Characterization of variants in the glucosylceramide synthase gene and their association with type 1 Gaucher disease severity.

Autores de IIS La Fe

• Pilar Alfonso Palacin

  Autor

• Joaquin Navascues Ortega

  Autor

• Silvia Navarro Rosales

  Autor

• 

  Pilar Medina Badenes

  Autor

• Vicente Andreu Fernandez

  Autor

• Pilar Irun Irun

  Autor

• Francisco España Furio

  Autor

• Pilar Giraldo Castellano

  Autor

Participantes ajenos a IIS La Fe

• Bolado-Carrancio A
• Rodríguez-Rey JC
• Pocoví M

Grupos

• Hemostasia, Trombosis, Arteriosclerosis y Biología vascular

  

  Investigador Principal

  Pilar Medina Badenes

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.

Keywords

• Gaucher disease, UGCG, glucosylceramide synthase, phenotype variability