Molecular genetic approaches to neurologic diseases

Recent advances of molecular biology has brought neurologists new and powerful approaches for the studies of neurologic diseases. The molecular genetic approaches have been successfully applied for the elucidation of molecular mechanisms of Gaucher disease, a sphingolipid storage disease. First a full length cDNA clone for glucocerebrosidase, the missing enzyme in Gaucher disease, was isolated, which enabled us to isolate the mutant as well as normal glucocerebrosidase genes. With detailed nucleotide sequence analysis of mutant genes, we have discovered two single base mutations within exons of glucocerebrosidase genes, one in type 2 and the other in type 1 Gaucher disease. Screening of the mutations among three phenotypes of Gaucher disease, it has been shown that there is a good correlation of occurrence of each mutation with the phenotypes. Moreover, we have shown that we have successfully restored glucocerebrosidase activity in Gaucher fibroblasts by retrovirus-mediated transfer of a normal human glucocerebrosidase cDNA. The results indicate that current molecular biology techniques can be utilized not only for the study of molecular mechanisms of neurologic diseases but also for the development of treatment of devastating neurologic diseases.