Children with I-cell disease (“I” for “Inclusion bodies”) synthesize perfectly g

Question

Children with I-cell disease (“I” for “Inclusion bodies”) synthesize perfectly good lysosomal enzymes, but secrete them outside the cell instead of sorting them to lysosomes. The mistake occurs because the cells lack GlcNAc-P-transferase, which is required to create the mannose-6-phosphate marker that is essential for proper delivery of hydrolytic enzymes into the lysosomes. In principle, I-cell disease could also be caused by deficiencies in two other proteins: the phosphoglycosidase that removes GlcNAc to expose mannose-6-phosphate, and the mannose 6-phosphate receptor itself.



These three potential kinds of I-cell disease could be distinguished by the ability of various culture supernatants to correct defects in mutant cells. Imagine that you have cell lines from three hypothetical I-cell patients (A, B, and C) that give the results below:



The supernatant from normal cells corrects the defects in B and C, but not the defect in A.



Hurler’s disease is due to the failure to make one particular lysosomal enzyme. The supernatant from A corrects the defect in Hurler’s cells, but supernatants from B and C do not.



If the supernatants from the mutant cells are first treated with the phosphoglycosidase that removes GlcNac, then the supernatants from A and C correct the defect in Hurler’s cells, but the supernatant from B does not.





From these results, deduce the nature of the defect in each of the three mutant cell lines (A, B, C). State your reasoning.

Explanation / Answer

There are 3 mutations: No GlcNAc-P-transferase (can be corrected by adding GlcNAc-P-transferase) No phosphoglycosidase (can be corrected by adding phosphoglycosidase) No mannose 6-phosphate receptor (can never be corrected) You actually need to deduce 4 things for this problem: mutations in A, B, C, and Hurler's cells. The first clue tells us that A must have a receptor problem. We know this because normal cells have both normal GlcNAc-P-transferase and phosphoglycosidase. We can correct cells that lack these enzymes, but not cells that lack the receptor. Since A is not corrected in the presence of the good enzymes, it must have a receptor problem. So, B and C must be either GlcNAc-P-transferase or phosphoglycosidase deficient. The second clue confirms that A lacks the receptor since it's supernatant corrects the Hurler's defect and thus has both enzymes. Since B and C do not correct the defect, Hurler's cells must have a problem with phosphoglycosidase. This is the only way to account for both B and C not working. If one worked, then the problem would be with GlcNAc-P-transferase. The third clue states that after adding phosphoglycosidase, C works. This means that C must have GlcNAc-P-transferase since phosphoglycosidase activity occurs after GlcNAc-P-transferase activity. Since B does not work, it must lack GlcNAc-P-transferase activity because the supplemented phosphoglycosidase had nothing to modify. To summarize: A- Receptor defect B- GlcNAc-P-transferase defect C- phosphoglycosidase defect

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