A 5-year-old boy with eight months of recurrent middle ear and upper respiratory infections has hepatosplenomegaly. Cultured skin fibroblasts show inclusion bodies and deficiency in N-acetylglucosamine-1-phosphotransferase; enzymes are secreted in large amounts into the culture medium and are unable to target which organelle?

A 5-year-old boy with eight months of recurrent middle ear and upper respiratory infections has hepatosplenomegaly. Cultured skin fibroblasts show inclusion bodies and deficiency in N-acetylglucosamine-1-phosphotransferase; enzymes are secreted in large amounts into the culture medium and are unable to target which organelle?

• A. Lysosomes
• B. Nucleus
• C. Golgi apparatus
• D. Endoplasmic reticulum

Answer: (A)

In this scenario, the key idea is how lysosomal enzymes get to the lysosome. Normally, enzymes destined for lysosomes receive a mannose-6-phosphate tag added in the Golgi by N-acetylglucosamine-1-phosphotransferase. This tag is recognized by mannose-6-phosphate receptors and directs the enzymes to lysosomes. If this tagging step is defective, those hydrolases are not delivered to lysosomes and are instead secreted outside the cell. The lysosomes then lack many digestive enzymes, causing substrates to accumulate inside, which leads to inclusion bodies in cultured fibroblasts and features like hepatosplenomegaly and recurrent infections. Thus, the organelle that cannot be targeted is the lysosome.

In this scenario, the key idea is how lysosomal enzymes get to the lysosome. Normally, enzymes destined for lysosomes receive a mannose-6-phosphate tag added in the Golgi by N-acetylglucosamine-1-phosphotransferase. This tag is recognized by mannose-6-phosphate receptors and directs the enzymes to lysosomes. If this tagging step is defective, those hydrolases are not delivered to lysosomes and are instead secreted outside the cell. The lysosomes then lack many digestive enzymes, causing substrates to accumulate inside, which leads to inclusion bodies in cultured fibroblasts and features like hepatosplenomegaly and recurrent infections. Thus, the organelle that cannot be targeted is the lysosome.