Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw–Schulman syndrome)

Abstract

Summary. ADAMTS13, the specific von Willebrand factor (VWF)-cleaving metalloprotease, prevents the spontaneous formation of platelet thrombi in the microcirculation by degrading the highly adhesive ultralarge VWF multimers into smaller forms. ADAMTS13 severe enzymatic deficiency and mutations have been described in the congenital thrombotic thrombocytopenic purpura (TTP or Upshaw-Schulman syndrome), a rare and severe disease related to multivisceral microvascular thrombosis. We investigated six French families with congenital TTP for ADAMTS13 enzymatic activity and gene mutations. Six probands with congenital TTP and their family were tested for ADAMTS13 activity in plasma using a two-site immunoradiometric assay and for ADAMTS13 gene mutations using polymerase chain reaction and sequencing. ADAMTS13 activity was severely deficient (< 5%) in the six probands and one mildly symptomatic sibling but normal (> 50%) in all the parents and the asymptomatic siblings. Ten novel candidate ADAMTS13 mutations were identified in all families, showing either a compound heterozygous or a homozygous status in all probands plus the previous sibling and a heterozygous status in the parents. The mutations were spread all over the gene, involving the metalloprotease domain (I79M, S203P, R268P), the disintegrin domain (29 bp deletion in intron/exon 8), the cystein-rich domain (acceptor splice exon 12, R507Q), the spacer domain (A596V), the 3rd TSP1 repeat (C758R), the 5th TSP1 repeat (C908S) and the 8th TSP1 repeat (R1096stop). This study emphasizes the role of ADAMTS13 mutations in the pathogenesis of congenital TTP and suggests that several structural domains of this metalloprotease are involved in both its biogenesis and its substrate recognition process.

ADAMTS13 and microvascular thrombosis

“…These and subsequent studies demonstrate that inhibitory autoantibodies are detectable in most patients with acquired TTP (32). Furthermore, following the first study linking hereditary TTP to mutations of the ADAMTS13 gene (4), other studies have identified more mutations in patients with the disease (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Together these two lines of evidence confirm that ADAMTS13 deficiency plays a pivotal role in causing the VWFplatelet thrombosis of TTP.…”

“…DNA nucleotide sequence analysis has detected at least 9 nonsense, 42 missense, 9 frameshifting insertion or deletion, and 6 splicing mutations (4,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). These mutations span the entire length of the protein without apparent hot spots.…”

The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

“…Inherited TTP is a rare autosomal recessive disorder due to homozygous or double heterozygous mutations in the ADAMTS-13 gene, causing a severe decrease of ADAMTS-13 level and activity (10)(11)(12)(13)(14)(15)(16). About 100 mutations causing inherited ADAMTS-13 deficiency have been identified so far in regions of the gene encoding different domains (10)(11)(12)(13)(14)(15)(16)(17) with only a few of them characterized by in vitro expression studies (12,15,(18)(19)(20)(21)(22). In this manuscript, we report cases of congenital TTP, due to the homozygous mutation in ADAMTS-13 gene in two young brothers born from two consanguineous parents of Romanian origin.…”

Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry

“…While some patients present with neurological symptoms and never show renal complications, renal involvement is the predominant manifestation in others (19,23,25,27,(30)(31)(32). Moreover, patients with neurological involvement tend to present with neurological symptoms also during subsequent episodes, the same applies for renal involvement.…”