The study, “Combination of acid β-glucosidase mutation and Saposin C deficiency in mice reveals Gba1 mutation dependent and tissue-specific disease phenotype,” was published in the journal Scientific Reports.
Gaucher disease is caused by mutations in the GBA gene, leading to a loss of functional beta-glucocerebrosidase (the protein for which GBA provides instructions) and, in turn, promotes the accumulation of complex fat molecules that can be toxic to cells.
Both the GBA enzyme and saposin C work in lysosomes — tiny vesicles inside cells that work as “recycling centers” — to help break down unnecessary molecules and cellular components. In these lysosomes, saposin C can protect GBA from being recycled itself, which allows the enzyme to do its job more effectively.
Previous studies in mice demonstrated that the loss of saposin C could lead to slowly progressive damage of the central nervous system and even severe neurological disease.
Based on these findings, researchers at the Cincinnati Children’s Hospital Medical Center decided to explore the impact of mutations in saposin C’s coding gene in Gaucher disease.
To find this out, they genetically engineered mouse models with four different mutations in the GBA gene — N370S, V394L, D409H, and D409V — which had previously been associated with different types of Gaucher disease.
All the mice showed lower GBA enzyme activity, but three of them didn’t have many other disease-related symptoms. These mice had no major nervous system problems, and they had a normal lifespan.
Mice that carried the N370S mutation had more severe disease, with mouse pups dying after one or two days due to defects in their skin, further demonstrating the variable impact of Gaucher-causing mutations.
Next, researchers generated new mice carrying the above-mentioned GBA mutations but also a mutation in the gene providing instructions for saposin C, which induced the loss of any functional saposin C protein.
Mice with N370S or D409V mutations that also lacked saposin C died within 24 hours from skin defects, and mice that had any of the other two mutations also had shorter lifespans (seven weeks for V394L and 13 months for D409H).
The mice also had fewer functional GBA enzymes, as expected, and those that survived had more nervous system damage that appeared earlier in life.
These results show that the lack of functional saposin C exacerbates Gaucher disease manifestations beyond what would occur if only a mutation in GBA was present, with variable effects, the researchers said.
Further analyses also revealed that different genetic mutations were associated with variable organ involvement. Mice that carried V394L mutation in addition to lacking saposin C had more irregular cells in their liver and lungs than mice with the D409H mutation. Researchers believe these diverse effects are due to specific physical changes each mutation causes in the GBA enzyme, particularly concerning how it interacts with its substrates and saposin C.
“The results of these studies provide insights to [GBA enzyme] mutations and their correlation with tissue specific variation in substrate accumulation and disease [manifestations],” the researchers wrote, adding that this study “lays the groundwork for comparative human studies in exploring genotype and [symptoms severity] correlations in Gaucher disease.”