Alt. symbols: C9orf8 | VWFCP | TTP | vWF-CP | FLJ42993 | MGC118899 | MGC118900 | DKFZp434C2322

Approved name: ADAM metallopeptidase with thrombospondin type 1 motif 13
Alt. names: a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 13

Location: 9q34.2: 133414358 - 133459402 (+)
Gene type: protein_coding, 9 transcripts.

Scores: LoFtool: 0.523000 | pLI: 0.00000000 | LOEUF: 0.683

HGNC: 1366

NCBI: 11093, RefSeq: NG_011934.2

Ensembl: ENSG00000160323.19

LRG_544 | Status: public

OMIM: 604134

Expression | ProteinAtlas

Von Willebrand factor is a multimeric plasma glycoprotein that plays a critical role in platelet adhesion and aggregation on vascular lesions. ADAMTS13 is a multidomain protease that cleaves VWF in circulating blood and thereby limits platelet thrombosis.

Most cases of all thrombotic thrombocytopenic purpura (TTP) (95%) are acquired via an autoimmune mechanism, but ~5% involve genetic predisposition stemming from biallelic mutations in ADAMTS13. Hereditary TTP, also known as Upshaw-Schulman syndrome (USS) [MIM:274150], is a rare autosomal recessive thrombotic microangiopathy (TMA) that manifests acutely as microangiopathic mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia. In the absence of functional ADAMTS13, large von Willebrand factor multimers are not cleaved, leading to platelet adherence and occlusive microvascular thrombosis. Organs particularly affected include the brain, heart and kidneys; if left untreated, mortality can exceed 90%. Hereditary TTP is more frequent amongst pediatric-onset (vs adult-onset) TTP, and clinical presentation can vary significantly with age of onset. Child-onset TTP usually starts in the neonatal period with hematological features and severe jaundice, while adult-onset hereditary TTP in women is often unmasked during their first pregnancy. Over 200 ADAMTS13 missense, nonsense, splice site, and frameshift mutations have been identified to date with new mutations continuing to be reported. These variants can be found across the ADAMTS13 gene in all protein domains without obvious mutational hot-spots and may abolish or impair ADAMTS13 synthesis, secretion or activity. For 97 patients with available information in the Hereditary TTP Registry, age at overt disease onset could not be strictly correlated to level of residual ADAMTS13 activity (PMID: 30792199). Additionally, some common missense ADAMTS13 polymorphisms in the Japanese population have also been shown to reduce VWF-cleaving protease (VWF-CP) activity, making these potential risk alleles for TTP (PMID: 29669506). Of note, Goodpasture’s disease has been reported for a 27-year-old man who was hospitalized for acute kidney injury associated with antiglomerular basement membrane antibodies (anti-GBM) and subsequently found to have an ADAMTS13 activity <1% (PMID: 23111709). Another case report similarly noted a link between Goodpasture’s disease and TTP in a 43 year old Caucasian man with pulmonary hemorrhage, confusion, persistent fever, acute oliguric renal failure, thrombocytopenia and microangiopathic hemolytic anemia (PMID: 20650907). Significantly more case reports link reduced ADAMTS13 activity, not always associated with detectable inhibitors or autoantibodies, to complications of systemic lupus erythematosus (SLE) (PMID: 27416846, 27720178, 27777394, 28707764, 29434134, 30008460, 31934484, 32859237, 32878846, 33274103). As George et al. (2012) describe, patients with TTP and severe ADAMTS13 deficiency can present with an extraordinary diversity of features, timelines and clinical course, so a low threshold of suspicion should be maintained (PMID: 22927184). [Load More]