title: Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function.
abstract: Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E.
authors.affiliation: Kresge Eye Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. jweiss@med.wayne.edu
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Weiss
authors.forename: Howard S
authors.initials: HS
authors.lastname: Kruth
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Karkera
authors.forename: Sunil
authors.initials: S
authors.lastname: Mahurkar
authors.forename: Walter
authors.initials: W
authors.lastname: Lisch
authors.forename: William J
authors.initials: WJ
authors.lastname: Dupps
authors.forename: Peter S
authors.initials: PS
authors.lastname: White
authors.forename: R Scott
authors.initials: RS
authors.lastname: Winters
authors.forename: Chaesik
authors.initials: C
authors.lastname: Kim
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rapuano
authors.forename: John
authors.initials: J
authors.lastname: Sutphin
authors.forename: Jim
authors.initials: J
authors.lastname: Reidy
authors.forename: Fung-Rong
authors.initials: FR
authors.lastname: Hu
authors.forename: Da Wen
authors.initials: DW
authors.lastname: Lu
authors.forename: Neil
authors.initials: N
authors.lastname: Ebenezer
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001057:Apolipoproteins E / Q000378:metabolism; D002648:Child; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004122:Dimethylallyltranstransferase; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D011506:Proteins; D004122:Dimethylallyltranstransferase; C425464:UBIAD1 protein, human