A novel mutation Gly603Arg of <i>TMPRSS6</i> in a Korean female with iron‐refractory iron deficiency anemia

Choi, Hyoung Soo; Yang, Hye Ran; Song, Sang Hoon; Seo, Ja Young; Lee, Ki O.; Kim, Hee Jin

doi:10.1002/pbc.23190

Cited by 20 publications

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“…4 Patients with mutations in Tmprss6 develop a condition referred to as iron-refractory iron-deficiency anemia (IRIDA). [5][6][7][8][9][10][11][12][13][14][15][16] Decreased Tmprss6 activity leads to increased hepcidin expression through the hemojuvelin-dependent pathway; increased hepcidin expression leads to decreased iron absorption and iron-deficiency anemia. Mouse models of Tmprss6 deficiency recapitulate this phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…Ile286 is a highly conserved residue in the first CUB domain of Tmprss6 and is situated within the vicinity of several other IRIDA-associated residues (Figure 2A-C). [5][6][7][8][9][10][11][12][13][14][15][16] Genotyping of all mice from the hem8 x CAST intercross described above revealed that F286/F286 mice had decreased mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) levels, total hemoglobin levels and hematocrit relative to I286/I286 and I286/F286 mice (Figure 2D,E; data not shown). To assess the in vitro significance of the I286F substitution on Tmprss6 function, we transfected mouse Tmprss6 cDNA expression constructs encoding the I286 or F286 variant into HEK293T cells.…”

Section: Sequencing Of Exons and Exon/intron Junctions Inmentioning

confidence: 99%

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Identification and characterization of a novel murine allele of Tmprss6

et al. 2013

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Section: Introductionmentioning

confidence: 99%

Section: Sequencing Of Exons and Exon/intron Junctions Inmentioning

confidence: 99%

Identification and characterization of a novel murine allele of Tmprss6

et al. 2013

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“…The active protease is released from the cell membrane into the extracellular medium by proteolytic cleavage within the stem . So far, 34 MT2 mutations have been identified in human patients with IRIDA [Altamura et al, 2010;Beutler et al, 2009;Choi et al, 2011;De Falco et al, 2010;Edison et al, 2009;Finberg et al, 2008;Guillem et al, 2008;Melis et al, 2008;Ramsay et al, 2009b;Sato et al, 2011;Silvestri et al, 2009;Tchou et al, 2009]. These include missense, nonsense, frameshift, and splice junction mutations.…”

Section: Introductionmentioning

confidence: 99%

Inactive matriptase-2 mutants found in IRIDA patients still repress hepcidin in a transfection assay despite having lost their serine protease activity

Guillem¹,

Kannengiesser²,

Oudin³

et al. 2012

Hum. Mutat.

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ABSTRACT:Mutations of the TMPRSS6 gene, which encodes Matriptase-2, are responsible for iron-refractory iron-deficiency anemia. Matriptase-2 is a transmembrane protease that downregulates hepcidin expression. We report one frameshift (p.Ala605ProfsX8) and four novel missense mutations (p.Glu114Lys, p.Leu235Pro, p.Tyr418Cys, p.Pro765Ala) found in IRIDA patients. These mutations lead to changes in both the catalytic and noncatalytic domains of Matriptase-2. Analyses of the mutant proteins revealed a reduction of autoactivating cleavage and the loss of N-Boc-Gln-Ala-Arg-p-nitroanilide hydrolysis. This resulted either from a direct modification of the active site or from the lack of the autocatalytic cleavage that transforms the zymogen into an active protease. In a previously described transfection assay measuring the ability of Matriptase-2 to repress the hepcidin gene (HAMP) promoter, all mutants retained some, if not all, of their transcriptional repression activity. This suggests that caution is called for in interpreting the repression assay in assessing the functional relevance of Matriptase-2 substitutions. We propose that Matriptase-2 activity should be measured directly in the cell medium of transfected cells using the chromogenic substrate. This simple test can be used to determine whether a sequence variation leading to an amino acid substitution is functionally relevant or not.

