Annotated Bibliography

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

This study was the first to implement strategies for treatment of Gaucher’s Disease. Enzyme replacement of placental GlcCerase for defective GlcCerase resulted in an increased hemoglobin concentration, a decrease in acid phosphatase activity, and skeletal improvement. The results of this study paved the way for further treatment of Gaucher’s Disease.

Beutler et al. 1971. Beta-glucosidase activity in fibroblasts from homozygotes and heterozygotes for Gaucher’s Disease. American Journal of Human Genetics. 23 (1): 62-66. PMID 55811982

In one of the earliest studies of Gaucher’s Disease, Beutler et al. characterizes the differing levels GlcCerase activity among normal individuals, heterozygous carriers, and homozygous Gaucher’s Disease patients. Activity of GlcCerase was diminished in heterozygotes and homozygotes compared to normal individuals, but more severely in homozygotes.

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

The Gaucher cell phenotype is described in this 2004 study by Boven et al. Additionally, clinical manifestations of Gaucher’s Disease are also characterized, including hepatosplenomegaly, skeletal disease, anemia, increased metabolic rate, and loss of fat tissue. Immunohistochemistry analysis was used to identify lysosomal acid phosphatase, as well as other macrophage markers, in an attempt to identify a characteristic Gaucher cell phenotype.

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

This is the first paper published about the fundamental biological defect associated with Gaucher’s Disease – a deficiency in GlcCerase.

Brill NE et al. 1909. Primary splenomegaly of the Gaucher type: a report of four cases occurring in a single generation of one family. American Journal of Medical Sciences. 8: 849-857. Link to E-book.

Brill et al. reported splenomegaly present amount members of the same family. The patients showed no signs of malignancy, highlighting Gaucher’s Disease as a candidate. This report was among others that bridged the gap between the initial discovery of Gaucher’s Disease and the elucidation of a molecular mechanism.

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

Gene therapy invites a new therapeutic option toward curing Gaucher’s Disease, according to a 2015 study by Dahl et al. In a proof-of-principle experiment, these authors demonstrated that driving GBA expression through the use of a lentiviral vector in mice could reverse Gaucher symptoms.

Daniels LB and Glew RH. 1982. Beta-glucosidase assays in the diagnosis of Gaucher’s Disease. Clinical Chemistry. 28 (4): 569-577. PMID: 6804115

Daniels and Glew report on the various ways to diagnose Gaucher’s Disease and highlight beta-glucosidase assays as being the definitive approach to diagnosis.

Dvir H et al. 2003. X-ray structure of human acid-beta-glucocerebrosidase, the defective enzyme in Gaucher’s disease. EMBO Reports. 4 (7): 704-709. doi:10.1038/sj.embor.embor873

Dvir et al. report a solved X-ray crystallography structure of acid-beta-glucocerebrosidase (GlcCerase), the defective enzyme in Gaucher’s disease, in an attempt to further understand critical residues important to the enzyme’s mechanism of action. GlcCerase consists of three domains that interact to create the three-dimensional structure that allows acid-beta-glucocerebrosidase to hydrolyze GlcCer in the membrane. The active site of GlcCerase is located in domain III, which contains a TIM barrel domain, and consists of aromatic residues involved in substrate recognition and glutamic acid residues that participate in acid-base chemistry.

Gaucher PCE. 1882. De l’epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie [academic thesis]. Paris, France.

Gaucher’s thesis outlines the original discovery of the disease. Although this paper is not written in English (and a translation could not be located), it seemed appropriate to include this reference as it led to the name “Gaucher’s Disease”.

Gery I et al. 1981. Selective effects of glucocerebroside (Gaucher’s storage material) on macrophage cultures. Journal of Clinical Investigation. 68 (5): 1182-1189. doi:10.1172/JCI110363

The effects of GlcCer accumulation in macrophages were investigated in this publication in order to understand the manifestation of Gaucher’s disease at the cellular level. Accumulation of GlcCer resulted in a release of macrophage cellular content, including lymphocyte activating factor and lactate dehydrogenase. The release of these contents from macrophages leads to many of the clinical manifestations associated with Gaucher’s disease.

Goldblatt J. 1988. Type I Gaucher’s Disease. Journal of Medical Genetics. 25 (6): 415-418. PMID: 3294411

A general overview of Type I GD is outlined in this article. Symptoms and methods of diagnosis are highlighted and supplemented with images.

Kampine et al. 1967. Diagnosis of Gaucher’s Disease and Niemann-Pick Disease with small samples of venous blood. Science. 155 (3758): 86-88. doi:10.1126/science.155.3758.86

The biochemical nature and diagnostic principle underlying Gaucher’s Disease is described by Kampine et al. Leukocytes of Gaucher patients display a reduced ability to hydrolyze GlcCer, leading to the development of a diagnostic assay that assesses GlcCerase activity.

