Gaucher disease mouse models: point mutations at the acid beta-glucosidase locus combined with low-level prosaposin expression lead to disease variants.

Gaucher disease is a common lysosomal storage disease caused by a defect of acid beta-glucosidase (GCase). The optimal in vitro hydrolase activity of GCase requires saposin C, an activator protein that derives from a precursor, prosaposin. To develop additional models of Gaucher disease and to test in vivo effects of saposin deficiencies, mice expressing low levels (4--45% of wild type) of prosaposin and saposins (PS-NA) were backcrossed into mice with specific point mutations (V394L/V394L or D409H/D409H) of GCase. The resultant mice were designated 4L/PS-NA and 9H/PS-NA, respectively. In contrast to PS-NA mice, the 4L/PS-NA and 9H/PS-NA mice displayed large numbers of engorged macrophages and nearly exclusive glucosylceramide (GC) accumulation in the liver, lung, spleen, thymus, and brain. Electron microscopy of the storage cells showed the characteristic tubular storage material of Gaucher cells. Compared with V394L/V394L mice, 4L/PS-NA mice that expressed 4--6% of wild-type prosaposin levels had approximately 25--75% decreases in GCase activity and protein in liver, spleen, and fibroblasts. These results imply that reduced saposin levels increased the instability of V394L or D409H GCases and that these additional decreases led to large accumulations of GC in all tissues. These models mimic a more severe Gaucher disease phenotype and could be useful for therapeutic intervention studies.