Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function

Kunz, G; Öhlin, Ann-Kristin; Adami, Antonella; Zöller, Bengt; Svensson, Peter; Lane, David A.

doi:10.1182/blood.v99.10.3646

Cited by 42 publications

(48 citation statements)

References 54 publications

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“…A decreased protein expression of mutants has also been observed for other proteins such as thrombomodulin and protein S mutants (31,32). The exact mechanism responsible for this diminished protein expression remains to be elucidated, but we hypothesize that the hNKCC2 mutants are subject to early degradation by the cellular ER quality control mechanism (33).…”

Section: Discussionmentioning

confidence: 60%

Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters

Starremans¹,

Kersten²,

Knoers

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Bartter syndrome (BS) is a heterogeneous renal tubular disorder affecting Na-K-Cl reabsorption in the thick ascending limb of Henle's loop. BS type I patients typically present with profound hypokalemia and metabolic alkalosis. The main goal of the present study was to elucidate the functional implications of six homozygous mutations (G193R, A267S, G319R, A508T, del526N, and Y998X) in the bumetanide-sensitive Na-K-2Cl cotransporter (hNKCC2) identified in patients diagnosed with BS type I. To this end, capped RNA (cRNA) of FLAG-tagged hNKCC2 and the corresponding mutants was injected in Xenopus laevis oocytes and transporter activity was measured after 72 h by means of a bumetanidesensitive 22 Na ϩ uptake assay at 30°C. Injection of 25 ng of hNKCC2 cRNA resulted in bumetanide-sensitive 22 Na ϩ uptake of 2.5 Ϯ 0.5 nmol/oocyte per 30 min. Injection of 25 ng of mutant cRNA yielded no significant bumetanide-sensitive 22 Na ϩ uptake. Expression of wild-type and mutant transporters was confirmed by immunoblotting, showing significantly less mutant protein compared with wild-type at the same cRNA injection levels. However, when the wild-type cRNA injection level was reduced to obtain a protein expression level equal to that of the mutants, the wild-type still exhibited a significant bumetanide-sensitive 22 Na ϩ uptake. Immunocytochemical analysis showed immunopositive staining of hNKCC2 at the plasma membrane for wild-type and all studied mutants. In conclusion, mutations in hNKCC2 identified in type I BS patients, when expressed in Xenopus oocytes, result in a low expression of normally routed but functionally impaired transporters. These results are in line with the hypothesis that the mutations in hNKCC2 are the underlying cause of the clinical abnormalities seen in patients with type I BS.

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Section: Discussionmentioning

confidence: 60%

Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters

Starremans¹,

Kersten²,

Knoers

et al. 2003

Journal of the American Society of Nephrology

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“…Constructs bearing the mutation were transiently transfected in COS-7 cells and the mutant TM showed a normal distribution around the cell surface membrane as well as normal cofactor activity (14). We have found that the mutation is not frequent in our population, since we did not detect any variant in 145 VTE patients and 162 controls (17).…”

Section: Thrombomodulinmentioning

confidence: 99%

“…Recently, Kunz et al (14) described two new TM mutations. One is a deletion, del791-801, leading to STOP306, and a missense mutation, Arg385Ser.…”

Section: Thrombomodulinmentioning

confidence: 99%

“…Therefore, any impaired function of the thrombin cofactor or reduced TM gene expression could also contribute to thrombotic disease. Direct gene screening of the TM gene in patients with thrombotic disease has showed the occurrence of several mutations (6)(7)(8)(9)(10)(11)(12)(13)(14), some of them associated with venous and arterial thrombosis, with varying results depending, in part, on the different population studied.…”

Section: Thrombomodulinmentioning

confidence: 99%

“…One of these TM mutations, the G127A mutation predicting an Ala25Thr substitution, has been associated with MI (11) but no abnormality in cell surface expression or TM cofactor function could be found (14).…”

Section: Thrombomodulinmentioning

confidence: 99%

See 2 more Smart Citations

Inherited Abnormalities in the protein C Activation Pathway

España

Medina²,

Navarro³

et al. 2002

Pathophysiol Haemos Thromb

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Thrombomodulin and its role in inflammation

2011

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The goal is to provide an extensive review of the physiologic role of thrombomodulin (TM) in maintaining vascular homeostasis, with a focus on its anti-inflammatory properties. Data were collected from published research. TM is a transmembrane glycoprotein expressed on the surface of all vascular endothelial cells. Expression of TM is tightly regulated to maintain homeostasis and to ensure a rapid and localized hemostatic and inflammatory response to injury. By virtue of its strategic location, its multidomain structure and complex interactions with thrombin, protein C (PC), thrombin activatable fibrinolysis inhibitor (TAFI), complement components, the Lewis Y antigen, and the cytokine HMGB1, TM exhibits a range of physiologically important anti-inflammatory, anti-coagulant, and anti-fibrinolytic properties. TM is an essential cofactor that impacts on multiple biologic processes. Alterations in expression of TM and its partner proteins may be manifest by inflammatory and thrombotic disorders. Administration of soluble forms of TM holds promise as effective therapies for inflammatory diseases, and infections and malignancies that are complicated by disseminated intravascular coagulation.

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Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function

Cited by 42 publications

References 54 publications

Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters

Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters

Inherited Abnormalities in the protein C Activation Pathway

Thrombomodulin and its role in inflammation

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