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การศึกษาคุณสมบัติของ Iduronate-2-Sulfatase ของผู้ป่วยคนไทยที่เป็นโรค Hunter: พยาธิกาเนิดทางชีวเคมีและโมเลกุล (Characterization of Iduronate-2-Sulfatase in Thai Patients with Hunter Syndrome: Biochemical and Molecular Pathogenesis) |
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| รหัสดีโอไอ | |
| Creator | วรรัตน์ แช่มพัฒนชัย |
| Title | การศึกษาคุณสมบัติของ Iduronate-2-Sulfatase ของผู้ป่วยคนไทยที่เป็นโรค Hunter: พยาธิกาเนิดทางชีวเคมีและโมเลกุล (Characterization of Iduronate-2-Sulfatase in Thai Patients with Hunter Syndrome: Biochemical and Molecular Pathogenesis) |
| Publisher | Genetics Society of Thailand |
| Publication Year | 2556 |
| Journal Title | Thai Journal of Genetics |
| Journal Vol. | S.1 |
| Journal No. | S1 (Special Issue 1) |
| Page no. | 402 |
| Keyword | Hunter syndrome, iduronate-2-sulfatase, mutation, protein processing, 3D-structure |
| ISSN | 8578664 |
| Abstract | Mucopolysaccharoidosis Type II or Hunter syndrome is an inherited X-linked recessive disorder caused by the deficiency of a IDS gene coding iduronate-2 sulfatase (IDS) which results in the lysosomal accumulation of dermatan sulfate and heparan sulfate. As this accumulation continues, it interferes with certain cells and organs in the body and leads to a number of serious symptoms. Although this disease is rare, the number of newborns and children suffering from Hunter syndrome is significant. We have investigated enzyme changes and characterized IDS mutants in Thailand. Here, we identified the molecular basis of MPS II in Thailand from 26 Thai patients with Hunter syndrome. A total of 23 different mutations were identified from patient blood samples by using direct DNA sequencing and restriction fragment length polymorphism (RFLP). Eleven of these were novel and first discovered from Thai patients including p.R101C, p.D148V, p.G224A, p.K227E, p.E254X, p.Q310X, p.W337X, p.Y348X, c.440_442delinsTT, p.R468P, and c.720_731delins TTTCAGATGTTCTCCCCAG. In addition, we constructed the recombinant proteins of wild type and mutants which are severe phenotype (p.R88C, p.D148V, p.G224A, p.Y348X, p.R 468P, and p.R468Q) to study enzyme activity and protein processing in COS-7 cells. All mutants had low or no activity compared to the wild type. Anti-human IDS was used to study the processing of IDS. The wild type showed both a precursor form (76 kDa) and a mature form (55 kDa), whereas all mutants revealed only the precursor form except p.Y348X which had a truncated form at 50 kDa. Moreover, all mutants were modeled into the predicted three dimensional models of IDS using human arylsulfatase as a template. Most of mutants except p.D148V and p.Y348X were located near the active site (Cys84). These results indicate that these severe mutants may, at least in part, alter the protein processing and consequently lead to a decrease or absence in ID S activity, causing Hunter disease. This work was supported by Chulabhorn Research Institute, Thailand |
