Viable Mouse Models of Acid β-Glucosidase Deficiency

Abstract

Gaucher disease is an autosomal recessively inherited disease caused by mutations at the acid beta-glucosidase (GCase) locus (GBA). To develop viable models of Gaucher disease, point mutations (pmuts), encoding N370S, V394L, D409H, or D409V were introduced into the mouse GCase (gba) locus. DNA sequencing verified each unique pmut. Mutant GCase mRNAs were near wild-type (WT) levels. GCase activities were reduced to 2 to 25% of WT in liver, lung, spleen, and cultured fibroblasts from pmut/pmut or pmut/null mice. The corresponding brain GCase activities were approximately 25% of WT. N370S homozygosity was lethal in the neonatal period. For the other pmut mice, a few storage cells appeared in the spleen at > or =7 months (D409H or D409V homozygotes) or > or =1 year (V394L homozygotes). V394L/null, D409H/null, or D409V/null mice showed scattered storage cells in spleen at approximately 3 to 4 months. Occasional storage cells (sinusoidal cells) were present in liver. In D409V/null mice, large numbers of Mac-3-positive storage cells (ie, macrophages) accumulated in the lung. Glycosphingolipid analyses showed varying rates of progressive glucosylceramide accumulation in visceral organs of pmut/pmut or pmut/null mice, but not in brain. These GCase-deficient mice provide tools for gaining insight into the pathophysiology of Gaucher disease and developing improved therapies.

Ex Vivo and in Vivo Effects of Isofagomine on Acid β-Glucosidase Variants and Substrate Levels in Gaucher Disease

“…In contrast to humans, N370S or L444P (as an insertional mutant) homozygosity in mice leads to death within 24 -48 h (11,12). Homozygosity for V394L or D409H leads to defective GCase activity, but mice survive to ϳ24 months with only minor visceral abnormalities (11). More extensive involvement in such mouse models was developed by cross-breeding of V394L or D409H with a hypomorphic prosaposin-deficient mouse, termed 4L/PS-NA or 9H/PS-NA, respectively (13).…”

“…In contrast to humans, N370S or L444P (as an insertional mutant) homozygosity in mice leads to death within 24 -48 h (11,12). Homozygosity for V394L or D409H leads to defective GCase activity, but mice survive to ϳ24 months with only minor visceral abnormalities (11).…”

“…Here, the effects of IFG on mutant GCases were evaluated with recombinant enzymes and in cultured fibroblasts and that displayed enzyme deficiencies (11). The effects of IFG on substrate levels were evaluated in the hG/4L/PS-NA model that has doxycycline (DOX)-controllable hGCase expression in the liver (14).…”

The sphingolipid salvage pathway in ceramide metabolism and signaling

“…Genetic defects in several of these hydrolytic enzymes cause various disorders with lysosomal accumulation of the substrate lipids, a group of disorders termed the sphingolipidoses [41,[90][91][92][93]. Particularly, some of the known sphingolipidoses might closely associate with aberrant metabolisms of ceramide because of defective activities of ceramide generating/degrading enzymes: Farber's disease, Gaucher disease, and Niemann-Pick type A and B diseases are caused by a deficiency of acid ceramidase [94,95], glucocerebrosidase (acid-β-glucosidase) [96][97][98], acid SMase [99,100], respectively. The salvage pathway is one of the routes for controlling cellular levels of ceramide.…”

Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease: implications for neuronal loss in Gaucher disease

“…In vivo approaches to understanding the pathophysiology of Gaucher disease and the development of new therapeutic strategies to address it have previously been hindered by the lack of a viable animal model (Tybulewicz et al, 1992;Liu et al, 1998). However, the generation of viable mouse models of Gaucher disease has recently been reported (Xu et al, 2003;Sun et al, 2005), and these mouse models will be useful in elucidating the pathogenesis of Gaucher disease.…”