| Autor: |
Ramarajan MG; Manipal Academy of Higher Education, Manipal, India.; Institute of Bioinformatics, Bangalore, India.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Parthasarathy KTS; Manipal Academy of Higher Education, Manipal, India.; Institute of Bioinformatics, Bangalore, India., Gaikwad KB; Manipal Academy of Higher Education, Manipal, India.; Institute of Bioinformatics, Bangalore, India., Joshi N; Manipal Academy of Higher Education, Manipal, India.; Institute of Bioinformatics, Bangalore, India.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Garapati K; Manipal Academy of Higher Education, Manipal, India.; Institute of Bioinformatics, Bangalore, India.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Kandasamy RK; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA., Sharma J; Manipal Academy of Higher Education, Manipal, India.; Institute of Bioinformatics, Bangalore, India., Pandey A; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA. |
| Abstrakt: |
Hurler-Scheie syndrome (MPS IH/S), also known as mucopolysaccharidosis type I-H/S (MPS IH/S), is a lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase (IDUA) leading to the accumulation of glycosaminoglycans (GAGs) in various tissues, resulting in a wide range of symptoms affecting different organ systems. Postgenomic omics technologies offer the promise to understand the changes in proteome, phosphoproteome, and phosphorylation-based signaling in MPS IH/S. Accordingly, we report here a large dataset and the proteomic and phosphoproteomic analyses of fibroblasts derived from patients with MPS IH/S ( n = 8) and healthy individuals ( n = 8). We found that protein levels of key lysosomal enzymes such as cathepsin D, prosaposin, arylsulfatases (arylsulfatase A and arylsulfatase B), and IDUA were downregulated. We identified 16,693 unique phosphopeptides, corresponding to 4,605 proteins, in patients with MPS IH/S. We found that proteins related to the cell cycle, mitotic spindle assembly, apoptosis, and cytoskeletal organization were differentially phosphorylated in MPS IH/S. We identified 12 kinases that were differentially phosphorylated, including hyperphosphorylation of cyclin-dependent kinases 1 and 2, hypophosphorylation of myosin light chain kinase, and calcium/calmodulin-dependent protein kinases. Taken together, the findings of the present study indicate significant alterations in proteins involved in cytoskeletal changes, cellular dysfunction, and apoptosis. These new observations significantly contribute to the current understanding of the pathophysiology of MPS IH/S specifically, and the molecular mechanisms involved in the storage of GAGs in MPS more generally. Further translational clinical omics studies are called for to pave the way for diagnostics and therapeutics innovation for patients with MPS IH/S. |
