Two new missense mutations in a non-Jewish Caucasian family with type 3 Gaucher disease.

Gaucher disease is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme glucocerebrosidase. The prevalence of this disorder differs significantly among various populations and is highest in some Jewish populations. More than 35 disease-producing mutations of the gene have been reported. The change of the amino acid leucine at position 444 to proline (444Leu-->Pro) is the most common mutation in non-Jewish populations, and a second mutation at amino acid 370 (370Asn-->Ser) is the most common one in Jewish populations. However, most of the mutations have been reported in very few cases or even in only one pedigree. We performed a direct DNA sequencing analysis of the complete functional glucocerebrosidase gene in a 22-year-old neuronopathic non-Jewish patient with Gaucher disease type 3 with myoclonic epilepsy and slight mental disturbances and in most members of his family. After selective amplification of the complete coding region of the patient's functional glucocerebrosidase gene, we identified two hitherto unreported mutations in exon 9 (genomic nucleotide 5224G-->C; 417Val-->Leu) and in exon 11 (genomic nucleotide 6668C-->T; 510Thr-->Ile). Each parent showed one of these mutations. Once we sequenced the complete active gene, we could rule out the existence of further mutations. Data that show that in about 15 to 25% of non-Jewish patients with Gaucher disease no mutations within the glucocerebrosidase gene are found may be due to inappropriate screening methods, mostly used for the genotyping. Until we have precise information about the frequency and distribution of single-point mutations in patients with Gaucher disease, it is necessary to analyze the complete glucocerebrosidase gene.