This technology includes mouse models for both mild and severe Gaucher disease. Gba-L444P and Gba-L444P A456P mice, respectively, carry common gene mutations for milder or severe Gaucher disease, a lysosomal storage disease. Gaucher Disease is caused by mutations in the lysosomal enzyme, glucocerebrosidase. Deficiency of enzyme activity leads to the accumulation of glucosylceramide in liver, spleen, bone, and in the most severe cases, the central nervous system. A single insertion mutagenesis procedure was used to introduce mutations found in human Gaucher Disease into the mouse glucocerebrosidase gene. Mice homozygous for the double mutation L444P A456P had little enzyme activity and accumulated glucosylceramide in brain and liver. Mice homozygous only for the L444P mutation seen in a milder chronic form of Gaucher disease had higher levels of enzyme activity and did not accumulate glucosylceramide in brain and liver. Mice with either point mutation died within 48 h of birth.
The mice can be useful for the study of disease pathogenesis and for devising new therapies, including gene transfer therapy, enzyme replacement therapy, cell replacement therapy and small molecule therapy (synthesis inhibitors, enzyme activators).
Gba-444 knock-in mice carrying the milder L444P Gaucher disease mutation (Gba-L444P mice) and the severe Gaucher disease mutation Gba-L444P A456P mice).