher
authors.forename: Chris
authors.initials: C
authors.lastname: Croasdale
authors.forename: Maria
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: John
authors.initials: J
authors.lastname: Sutphin
authors.forename: S Bruce
authors.initials: SB
authors.lastname: Malkowicz
authors.forename: Ludger
authors.initials: L
authors.lastname: Wessjohann
authors.forename: Howard S
authors.initials: HS
authors.lastname: Kruth
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism; D017124:Conserved Sequence; D003315:Cornea / Q000201:enzymology / Q000473:pathology; D003317:Corneal Dystrophies, Hereditary / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D003710:Demography; D004122:Dimethylallyltranstransferase / Q000235:genetics*; D005190:Family; D006801:Humans; D016014:Linear Models; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D000596:Amino Acids; D050505:Mutant Proteins; D011506:Proteins; D002784:Cholesterol; D004122:Dimethylallyltranstransferase; C425464:UBIAD1 protein, human