title: Characterization of variants in the glucosylceramide synthase gene and their association with type 1 Gaucher disease severity.
abstract: The extreme phenotypic variability of patients with Gaucher disease (GD) is not completely explained by glucocerebrosidase gene mutations. It has been proposed that genetic modifiers might influence GD phenotype. We examined seven polymorphisms of the glucosylceramide synthase gene (UGCG) and their correlation with severity of GD. Five UGCG variants were significantly associated with disease severity, according to the DS3 scoring system: c.-295C>T, c.-232_-241ins10, c.98+50A>G, c.98+68A>T, and c.861A>G. Heterozygous [N370S]+[L444P] patients with c.[-232_-241ins10;98+50G] haplotype had a significantly lower DS3 score in relation to patients carrying only one of these polymorphisms. Electrophoretic mobility shift assay analysis showed an increased nuclear protein binding ability for the G allele at the cDNA position c.98+50, as well as an altered pattern for the c.-232_-241ins10 allele. The promoter activity of the haplotypes decreased significantly with respect to wild type activity in HepG2 and COS-7 cells (-14% and -16% for the c.[-232_-241ins10;98+50A] haplotype, -44% and -25% for c.[-222nonins;98+50G] haplotypes, and -64% and -75% for c.[-232_-241ins10;98+50G] haplotype, respectively). These data indicate that the c.-232_-241ins10 and c.98+50A>G variants are modifying factors of GD severity, which can partly explain the variability in severity of the disease.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Valencia, Spain; Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alfonso
authors.forename: Joaquín
authors.initials: J
authors.lastname: Navascués
authors.forename: Silvia
authors.initials: S
authors.lastname: Navarro
authors.forename: Pilar
authors.initials: P
authors.lastname: Medina
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bolado-Carrancio
authors.forename: Vanesa
authors.initials: V
authors.lastname: Andreu
authors.forename: Pilar
authors.initials: P
authors.lastname: Irún
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Rodríguez-Rey
authors.forename: Miguel
authors.initials: M
authors.lastname: Pocoví
authors.forename: Francisco
authors.initials: F
authors.lastname: España
authors.forename: Pilar
authors.initials: P
authors.lastname: Giraldo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D005776:Gaucher Disease / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D015870:Gene Expression; D017930:Genes, Reporter; D056726:Genetic Association Studies; D005838:Genotype; D005964:Glucosyltransferases / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D055815:Young Adult
chemical_list: D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
keywords: Gaucher disease; UGCG; glucosylceramide synthase; phenotype variability