Combination of acid β-glucosidase mutation and Saposin C deficiency in mice reveals Gba1 mutation dependent and tissue-specific disease phenotype
- PMID: 30944381
- PMCID: PMC6447580
- DOI: 10.1038/s41598-019-41914-7
Combination of acid β-glucosidase mutation and Saposin C deficiency in mice reveals Gba1 mutation dependent and tissue-specific disease phenotype
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.
Conflict of interest statement
The authors declare no competing interests.
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References
-
- Grabowski, G. A., Petsko, G. A. & Kolodny, E. H. In The Online Metabolic and Molecular Bases of Inherited Diseases (eds Valle, D. et al.) Ch. 146, (The McGraw-Hill Companies, Inc., 2010).
-
- Grabowski, G. A. et al. In The Metabolic and Molecular Bases of Inherited Diseases (eds Scriver, C. R. et al.) (McGraw-Hill, 2006).
-
- Petrucci, S., Consoli, F. & Valente, E. M. Parkinson Disease Genetics: A “Continuum” From Mendelian to Multifactorial Inheritance. Curr Mol Med (2014). - PubMed
-
- Beutler, E. & Grabowski, G. A. In The Metabolic and Molecular Basis of Inherited Disease Vol. III (eds Scriver, C. R., Beaudet, A. L., Sly, W. S., & Valle, D.) 3635–3668 (McGraw-Hill, 2001).
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