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Characterization of Variants in the Glucosylceramide Synthase Gene and their Association with T ype 1 G aucher Disease Severity
Author(s) -
Alfonso Pilar,
Navascués Joaquín,
Navarro Silvia,
Medina Pilar,
BoladoCarrancio Alfonso,
Andreu Vanesa,
Irún Pilar,
RodríguezRey José Carlos,
Pocoví Miguel,
España Francisco,
Giraldo Pilar
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22381
Subject(s) - haplotype , biology , allele , gene , glucocerebrosidase , genotype , genetics , phenotype , polymorphism (computer science) , microbiology and biotechnology
The extreme phenotypic variability of patients with G aucher 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 DS 3 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 DS 3 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 c DNA 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.