Molecular Basis of Disease

Gaucher’s Disease is an inborn error of metabolism passed from generation to generation through an autosomal recessive mode of inheritance. It is caused by a mutation in the GBA gene that results in a defective GlcCerase, resulting in a buildup of the GlcCer substrate (Brady et al. 1965). GlcCerase is a lysosomal enzyme, explaining the cellular localization of GlcCer in patients with Gaucher’s Disease. The most prevalent GBA mutation among type I Gaucher patients is a missense mutation that results in an N370S substitution (Dvir et al. 2003).

GlcCerase Structure

Dvir et al. crystallized GlcCerase in 2003, which paved the way for understanding the molecular mechanism of Gaucher’s Disease. X-ray crystallography data showed that GlcCerase contained three domains. Notably, the catalytic domain III of GlcCerase resembles a TIM barrel structure and glycosylation is present in domain I (Dvir et al. 2003). Dvir et al. also employed site-directed mutagenesis modeling and suggested that E235 serves as the acid-base catalyst while E340 serves as the nucleophile for GlcCerase’s hydrolysis reaction (Dvir et al. 2003). The authors placed the three-dimensional structure of GlcCerase in conversation with the most common mutation in type I Gaucher patients: an N370S substitution. They proposed that position 370 is too far away from domain III to be involved in direct catalysis, so this substitution may have an effect on the association of GlcCerase to other biomolecules that enhance its catalytic activity (Dvir et al. 2003).

X-ray structure of GlcCerase. The location of the most common mutation that results in type I Gaucher's Disease (N370S) is highlighted. The domains of GlcCerase are also outlined. Source: Dvir et al. 2003.
X-ray structure of GlcCerase. The location of the most common mutation that results in type I Gaucher’s Disease (N370S) is highlighted. The domains of GlcCerase are also outlined. Source: Dvir et al. 2003.

Effects of Mutation

Salvioli et al. investigated the effects of defective GlcCerase with an N370S substitution and proposed a molecular mechanism for reduced GlcCerase activity. This team of scientists previously demonstrated that saposin C is an activator of GlcCerase and enhances the ability of normal GlcCerase to associate with the plasma membrane (Salvioli et al. 2005). However, under conditions of reduced lipid content similar to the lysosome, N370S GlcCerase associates with the plasma membrane to a lesser extent than normal GlcCerase even after interaction with a saposin C activator (Salvioli et al. 2005). This phenomenon was observed through co-localization experiments involving murine antibodies. The nature of the amino acid substitution likely explains this phenomenon – a positively charged Asn residue at position 370 allows GlcCerase to more readily associate with the negatively charged plasma membrane than a polar Ser residue. A relative activity of 10% was observed for N370S GlcCerase compared to normal GlcCerase (Salvioli et al. 2005). The authors were also careful to point out that the levels of GlcCerase, saposin C and anionic phospholipid content were similar in wild type cells and Gaucher cells (ie. cells with a high concentration of GlcCer), thus attributing the differential association between GlcCerase and its activators to the substitution.

Part A: Colocalization experiments by Salvioli et al. Under normal cellular conditions, GlcCerase and SapC activator colocalize. Source: Salvioli et al. 2005
Part A: Colocalization experiments by Salvioli et al. Under normal cellular conditions, GlcCerase and SapC activator colocalize. Source: Salvioli et al. 2005
Part B: Colocalization experiments by Salvioli et al. Gaucher's Disease results in a lack of colocalization between GlcCerase and Sap C activator. Source: Salvioli et al. 2005
Part B: Colocalization experiments by Salvioli et al. Gaucher’s Disease results in a lack of colocalization between GlcCerase and Sap C activator. Source: Salvioli et al. 2005

Cellular Trafficking Problems

GlcCerase is synthesized on an endoplasmic reticulum-bound polyribosome and is subsequently glycosylated for trafficking to the lysosome. Ron and Horowitz attribute the severity of Gaucher’s Disease to the ability for the endoplasmic reticulum to retain GlcCerase, as opposed to being degraded by the proteasome (Ron and Horowitz 2005). This is most likely due to the improper folding intrinsic to defective GlcCerase, and this improper folding is detected by ER quality control measures, including the ubiquitin-proteasome system (Ron and Horowitz 2005). Differential levels of ER retention were confirmed by lower levels of GlcCerase in Gaucher cells than normal cells. This phenomenon was also supported by the association of mutant GlcCerase with calnexin, a protein localized in the endoplasmic reticulum (Ron and Horowitz 2005).


The mechanism through which the symptoms of Gaucher’s Disease present in a patient is a difficult concept to investigate. The tell-tale clinical presentation of Gaucher cells (ie. macrophages with large concentrations of GlcCer) was well documented, but the pathophysiology still remained unclear. Gery et al. studied how an accumulation of GlcCer in macrophages leads to physiological effects at the cellular level (Gery et al. 1981). Using a mouse model, these scientists observed a high concentration of lymphocyte activating factor released from macrophages. When GlcCer was added to epithelial cells, however, no cytotoxic effects were detected (Gery et al. 1981). This was the first study that evaluated the pathophysiology of Gaucher’s Disease.

