ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw-Schulman Syndrome

Thromb Haemost. 2018 Nov;118(11):1902-1917. doi: 10.1055/s-0038-1673686. Epub 2018 Oct 12.


Background: Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw-Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer-CUB interaction is abrogated when ADAMTS13 is conformationally activated.

Objective: This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS.

Patients and methods: All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS.

Results: Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation.

Conclusion: In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation.

MeSH terms

  • ADAMTS13 Protein / genetics*
  • ADAMTS13 Protein / metabolism
  • Adolescent
  • Adult
  • Age of Onset
  • Autoantibodies / blood
  • Child
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • France / epidemiology
  • Genotype*
  • Humans
  • Infant
  • Infant, Newborn
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Genetic
  • Pregnancy
  • Protein Conformation
  • Purpura, Thrombotic Thrombocytopenic / epidemiology
  • Purpura, Thrombotic Thrombocytopenic / genetics*
  • Young Adult


  • Autoantibodies
  • ADAMTS13 Protein
  • ADAMTS13 protein, human