Lee L, Abe A, and Shayman JA. 1999. Improved inhibitors of glucosylceramide synthase. Journal of Biological Chemistry. 274 (21): 14662-14669. doi:10.1074/jbc.274.21.14662

GlcCer, the substrate of GlcCerase, is the precursor for many different sphingolipids. Defective GlcCerase results in the accumulation of GlcCer in cells, resulting in a wide variety of adverse phenotypic effects. Lee et al. describe possible inhibitors of glucosylceramide synthase, which could pave way to therapeutic options for Gaucher’s Disease.

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

Sponsored by the National Institute of Health, this manuscript addresses the normal biochemical context of the sphingolipid metabolism that is defective in Gaucher patients as a result of defective GlcCerase.

Pavlova EV et al. 2015. Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy. Journal of Pathology. 235: 113-124. doi:10.1002/path.4452

One of the characteristic signs of Gaucher’s Disease is B cell proliferation and associated malignancy as a result of the accumulation of GlcCerase substrates. Pavlova et al. induced mice with GlcCerase deficiency and observed associated B cell proliferation. In Gaucher-induced mice treated with an inhibitor of the first committed step of glycosphingolipid biosynthesis, the level of B cell malignancy declined.

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

Ron and Horowitz describe the molecular basis of Gaucher’s Disease in relation to the retention of misfolded GlcCerase in the endoplasmic reticulum. These authors assert that one of the factors that determine the severity of Gaucher’s disease is the degree of ER retention and proteasome degradation of defective GlcCerase.

Rosenbloom BE et al. 2005. Gaucher disease and cancer incidence: a study from the Gaucher Registry. Blood. 105: 4569 – 4572. doi:10.1182/blood-2004-12-4672

Accumulating GlcCer in macrophages occurs because of a high rate of erythrocyte phagocytosis. High stimulation of the immune system is predicted to increase the incidence of cancer in patients with Gaucher’s Disease. This study used the Gaucher Registry to assess the increased prevalence of malignancy among Gaucher patients.

Salvioli R et al. 2005. The N370S (Asn370→Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C. Biochem J. 390: 95-103. doi:10.1042/BJ20050325

A N370S mutation is by far the most common mutation present in Gaucher patients, directly affecting the mechanism of GlcCerase and its association with its activator Sap C. Salvioli et al. attempted to understand the mechanistic implications of this mutation in great detail. These authors report that the activity of mutated GlcCerase was dramatically affected by the concentration of anionic phospholipids in the assay mixture, implying that the positively charged asparagine residue at position 370 is critical to association with anionic phospholipids.

Sinha G. 2014. Gaucher’s disease oral therapy gets nods from FDA. Nature Biotechnology. 32: 970-971. doi:10.1038/nbt1014-970

In this brief article, Sinha describes two oral therapy options for the treatment of type I Gaucher’s Disease: Cerdelga and Zavesca. Both of these drug molecules serve as GlcCer synthase inhibitors and have been shown to decrease the accumulation of GlcCer in Gaucher patients.

Tan YL et al. 2014. ERdj3 is an endoplasmic reticulum degradation factor for mutant glucocerebrosidase variants linked to Gaucher’s Disease. Chemistry & Biology. 21: 967–976. doi:10.1016/j.chembiol.2014.06.008

Tan et al. propose a combinational therapy for the treatment of Gaucher’s Disease through knockout of ERdj3, a degredation factor of GlcCerase, and an enhancement of the ER calnexin profolding pathway. Together, these strategies promote the proper folding of GlcCerase, resulting in less accumulation of GlcCerase.

Weinrab NJ et al. 2013. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis. 36: 543-553. doi:10.1007/s10545-012-9528-4

Weinrab et al. evaluated the effectiveness of imiglucerase treatment in terms of clinical outcomes for ten years. It was determined that patients responded favorably to imiglucerase treatment as compared to the control group. Parameters for analysis included bone pain, thrombocytopenia, hepatomegaly, and anemia.

Yang C et al. 2015. Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation. PNAS. 112 (4): 1137-1142. doi:10.1073/pnas.1424288112

Mutations in the GBA gene result in a misfolded and defective GlcCerase. These researchers used heat shock protein complexes specific to mutant GlcCerase to propose a treatment for Gaucher’s Disease that involves targeting and degrading the misfolded protein.

Zimran A et al. 1991. High frequency of the Gaucher Disease mutation at nucleotide 1226 among Ashkenazi Jews. Am. J. Hum. Genet. 49: 855-859. PMID 1897529

This study aimed to determine the frequency of the mutation associated with Gaucher’s Disease – a N370S mutation of the GBA gene. The authors screened a population of Ashkenazi Jews and determined a 4.7% rate of disease incidence, 8.9% carrier rate, and a 1:450 birth incidence, which is 100 times greater than the general population.