The pathophysiology of Gaucher’s Disease was also addressed in a recent study by Pavlova et al. As part of normal intracellular turnover, macrophages recycle leukocytes of the immune system and engulf large quantities of GlcCer present on the plasma membrane (Pavlova et al. 2014). When GlcCerase of macrophages is defective, GlcCer accumulates in these cells and presents with the clinical manifestation of Gaucher cells. The result of GlcCer accumulation is a release of cytokines and chemokines, as well as macrophage invasion of tissues of other organ systems (Pavlova et al. 2014). A consequence of high levels of cytokine release is an activation of the inflammatory response in different tissues, explaining the clinical presentation of hepatosplenomegaly. Another consequence is a higher likelihood of developing lymphoma. Pavlova et al. reported a decreased rate of lymphoma and B cell proliferation among mice treated with GENZ 112638, an inhibitor of GlcCer synthesis (Pavlova et al. 2014). Their results also demonstrated a role for sphingolipids in the propensity of B cell proliferation and other Gaucher-associated symptoms (Pavlova et al. 2014).

To learn more about Gaucher’s Disease, visit the following pages:

Treatments and Disease Management

Conclusions and Proposals for Future Work

6 Replies to “Molecular Basis of Disease”

  1. This is a very helpful website on Gaucher’s disease! Why does the liver specifically gets inflamed as GlcCer accumulates in macrophages? It’s interesting to me since there are residential macrophages all over the body– is there an additional element of the pathophysiology that makes the liver more susceptible to inflammation and enlargement?

    1. Interesting questions, Rebecca. It’s funny that you ask these questions because I was wondering the same thing as I was perusing the Gaucher literature. I was really looking for a paper that clearly outlined the pathophysiology, but I did not come across one. I tried to string concepts together as best I could. I believe that because the liver and spleen are organs that are involved in detoxification, they may accrue macrophages at an increased rate, leading to inflammation and enlargement caused by accumulating GlcCer. Thanks!

  2. Hi Zach,

    Great job on your disease! I noticed that you mentioned that macrophages can invade the tissues of patients with Gaucher’s disease. Excessive accumulation of macrophages has been shown to cause a wide variety of diseases, including obesity and atherosclerosis, so do you know if patients with Gaucher’s are particularly prone to any of these diseases? You did mention that these patients are at increased risk for cancer, so do you think this might also be related to the macrophage accumulation? Or perhaps this might be caused by the release of cytokines and chemokines, which we know play important signaling roles in the cell?

    On a similar note, you mentioned that the telltale sign of the disease is increased concentrations of GlcCer in macrophages. Does this cause any effects in the macrophages themselves? Lipid accumulation, like the over-accumulation of any macromolecule, is likely detrimental to the cell, so does this manifest with clinical symptoms? If these symptoms do exist, do you think they could be cured by a treatment like PDMP homologues, which are known to inhibit GlcCer synthase, thus reducing the concentration of free GlcCer?

    1. Thanks for your thoughts, Mike. I will answer each of your questions in turn. 1) I have read some papers suggesting that glycosphingolipids may be involved in the induction of insulin resistance, which we learned could lead to Alzheimer’s Disease. This would also relate to your point about obesity relating to Gaucher’s Disease. 2) According to the Pavlova paper, the release of cytokines stimulates clonal expansion of B cells, but the link between this is unknown. 3) The effect of GlcCer accumulation on macrophages themselves leads to the effects of increased release of cytokines and cheekiness. 4) Yes, an inhibition of GlcCer synthase is a treatment option for Gaucher’s Disease, which was explained in the treatment section of my website. Thanks!

  3. Hey Zach,

    Great paper! I was looking through the Pavlova et. al paper, and was likewise curious as to the different types of gauchers disease they refer to, depending on the activity of the central nervous system. I was specifically curious as to how the aggregation of GlcCer by macrophages might manage to affect the behavior and activity of neural cells, and what (if any) treatments could be provided for such a case. Additionally, given that the resultant cytokine storms appear to be the most motile source of damage into other organelles, are there any reasons why cytokine aggregation inhibitors such as angiotensin converting enzyme (ACE) could not be used to mitigate some of the emergent effects of the disease, if not necessarily addressing the cause?

    1. Regarding the neural effects of cytokine release, I can’t really answer this question. As mentioned on my title page, I focused on type 1 Gaucher’s Disease, which does not affect the nervous systems of patients. I thought it would be best to only address type 1 since it is the most common lysosomal storage disease and I could go more in-depth about one type as opposed to covering all the types. Regarding your second question, cytokines are very important in regulating the normal inflammation response. Inflammation is a key component of innate immunity, so shutting down the inflammation pathway completely would be very detrimental. Also, the cytokine pathophysiology is still under investigation, so more information should be out in the near future. Thanks!

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