Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease

Gaucher disease, an inherited glycolipid storage disorder, is caused by a d eficiency of the catabolic enzyme glucocerebrosidase (EC 3.2.1.45). The gen e for human glucocerebrosidase is located on chromosome 1q21 and has a high ly homologous pseudogene situated 16 kb downstream. We report two novel pol ymorphic sequences in the glucocerebrosidase gene region: the first consist s of a variable number of dinucleotide (CT) repeats located 3.2 kb upstream from the glucocerebrosidase gene, and the second is a tetranucleotide (AAA T) repeat found between the glucocerebrosidase gene and its pseudogene, 9.8 kb downstream from the functional gene. These polymorphic sequences, along with a previously reported PvuII polymorphism in intron 6 of the glucocere brosidase gene, were analyzed in patients with Gaucher disease (n=106) and in two normal control populations, one of Ashkenazi Jewish ancestry (n=72) and the second comprising non-Jewish individuals (n=46). In these samples, strong linkage disequilibrium was found between mutations N370S, c.84-85ins G, and R463C and specific haplotypes; no significant linkage disequilibrium was found when examining haplotypes of patients with the L444P mutation. S tudies of these polymorphic sites in several instances also led to the reco gnition of genotyping errors and the identification of unusual recombinant alleles. These new polymorphic sites provide additional tools for mutationa l screening and founder effect studies of Gaucher disease.