Abstract
Gaucher disease is caused by mutations in GBA1 encoding acid β-glucosidase (GCase). Saposin C enhances GCase activity and protects GCase from intracellular proteolysis. Structure simulations indicated that the mutant GCases, N370S (0 S), V394L (4L) and D409V(9V)/H(9H), had altered function. To investigate the in vivo function of Gba1 mutants, mouse models were generated by backcrossing the above homozygous mutant GCase mice into Saposin C deficient (C*) mice. Without saposin C, the mutant GCase activities in the resultant mouse tissues were reduced by ~50% compared with those in the presence of Saposin C. In contrast to 9H and 4L mice that have normal histology and life span, the 9H;C* and 4L;C* mice had shorter life spans. 9H;C* mice developed significant visceral glucosylceramide (GC) and glucosylsphingosine (GS) accumulation (GC»GS) and storage macrophages, but lesser GC in the brain, compared to 4L;C* mice that presents with a severe neuronopathic phenotype and accumulated GC and GS primarily in the brain. Unlike 9V mice that developed normally for over a year, 9V;C* pups had a lethal skin defect as did 0S;C* mice resembled that of 0S mice. These variant Gaucher disease mouse models presented a mutation specific phenotype and underscored the in vivo role of Saposin C in the modulation of Gaucher disease.
Highlights
To investigate the in vivo function of Gba[1] mutants, mouse models were generated by backcrossing the above homozygous mutant GCase mice into Saposin C deficient (C*) mice
The force field energy value for D409V was positive, i.e., unfavorable, 56.649 KJ/mole at pH 7.2, and more unfavorable, 72.925 KJ/mole at pH 5.5, relative to wild type (WT) and D409H. These results indicate that D409V has greater unfavorable energy environment than D409H that could result in their differential in vivo hydrolytic properties
Mutation at this position (D409V, D409H) leads to an unstable enzymes that predisposed them to protease degradation compared to WT
Summary
To investigate the in vivo function of Gba[1] mutants, mouse models were generated by backcrossing the above homozygous mutant GCase mice into Saposin C deficient (C*) mice. Unlike 9V mice that developed normally for over a year, 9V;C* pups had a lethal skin defect as did 0S;C* mice resembled that of 0S mice These variant Gaucher disease mouse models presented a mutation specific phenotype and underscored the in vivo role of Saposin C in the modulation of Gaucher disease. The presence of the N370S allele in Gaucher disease patients is associated with type 1 and highly variable visceral involvement[2,7,8]. A computation tool (Swiss-Pdb Viewer) can be applied to simulate GBA1 mutations and their dynamic alterations, side chain interactions and force field energy changes at the atomic resolution for better understanding mutant GCases protein function
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