title: Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Haemostasis Research Unit, Department of Haematology, University College London School of Medicine, London, UK. r.camilleri@ucl.ac.uk
authors.forename: R S
authors.initials: RS
authors.lastname: Camilleri
authors.forename: H
authors.initials: H
authors.lastname: Cohen
authors.forename: I J
authors.initials: IJ
authors.lastname: Mackie
authors.forename: M
authors.initials: M
authors.lastname: Scully
authors.forename: R D
authors.initials: RD
authors.lastname: Starke
authors.forename: J T B
authors.initials: JT
authors.lastname: Crawley
authors.forename: D A
authors.initials: DA
authors.lastname: Lane
authors.forename: S J
authors.initials: SJ
authors.lastname: Machin
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D000071120:ADAMTS13 Protein; D000328:Adult; D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D002460:Cell Line; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D011697:Purpura, Thrombotic Thrombocytopenic / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D011993:Recombinant Fusion Proteins; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human