Dislocated Enzyme Causes Hereditary Lysosomal Storage Disease
By LabMedica International staff writers Posted on 03 Mar 2014 |
Image: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Photo courtesy of Dr. Eline van Meel, Washington University School of Medicine).
Image: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Photo courtesy of Dr. Eline van Meel, Washington University School of Medicine).
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.”
Related Links:
Washington University School of Medicine
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.”
Related Links:
Washington University School of Medicine
Latest BioResearch News
- Genome Analysis Predicts Likelihood of Neurodisability in Oxygen-Deprived Newborns
- Gene Panel Predicts Disease Progession for Patients with B-cell Lymphoma
- New Method Simplifies Preparation of Tumor Genomic DNA Libraries
- New Tool Developed for Diagnosis of Chronic HBV Infection
- Panel of Genetic Loci Accurately Predicts Risk of Developing Gout
- Disrupted TGFB Signaling Linked to Increased Cancer-Related Bacteria
- Gene Fusion Protein Proposed as Prostate Cancer Biomarker
- NIV Test to Diagnose and Monitor Vascular Complications in Diabetes
- Semen Exosome MicroRNA Proves Biomarker for Prostate Cancer
- Genetic Loci Link Plasma Lipid Levels to CVD Risk
- Newly Identified Gene Network Aids in Early Diagnosis of Autism Spectrum Disorder
- Link Confirmed between Living in Poverty and Developing Diseases
- Genomic Study Identifies Kidney Disease Loci in Type I Diabetes Patients
- Liquid Biopsy More Effective for Analyzing Tumor Drug Resistance Mutations
- New Liquid Biopsy Assay Reveals Host-Pathogen Interactions
- Method Developed for Enriching Trophoblast Population in Samples