Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS)

Licht, Christoph; Stapenhorst, Ludwig; Simon, Thorsten; Budde, Ulrich; Schneppenheim, Reinhard; Höppe, Bernd

doi:10.1111/j.1523-1755.2004.00841.x

Cited by 54 publications

(38 citation statements)

References 26 publications

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“…18 Eight different mutations in the first and second CUB domain were reported previously and some were analyzed by in vitro-expression studies, suggesting, consistently with our results, that the CUB domains play a critical role in the biosynthesis and secretion of ADAMTS13. 8,35,36 The 4143_4144insA mutation has been frequently detected in patients with hereditary ADAMTS13 deficiency in northern and central European countries. Schneppenheim and colleagues, after analyzing the segregation of 4143_4144insA mutation using 17 intragenic polymorphic markers in patients and their relatives, suggested that 4143_4144insA is a founder mutation most probably derived from a common ancestor in central Europe.…”

Section: Discussionmentioning

confidence: 99%

Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion

Garagiola¹,

Valsecchi²,

Lavoretano³

et al. 2008

Haematologica

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Section: Discussionmentioning

confidence: 99%

Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion

Garagiola¹,

Valsecchi²,

Lavoretano³

et al. 2008

Haematologica

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“…27 Of more interest, mutations in the CUB domains result in severe deficiency of plasma ADAMTS13 activity. 9,28,29 In vitro studies have shown that some of the mutants exhibit secretion defect. 30,31 For example, one of the mutations occurs in the second CUB domain, inserts an "A" in between the nucleotides 4143 and 4144 of ADAMTS13 (4143-4144insA), deletes the second CUB domain, and appends REQPG after S1381.…”

Section: Introductionmentioning

confidence: 99%

Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts

Shang

Zheng

Niiya

2006

Blood

102

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ADAMTS13 biosynthesis appeared to occur mainly in hepatic stellate cells, but detection of ADAMTS13 mRNA in many other tissues suggests that vascular endothelium may also produce ADAMTS13. We showed that ADAMTS13 mRNA and protein were detectable in human umbilical vein endothelial cells, aortic endothelial cells, and endothelium-derived cell line (ECV304). ADAMTS13 in cell lysate or serum-free conditioned medium cleaved von Willebrand factor (VWF) specifically. IntroductionADAMTS13, a member of a disintegrin and metalloprotease with thrombospondin type 1 repeats (ADAMTS) family, limits plateletrich thrombi by cleaving von Willebrand factor (VWF) between the Tyr 1605 and Met 1606 residues. VWF is synthesized in vascular endothelial cells and megakaryocytes or platelets, and normally stored in Weibel-Palade bodies 1 of endothelial cells or the ␣-granules of platelets. 2,3 Upon stimulation, VWF is secreted as unusually large (UL) multimers that may remain associated with the endothelial cell surface. [4][5][6] These UL-VWF multimers may be the preferred substrate for ADAMTS13. 4,5 Inability to cleave these UL-VWF multimers to smaller sizes on the endothelial cell surface may result in an accumulation of UL-VWF, leading to enhanced platelet adhesion and aggregation, and thrombotic thrombocytopenic purpura (TTP), 7,8 characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, and organ failure. 7,8 ADAMTS13 appears to be synthesized in liver, 9-11 particularly in hepatic stellate cells, [12][13][14] which reside in the space of Disse adjacent to the hepatocytes. However, the contribution of hepatic stellate cells in regulation of plasma ADAMTS13 levels remains to be determined. We have recently shown that despite a dramatic increase in ADAMTS13 expression in hepatic stellate cells upon activation by administration of carbon tetrachloride, plasma ADAMTS13 activity is not proportionally increased in rats. 14 In addition, patients with liver cirrhosis or with significant proliferation and activation of hepatic stellate cells exhibit variable or reduced levels of plasma ADAMTS13 activity. 15 Therefore, plasma ADAMTS13 protease may be derived from other sources as well.Recent reports have shown that ADAMTS13 is synthesized and released from human megakaryocytes and platelets. 16,17 ADAMTS13 mRNA is detected in almost every organ tissue by reversetranscriptase-polymerase chain reaction (RT-PCR), [9][10][11]18,19 suggesting that the vascular endothelium may also be the source of plasma ADAMTS13. Considering the enormous surface area of vascular endothelial beds, a small fraction of endothelial cells producing ADAMTS13 at any given time may contribute significantly to plasma levels of ADAMTS13 activity. Consequently, any perturbation of endothelial cell function or ADAMTS13-VWF interactions at the site of their syntheses by inflammatory cytokines or drugs may play an important role in the pathogenesis of TTP 20,21 and perhaps other thrombotic complications. 22 ADAMTS13 consists of signal peptide, propepti...

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“…More than forty different mutations of the ADAMTS13 gene have been described (17,58,59,60) and are shown in an extensive table available online (see the Supplemental Material link in the online version of this chapter or at http://www.annualreviews.org). The mutations, which include mis-senses, non-senses, frame-shifting deletions or insertions, and intronic splicing mutations, distribute throughout the various domains of ADAMTS13.…”

Section: Genetic Mutationsmentioning

confidence: 99%

Current Concepts in Thrombotic Thrombocytopenic Purpura

Tsai

2006

Annu. Rev. Med.

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Recent advances have demonstrated that thrombotic thrombocytopenic purpura (TTP), characterized by widespread thrombosis in the arterioles and capillaries, is caused by deficiency of a circulating zinc metalloprotease ADAMTS13. Two types of TTP are recognized: Autoimmune TTP caused by inhibitory antibodies of ADAMTS13 and hereditary TTP in association with genetic mutations of the ADAMTS13 gene. This article reviews the characteristic and function of ADAMTS13, the mechanism by which ADAMTS13 deficiency may cause thrombosis, and the causes of ADAMTS13 deficiency. It also discusses how the new knowledge may improve the diagnosis and treatment of this previously mysterious disorder.

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Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS)

Cited by 54 publications

References 26 publications

Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion

Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion

Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts

Current Concepts in Thrombotic Thrombocytopenic Purpura

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