Document Detail

A phenotype-genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom.
MedLine Citation:
PMID:  22783805     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: ADAMTS13 mutations play a role in thrombotic thrombocytopenic purpura (TTP) pathogenesis.
OBJECTIVES: 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, and DNA sequencing and in vitro expression were 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 patients with pregnancy-associated TTP and six patients with childhood TTP were homozygous or compound heterozygous for ADAMTS13 mutations located in the metalloprotease (MP), cysteine-rich, spacer and/or distal thrombospondin type 1 domains. The adults had TTP precipitated by pregnancy, and had overall higher antigen levels (median, 30 ng mL(-1) ; range, < 10-57 ng mL(-1) ) than the children (median, 14 ng mL(-1) ; range, < 10-40 ng mL(-1)). 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 type 1 motif 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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  10     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-04     Completed Date:  2013-02-07     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  1792-801     Citation Subset:  IM    
Copyright Information:
© 2012 International Society on Thrombosis and Haemostasis.
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MeSH Terms
ADAM Proteins / genetics*
Blotting, Western
Case-Control Studies
Child, Preschool
Great Britain
Infant, Newborn
Purpura, Thrombotic Thrombocytopenic / genetics*
Grant Support
FS/10/013/28073//British Heart Foundation; G0800671//Medical Research Council; PG/09/017//British Heart Foundation; //Arthritis Research UK; //Medical Research Council
Reg. No./Substance:
EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/ADAMTS13 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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