Dislocated Enzyme Causes Hereditary Lysosomal Storage Disease

The molecular mechanism that underlies the hereditary lysosomal disorder mucolipidosis III has been traced to a mutation that causes a specific enzyme to leach out of the Golgi apparatus and into the cell where it is degraded by the lysosome or released into the medium.

Mucolipidosis III results from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase, which phosphorylates target carbohydrate residues on N-linked glycoproteins. Without this phosphorylation, the glycoproteins are not shipped to the lysosomes, and they escape outside the cell. This rare disorder is characterized by skeletal and heart abnormalities, which can result in a shortened lifespan.


Investigators at Washington University School of Medicine (St. Louis, MO, USA) reported in the February 18, 2014, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that the Golgi-localized enzyme normally mediates the first step in the synthesis of the mannose 6-phosphate recognition marker on lysosomal acid hydrolases, and loss of this function results in impaired lysosomal targeting of these acid hydrolases and decreased lysosomal degradation.

They described two missense mutations in the N-terminal cytoplasmic tail of the alpha subunit of the phosphotransferase that impair retention of the catalytically active enzyme in the Golgi complex. This results in mistargeting of the mutant phosphotransferases to lysosomes, where they are degraded, or to the cell surface and release into the medium. As a result, children with this disorder have lysosomal proteins in their blood at levels 10 to 20 times higher than normal.

“Type III patients live into adulthood, but they are very impaired,” said senior author Dr. Stuart A. Kornfeld, professor of medicine at Washington University School of Medicine. “They have joint and heart problems and have trouble walking. In the most severe form, type II, there is zero activity of phosphotransferase. None of the 60 enzymes are properly tagged, so these patients’ lysosomes are empty. Children with type II usually die by age 10.”

“Under normal circumstances, the phosphotransferase moves up through the Golgi, but then it is recaptured and sent back,” said Dr. Kornfeld. “Our study shows that the mutant phosphotransferase moves up but is not recaptured. Ironically, the phosphotransferase that escapes the Golgi ends up in the lysosomes, where it is degraded. There is a lot of interest and study about how cells distribute proteins to the right parts of the cell. Our study has identified one of the few examples of a genetic disease caused by the misplacement of a protein. The protein functions just fine. It just does not stay in the right place. We think there must be some protein in the cell that recognizes phosphotransferase when it gets to the end of the Golgi, binds it and takes it back. Now we are trying to understand how that works.”

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