Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura
ABSTRACTCongenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studie...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
|
| Series: | Hematology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/16078454.2023.2269513 |
| _version_ | 1827790946087993344 |
|---|---|
| author | Zhitao Wang Xinhui Zhang Xueqin Lu Peng Peng Huiru Wang Shanglong Feng Li Zhou |
| author_facet | Zhitao Wang Xinhui Zhang Xueqin Lu Peng Peng Huiru Wang Shanglong Feng Li Zhou |
| author_sort | Zhitao Wang |
| collection | DOAJ |
| description | ABSTRACTCongenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 (1.9q34.2) in the patient’s ADAMTS13 gene. One mutation was a non-synonymous mutation (exon 5: c.A530G: p.Y177C), while the other was a nonsense mutation (exon 21: c.G2651A: p.W884X). Both mutations were found to be heterozygous. The patient’s parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient’s father was a heterozygote for the nonsense mutation of the ADAMTS13 gene (exon 21: c.G2651A: p.W884X), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C, and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments. |
| first_indexed | 2024-03-11T17:39:59Z |
| format | Article |
| id | doaj.art-9f4e810545d44a4abc5443cba4a2b889 |
| institution | Directory Open Access Journal |
| issn | 1607-8454 |
| language | English |
| last_indexed | 2024-03-11T17:39:59Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Hematology |
| spelling | doaj.art-9f4e810545d44a4abc5443cba4a2b8892023-10-18T11:34:34ZengTaylor & Francis GroupHematology1607-84542023-12-0128110.1080/16078454.2023.2269513Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpuraZhitao Wang0Xinhui Zhang1Xueqin Lu2Peng Peng3Huiru Wang4Shanglong Feng5Li Zhou6Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of ChinaDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of ChinaDepartment of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaABSTRACTCongenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 (1.9q34.2) in the patient’s ADAMTS13 gene. One mutation was a non-synonymous mutation (exon 5: c.A530G: p.Y177C), while the other was a nonsense mutation (exon 21: c.G2651A: p.W884X). Both mutations were found to be heterozygous. The patient’s parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient’s father was a heterozygote for the nonsense mutation of the ADAMTS13 gene (exon 21: c.G2651A: p.W884X), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C, and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.https://www.tandfonline.com/doi/10.1080/16078454.2023.2269513Congenital thrombotic thrombocytopenic purpuraADAMTS13 genenonsense mutationnon-synonymous mutationprotein conformation |
| spellingShingle | Zhitao Wang Xinhui Zhang Xueqin Lu Peng Peng Huiru Wang Shanglong Feng Li Zhou Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura Hematology Congenital thrombotic thrombocytopenic purpura ADAMTS13 gene nonsense mutation non-synonymous mutation protein conformation |
| title | Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura |
| title_full | Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura |
| title_fullStr | Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura |
| title_full_unstemmed | Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura |
| title_short | Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura |
| title_sort | novel adamts13 mutations in a patient with congenital thrombotic thrombocytopenic purpura |
| topic | Congenital thrombotic thrombocytopenic purpura ADAMTS13 gene nonsense mutation non-synonymous mutation protein conformation |
| url | https://www.tandfonline.com/doi/10.1080/16078454.2023.2269513 |
| work_keys_str_mv | AT zhitaowang noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura AT xinhuizhang noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura AT xueqinlu noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura AT pengpeng noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura AT huiruwang noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura AT shanglongfeng noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura AT lizhou noveladamts13mutationsinapatientwithcongenitalthromboticthrombocytopenicpurpura |