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“…[15][16][17][18] TMPRSS6, also known as matriptase-2, is a membrane-bound serine protease 19 expressed in hepatocytes that negatively modulates hepcidin production. Mutations of TMPRSS6 in both humans [20][21][22][23][24][25] and mice 26-29 result in excess hepcidin expression and iron-refractory iron deficiency anemia. In vitro, TMPRSS6 cleaves hemojuvelin (HJV) from the plasma membrane.…”

mentioning

confidence: 99%

An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe−/− mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia

Schmidt

Toudjarska

Sendamarai

et al. 2013

Blood

187

193

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• Tmprss6 siRNA induces hepcidin and diminishes iron in hemochromatosis or thalassemia mice, improving the anemia seen in the latter model. • Manipulation of TMPRSS6with RNAi therapeutics may be an approach to treating iron overload diseases associated with low hepcidin levels.Mutations in HFE lead to hereditary hemochromatosis (HH) because of inappropriately high iron uptake from the diet resulting from decreased hepatic expression of the iron-regulatory hormone hepcidin. ␤-thalassemia is a congenital anemia caused by partial or complete loss of ␤-globin synthesis causing ineffective erythropoiesis, anemia, decreased hepcidin production, and secondary iron overload. Tmprss6 is postulated to regulate hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the hepatocyte surface. On this basis, we hypothesized that treatment of mouse models of HH (Hfe ؊/؊ ) and ␤-thalassemia intermedia (Hbb th3/؉ ) with Tmprss6 siRNA formulated in lipid nanoparticles (LNPs) that are preferentially taken up by the liver would increase hepcidin expression and lessen the iron loading in both models. In the present study, we demonstrate that LNP-Tmprss6 siRNA treatment of Hfe ؊/؊ and Hbb th3/؉ mice induces hepcidin and diminishes tissue and serum iron levels. Furthermore, LNP-Tmprss6 siRNA treatment of Hbb th3/؉ mice substantially improved the anemia by altering RBC survival and ineffective erythropoiesis. Our results indicate that pharmacologic manipulation of Tmprss6 with RNAi therapeutics isa practical approach to treating iron overload diseases associated with diminished hepcidin expression and may have efficacy in modifying disease-associated morbidities of ␤-thalassemia intermedia. (Blood. 2013;121(7):1200-1208) IntroductionIron is essential for erythropoiesis and numerous other cellular processes. However, excess iron is toxic because of its ability to generate reactive oxygen species through Fenton-mediated chemistry, and therefore it must be tightly regulated. Mutations in HFE 1 lead to the most common form of hereditary hemochromatosis (HH) in humans. Loss of HFE function results in chronically elevated dietary iron uptake because of dysregulation of hepcidin, a peptide hormone largely produced by hepatocytes in the liver 2-6 that negatively regulates cellular iron export by promoting the degradation of ferroportin, 7 an iron exporter present on the surface of macrophages of the reticuloendothelial system, duodenal enterocytes, and hepatocytes. [8][9][10] ␤-Thalassemia is an inherited anemia caused by the partial or complete lack of ␤-globin synthesis. The most severe form, ␤-thalassemia major, requires chronic RBC transfusional support, leading to secondary iron overload. 11 Less severe disruption of ␤-globin synthesis leads to the clinical phenotype of ␤-thalassemia intermedia, which by definition does not require chronic transfusions. Nonetheless, patients with ␤-thalassemia intermedia still develop iron overload as a consequence of chronic suppression of hepcidin synthesis by inef...

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A novel mutation Gly603Arg of TMPRSS6 in a Korean female with iron‐refractory iron deficiency anemia

Cited by 20 publications

References 20 publications

Identification and characterization of a novel murine allele of Tmprss6

Identification and characterization of a novel murine allele of Tmprss6

Inactive matriptase-2 mutants found in IRIDA patients still repress hepcidin in a transfection assay despite having lost their serine protease activity

An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe−/− mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia

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