Gaucher disease, the most common lysosomal storage disease, is an inherited metabolic disorder in which harmful quantities of the lipid glucocerebroside accumulate in the spleen, liver, lungs, bone marrow and in rare cases in the brain, due to a deficiency of the enzyme glucocerebrosidase (Gba) that catalyses the first step in the biodegradation of glucocerebrosides. Type 1 Gaucher disease is the most common and is distinguished from the other forms of the disease, types 2 and 3, by the lack of neurologic involvement. The clinical features of Type 1 are heterogeneous, vary broadly in clinical severity and affect many organ systems. The major disease manifestations include enlarged spleen and liver, bone lesions, hematologic abnormalities and lung involvement. The disease has also been associated with a sustained inflammatory reaction. Gaucher disease is most prevalent in the Ashkenazi Jewish population with an incidence of approximately 1 in 450 persons while in the general public the incidence is 1 in 100,000. There are an estimated 30,000 Gaucher disease patients world-wide with approximately 3000 patients currently receiving enzyme replacement therapy which has been shown to be highly effective in treatment of the disease. The cost of therapy is approximately $100,000-$300,000 annually and is a life-long treatment, which makes the case for affordable new therapies urgent.
The etiology of the disease has been difficult to study due to the absence of viable mouse models for the disease, as a complete disruption of the glucocerebrosidase (Gba) gene results in rapid neonatal death. In an attempt to produce a viable model scientists at the NIDDK introduced a human Gaucher disease point mutation, L444P, into the mouse Gba gene in order to cause a partial enzyme deficiency (J. Clin. Invest. (2002) 109, 1215-1221; Proc. Natl. Acad. Sci. USA (1998) 95, 2503-2508).
The mice exhibit a partial glucocerebrosidase deficiency (15-20% of normal activity), without bulk accumulation of glucosylceramide or the presence of Gaucher cells. The mice demonstrate other clinical features of Gaucher disease, including multisystem inflammation, B cell hyperproliferation, skin abnormalities, anemia and lymphadenopathy. These mice provide a useful model for studying certain aspects of Gaucher disease pathology and in evaluating new therapeutic treatments.