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Prevalence of the ADAMTS‐13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura
Author(s) -
CAMILLERI R. S.,
COHEN H.,
MACKIE I. J.,
SCULLY M.,
STARKE R. D.,
CRAWLEY J. T. B.,
LANE D. A.,
MACHIN S. J.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.02846.x
Subject(s) - adamts , missense mutation , medicine , thrombotic thrombocytopenic purpura , proband , von willebrand factor , compound heterozygosity , gastroenterology , adamts13 , immunology , mutation , platelet , metalloproteinase , thrombospondin , biology , genetics , gene , matrix metalloproteinase
Summary. Background: Thrombotic thrombocytopenic purpura (TTP) is most commonly associated with deficiency or inhibition of von Willebrand factor‐cleaving protease (ADAMTS‐13) activity. ADAMTS‐13 mutations and polymorphisms have been reported in childhood congenital TTP, but their significance in adult onset TTP remains unclear. Objectives: We sought to identify common ADAMTS‐13 mutations in adults with late onset TTP and to investigate whether they may predispose acute clinical episodes of the disorder in adulthood. Patients/Methods/Results: We detected a missense mutation (C3178T) in exon 24 of ADAMTS‐13 in 6/53 (11.3%) adult onset TTP patients, but no normal controls ( n = 100). Three of the patients had pregnancy‐associated TTP; three had chronic relapsing acute idiopathic TTP. C3178T encodes an arginine to tryptophan (R1060W) substitution in the TSP1‐7 domain of ADAMTS‐13. In vitro expression of mutant and wild‐type ADAMTS‐13 demonstrated that R1060W caused severe intracellular retention of ADAMTS‐13 (<5% secretion) without affecting its metalloprotease activity. One homozygous and five heterozygous patients were identified. No other causative mutations were discovered, yet all six patients had ADAMTS‐13 activity levels <5% at presentation (normal: 66–126%). Antibodies/inhibitors to ADAMTS‐13 were detected in three/five heterozygous patients, and all six patients had subnormal antigen levels. Six asymptomatic first‐degree relatives, including those of two probands with antibodies, were also heterozygous for C3178T; all but one had subnormal ADAMTS‐13 activity. Conclusion: The high prevalence of R1060W ADAMTS‐13 in adult onset TTP, together with its absence in childhood congenital TTP cases reported elsewhere, suggests it may be a factor in the development of late onset TTP.