Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome

Abstract

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the lysosomal beta-glucocerebrosidase (GBA) gene. As the disease is particularly prevalent among Ashkenazi Jews, most studies have been carried out on this ethnic group. In the current study, we present a mutation analysis of the GBA gene in Spanish patients together with the clinical findings. We conducted a systematic analysis in 53 unrelated GD patients. The GBA gene was initially scanned for nine previously described mutations by ASO hybridization or restriction analysis after PCR amplification. The remaining unidentified alleles were screened by nonisotopic PCR-SSCP analysis and sequenced. This approach allowed the identification of 101 of 106 GD alleles (95.3%) involving 24 different mutations, 11 of which are described for the first time: G113E (455G-->A), T134P (517A-->C), G389E (1283G-->A), P391L (1289C-->T), N392I (1292A-->T), Y412H (1351T-->G), W(-4)X (108G-->A), Q169X (662C-->T), R257X (886C-->T), 500insT, and IVS5+1G-->T. Most mutations are present in one or few GD chromosomes. However, two mutations, N370S (1226A-->G) and L444P (1448T-->C), are very frequent and account for 66.1% of the total number of alleles. Linkage disequilibrium was detected between these two mutations and an intragenic polymorphism, indicating that expansion of founder alleles occurred in both cases. Analysis of several microsatellite markers close to the GBA gene allowed us to establish the putative haplotype of the ancestral N370S chromosome.