MOLECULAR SCREENING OF JAPANESE PATIENTS WITH GAUCHER DISEASE - PHENOTYPIC VARIABILITY IN THE SAME GENOTYPES

Gaucher disease is the most prevalent sphingolipidosis, characterized by genetic deficiency of lysosomal hydrolase glucocerebrosidase, and i s inherited in an autosomal recessive manner. To characterize the mole cular basis of Gaucher disease in Japan, we analyzed for the presence of the two known mutations (1448C and 754A) in the glucocerebrosidase gene of 15 patients (14 families) with Gaucher disease by selective am plification and restriction endonuclease analysis. We found that the 1 448C and 754A mutations occurred in all three clinical subtypes of Jap anese Gaucher disease patients. The 1448C mutation was found on 12 (40 %) out of 30 chromosomes (44% allele frequency in nonneuronopathic for m, and 33% in neuronopathic forms), while homozygosity for this mutati on was only found in two nonneuronopathic patients (age of 1 year 6 mo nths and 7 years). We detected the 754A mutation on 6 (20%) out of 30 chromosomes. No patient was homozygous for 754A mutation. Furthermore, we identified four patients who were compound hetrozygote for 754A an d 1448C. One of these was a type 3 Gaucher patient, but the other thre e patients were free from central nervous system manifestations at the time of observation. These results indicate that phenotypic presentat ion of Gaucher disease including the presence of nervous manifestation , progression, and severity of disease, may be affected by other genet ic, environmental, or developmental factors, as well as the glucocereb rosidase genotype. (C) 1993 Wiley-Liss, Inc.