Gaucher’s Disease (GD) is an inherited lysosomal storage disorder. There are three types of Gaucher’s Disease, which differ in their severity and clinical presentation. Type I Gaucher’s Disease (GD1) is known as non-neuropathic Gaucher’s Disease because the nervous systems of GD1 patients are unaffected. By contrast, types II and III GD patients present with neurological symptoms. This website will focus on GD1, which is the most common lysosomal storage disorder discovered thus far.
Gaucher’s Disease is caused by inherited mutations in the GBA gene located on chromosome I. Mutations in the GBA gene cause the gene’s protein product, acid-beta glucocerebrosidase (GlcCerase), to misfold during the process in which the protein adopts the three-dimensional structure necessary to perform its function (Brady et al. 1965).
GlcCerase is an enzyme located in the lysosome, an organelle that contains many different enzymes that break down complex molecules. This enzyme is involved in the metabolism of sphingolipids. Specifically, GlcCerase converts the lipid glucosylceramide (GlcCer) to ceramide and glucose (National Institute of Health, 2010).
Ceramide eventually forms sphingolipids that become part of the plasma membrane and perform a variety of functions (National Institute of Health, 2010). When GlcCerase does not fold properly, as in Gaucher’s Disease, it cannot make ceramide from GlcCer, which results in an accumulation of GlcCer in the cell. GlcCer accumulation is the root cause of Gaucher’s Disease symptoms, which include enlargement of the spleen and liver, anemia, cancer, and bone abnormalities (Boven et al. 2004).
Treatment of Gaucher’s Disease comes in a variety of forms. One approach is to replace the misfolded GlcCerase with properly folded and functional GlcCerase, known as enzyme replacement therapy. If defective GlcCerase is replaced with functional GlcCerase, GlcCer accumulation will greatly decrease (Barton et al. 1991). Another approach is to remove protein degradation factors in the endoplasmic reticulum that cause GlcCerase to misfold in an attempt to promote proper folding of GlcCerase (Ron and Horowitz 2005). Gene therapy can also serve as a viable future therapeutic option. Studies have shown that inserting a wild-type (normal) GBA gene into mice and promoting its expression can cause a decrease in GlcCer accumulation due to an increased concentration of functional GlcCerase (Dahl et al. 2015).
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Barton NW et al. 1991. Replacement therapy for inherited enzyme deficiency–macrophage-targeted glucocerebrosidase for Gaucher’s disease. New England Journal of Medicine. 324 (21): 1464-1470. doi:10.1056/NEJM199105233242104
Boven LA et al. 2004. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Hematopathology. 122 (3): 359-369. doi:10.1309/BG5VA8JRDQH1M7HN
Brady RO, Kanfer JN, and Shapiro D. 1965. Metabolism of glucocerebrosides II: evidence of an enzvmatic deficiency in Gaucher’s Disease. Biochem Biophys Res Commun 18: 221-225. doi:10.1016/0006-291X(65)90743-6
Dahl M et al. 2015. Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice. Molecular Therapy. doi:10.1038/mt.2015.16
National Institute of Health. 2010. An overview of sphingolipid metabolism: from synthesis to breakdown. Advances in Experimental Medicine and Biology. 688: 1-23. PMID 20919643
Ron I and Horowitz M. 2005. ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Human Molecular Genetics. 14 (16): 2387-2398. doi:10.1093/hmg/ddi240