| A phenotype-genotype correlation of ADAMTS13 mutations in congenital TTP patients treated in the United Kingdom. | |
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MedLine Citation:
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PMID: 22783805 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background: ADAMTS13 mutations play a role in thrombotic thrombocytopenic purpura (TTP) pathogenesis. Objectives: We sought to establish a phenotype-genotype correlation in a cohort of congenital TTP patients. Patients/Methods: Clinical history and ADAMTS13 activity, antigen and anti-ADAMTS13 antibody assays were used to diagnose congenital TTP, whilst DNA sequencing and in vitro expression was performed to identify the functional effects of the ADAMTS13 mutations responsible. Results: Seventeen (11 novel) ADAMTS13 mutations were identified in 17 congenital TTP patients. All had severely reduced ADAMTS13 activity and antigen levels at presentation. Six pregnancy-associated and six childhood TTP patients were homozygous or compound heterozygous for ADAMTS13 mutations located in the metalloprotease (MP), Cys-rich, spacer and/or distal TSP1 domains. The adults had TTP precipitated by pregnancy and had overall higher antigen levels (median 30ng/ml, range <10-57ng/ml) than the children (median 14ng/ml, range <10-40ng/ml). Presentation in the neonatal period was associated with more intensive treatment requirements. The two neonates with the most severe phenotype had mutations in the first thrombospondin repeat of ADAMTS13 (p.R398C, p.R409W and p.Q436H). Using transfected HEK293T cells, we have shown that p.R398C and p.R409W block ADAMTS13 secretion, whereas p.Q436H allows secretion at reduced levels. Conclusions: This study confirms the heterogeneity of ADAMTS13 defects and an association between ADAMTS13 genotypes and TTP phenotype. © 2012 International Society on Thrombosis and Haemostasis. |
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Authors:
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R S Camilleri; M Scully; M Thomas; I J Mackie; R Liesner; W J Chen; K Manns; S J Machin |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-7-11 |
Journal Detail:
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Title: Journal of thrombosis and haemostasis : JTH Volume: - ISSN: 1538-7836 ISO Abbreviation: - Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-7-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101170508 Medline TA: J Thromb Haemost Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 International Society on Thrombosis and Haemostasis. |
Affiliation:
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Haemostasis Research Unit, Department of Haematology, University College London School of Medicine Department of Biomedical Sciences, School of Life Sciences, University of Westminster Department of Haematology, University College London Hospitals NHS Foundation Trust and Department of Haematology, Great Ormond Street Hospital for Sick Children, London, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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