The Molecular Biology of Gaucher Disease and the Potential for Gene Therapy

Our understanding of the molecular basis of lysosomal storage diseases has rapidly increased as a result of investigations utilizing both biochemical and recombinant DNA techniques. One of these disorders, Gaucher disease, results from recessively inherited autosomal mutations in the gene for the lysosomal hydrolase glucocerebrosidase (EC 3.2.1.45). These mutations result in the synthesis of catalytically defective glucocerebrosidases that are abnormally processed and/or improperly compartmentalized (Ginns et al. 1982, 1983, 1985; Erickson et al. 1985; Ginns 1985a; Jonsson et al. 1985). The accumulation of the neutral glycosphingolipid glucosylceramide occurs primarily within cells of the reticuloendothelial system (Gaucher 1982; Brady and Barranger 1983). In this paper, we describe the molecular mechanisms involved in glucocerebrosidase synthesis and compartmentalization as well as protein abnormalities characteristic of the different phenotypes of Gaucher disease. The information derived from these studies is discussed in terms of its usefulness for improved diagnosis and for the rational development of...