|Title||A phenotype–genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom|
|Authors||Camilleri, R., Scully, M., Thomas, M., Mackie, I.J., Liesner, R., Chen, W., Manns, K. and Machin, S.J.|
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.
|Journal||Journal of Thrombosis and Haemostasis|
|Journal citation||10 (9), pp. 1792-1801|
|Digital Object Identifier (DOI)||doi:10.1111/j.1538-7836.2012.04852.x|