Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

“…Separately, another study has linked hereditary TTP to mutations of the ADAMTS13 gene on chromosome 9q34 [37]. Taken together, these observations demonstrate that ADAMTS13 deficiency causes TTP.…”

“…The ADAMTS13 gene contains 29 exons spanning approximately 37 kb on chromosome 9q34 [6][7][8]. ADAMTS13 encodes a 4.7-kb transcript that is detectable in the liver, and a 2.4-kb transcript detectable in placenta, skeletal muscle, and certain tumor cell lines.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…ADAM and ADAMTS molecules have also been implicated in several pathologies [16,[43][44][45]. ADAMTS-13 deficiency is responsible for thrombotic thrombocytopenic purpura characterized by the formation of microvascular von Willebrand Factor (vWF) and platelet-rich thrombi, associated with anaemia, renal failure and neurological dysfunction [46]. ADAM-17 expression and activity are increased in inflammatory bowel diseases [47].…”

Simplified assay for VWF cleaving protease (ADAMTS13) activity and inhibitor in plasma

“…Work by a number of groups has demonstrated very low levels of the activity of this enzyme in plasma from TTP patients, establishing its role in the pathogenesis of this previously poorly understood disease process [5][6][7]. A causal relationship between very low ADAMTS13 activity and TTP has been bolstered by the demonstration of mutations in the ADAMTS13 gene in the familial variant of TTP [8,9]. *Correspondence to: Mary Ann Knovich, Wake Forest University Health Sciences, Medical Center Blvd., Winston-Salem, NC 27157.…”