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

作者：Camilleri R S^*; Scully M; Thomas M; Mackie I J; Liesner R; Chen W J; Manns K; Machin S J

来源：Journal of Thrombosis and Haemostasis, 2012, 10(9): 1792-1801.

DOI：10.1111/j.1538-7836.2012.04852.x

• ADAMTS13
• congenital TTP
• missense mutations
• phenotype-genotype correlation
• thrombotic thrombocytopenic purpura

Background: ADAMTS13 mutations play a role in thrombotic thrombocytopenic purpura (TTP) pathogenesis. Objectives: To establish a phenotypegenotype 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 similar to 1 domains. The adults had TTP precipitated by pregnancy, and had overall higher antigen levels (median, 30 ng mL-1; range, < 1057 ng mL-1) than the children (median, 14 ng mL-1; range, < 1040 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.

• 出版日期2012-9