I Cell disease

As promised, here are the answers! You will find two sets of answers. The first ones are the brief "official" ones. The second set are my own; they are a bit lengthier.

1. The enzymes lack the mannose-6-phosphate markere which would direct them from the endoplasmic reticulum (ER) to the lysosome and so are secreted via the constitutive pathway.

2. Some lysosomal enzymes would be secreted into the extracellular matrix since the receptors which mediate the transport of these proteins would be saturated by the exogenously applied mannose-6-phosphate.

3. In the gene for some other protein. The enzyme most likely to be affected is one for the modification of the polysaccharide moeity added to the protein in the ER and Golgi complex. It is likely that all lysosomal proteins will be similarly affected.

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1. The problem resides in the fact that enzymes are produced but are mislocated. In normal circumstances, enzymes leaving the Golgi complex are given a molecular marker in the form of an oligosaccharide containing a mannose-6-phosphate residue. The latter is produced by a phosphotransferase and is recognised by a receptor on the Golgi membrane. Proteins containing this marker are bound and directed to lysosomes. Patients suffering from I-cell disease lack this phosphotransferase and thus the attached mannose is not modified to mannose-6-phosphate. Consequently the receptors on the Golgi membrane, being highly discriminating, do not recognise the enzymes. Thus, they are not stored in the lysosomes on leaving the Golgi complex, but are expelled out of the fibroblasts into the extracellular medium.

2. Enlarged lysosomes containing high concentrations of mannose 6-phosphate could be observed in the fibroblasts. The mannose-6-phosphate would diffuse into the fibroblasts and interfere with the transport mechanism of the enzymes from the Golgi complex to the lysosomes. The mannose-6-phosphate molecules may be wrongly identified as proteins containing the oligosaccharide and bound into vesicles destined to form lysosomes. Therefore lysosomes in the fibroblasts would be enlarged as they would contain a large quantity of mannose-6-phosphate and a relatively low concentration of enzymes.

3. It may be deduced that the defect is not in the gene coding for ß-glucoronidase, but in the gene for some other protein. This is because biochemical analysis revealed that ß-glucoronidase is indeed produced, but is only mislocated. Therefore the defect must be in the gene coding for another protein responsible for the transport and stocking of ß-glucoronidase.

4. Lysosomes are organelles containing digestive enzymes capable of digesting all major classes of biological macromolecules. These enzymes are acid hydrolases needed to digest foreign materials brought into the cell for nutrition by endocytosis and also for autolysis, i.e. the destruction of molecules or cellular structures that are damaged or no longer needed. In some cases, lysosomes may also release their enzymes outside the cell by exocytosis for extracellular digestion.

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