Gaucher's Disease

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Lysosomes are one of the abounding organelles that make up a typical eukaryotic cell. A typical human cell contains hundreds of lysosomes but can be found in much higher quantities in cells more directly involved in exocytosis and cells of the immune system. Under a microscope, lysosomes can be observed as spherical-shaped, tiny membranous sacs composed of a single phospholipid bilayer that separates the acidic interior (pH 4.8-5) from the rest of the cell. The acidity is maintained by the continuous pumping of hydrogen ions into the cell, allowing for lysosomal hydrolases to carry out optimal function. Lysosomes act as the digestive agent within the cell breaking down cellular waste, proteins, fats, and carbohydrates into simpler molecules …show more content…
Patients of Gaucher’s disease possess Beta-Glucocerebrosidase enzymes that are deficient in their ability to breakdown glycolipid resulting in enlarged and irregularly shaped cells. Enlarged Gaucher’s cells can cause tissue invasion, posing threatening health problems such as hepatomegaly and splenomegaly as well as glycolipid deposits in the kidneys, lungs, bone marrow, and brain. The symptoms of this autosomal recessive disease, as Dr. Roscoe Brady discovered, are due to a mutation in the GBA 1 gene. After developing a diagnostic test that measured glucocerebrosidase activity in white blood cells, he discovered that the severity depends on the amount of functional beta glucocerebrosidase present. In fact, Gaucher’s isn’t just one disease but rather divided into three types based on the amount of functional enzyme present. Type 1 Gaucher’s Disease, containing some functional enzyme, is phenotypically characterized by null or mild effects. Type 2 and 3 Gaucher’s contain very little functional enzyme and result in neurological complications that can result in …show more content…
N370S mutation leads to Type 1 Gaucher’s, while L444P leads to type 2 or type 3 Gaucher’s disease. Patients with the N370S variant often bear distinct phenotypes than those with the L444P variant. That being said, the relationship between the phenotype and the genotype are not well understood. Individuals with identical genotypes for the GBA1 alleles may still experience drastic differences in phenotypes. Research carried out by molecular biologist Rosa Salvioli noticed the involvement of an additional protein that could contribute to this phenotypic variability. A specific sphingolipid activator protein called Saposin C is required for the breakdown of glucocerebroside. Saposin C promotes degradation of glycolipid on normal and mutated N370S (Type 1) enzymes when anionic phospholipids were abundant on the lysosomal membrane. Saposin C cannot promote binding to mutated N370S when the anionic phospholipids were low on the lysosomal membrane. Based off her findings, it was proposed that deficiencies in Saposin C could be another factor in the phenotypic variation amongst patients. Mutations to the GBA1 gene are central to Gaucher’s disease, however there are many related diseases that also affect the lysosome; known as lysosomal storage disorders. These diseases include Tay-Sachs and Mucolipidosis. Both of which result in an accumulation of

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