A phenotype–genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom

Camilleri, R., Scully, M., Thomas, M., Mackie, I.J., Liesner, R., Chen, W., Manns, K. and Machin, S.J. 2012. A phenotype–genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom. Journal of Thrombosis and Haemostasis. 10 (9), pp. 1792-1801.

TitleA phenotype–genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom
AuthorsCamilleri, R., Scully, M., Thomas, M., Mackie, I.J., Liesner, R., Chen, W., Manns, K. and Machin, S.J.
Abstract

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.

JournalJournal of Thrombosis and Haemostasis
Journal citation10 (9), pp. 1792-1801
ISSN1538-7933
YearSep 2012
PublisherWiley
Digital Object Identifier (DOI)doi:10.1111/j.1538-7836.2012.04852.x
Publication dates
PublishedSep 2012

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