Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activities of mitochondrial enzymes in blood cells from 69 patients with primary sideroblastic anemia were determined to elucidate the pathogenesis of the disease. In erythroblasts of patients with primary acquired type the activities of both delta-aminolevulinic acid synthetase and mitochondrial serine protease were inevitably decreased. The susceptibility to the protease of apo-delta-aminolevulinic acid synthetase prepared from erythroblasts of patients with this type was within the normal range, in contrast to that of pyridoxine-responsive anemia. The activities of mitochondrial enzymes such as cytochrome oxidase, serine protease, and oligomycin-sensitive ATPase, except citrate synthetase, were usually decreased in mature granulocytes of the patients. Patients with hereditary sideroblastic anemia also had decreased delta-aminolevulinic acid synthetase activity in erythroblasts, and decreased serine protease activity in both erythroblasts and mature granulocytes. Mature granulocytes obtained from patients with pyridoxine-responsive anemia before therapy had decreased cytochrome oxidase activity, however, the activity increased to a normal level when the patients were in remission. The activities of other mitochondrial enzymes in mature granulocytes were within normal range in these patients before pyridoxine therapy. The activities of these mitochondrial enzymes in lymphocytes were within normal range in all groups of patients with primary sideroblastic anemia. We suggest that patients with primary acquired, and possibly also those with hereditary sideroblastic anemia have impaired mitochondrial function in both erythroblasts and granulocytes. That only anemia is observed in these patients is because a functional abnormality of mitochondria in erythroblasts is most important because of the role of mitochondria in the formation of heme in erythrocyte development. In contrast to these two types of sideroblastic anemia, only delta-aminolevulinic acid synthetase in both erythroblasts and granulocytes seems to be impaired in patients with pyridoxine-responsive anemia.
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PMID:Multiple enzymatic defects in mitochondria in hematological cells of patients with primary sideroblastic anemia. 624 45

The liver peptide hepcidin regulates body iron, is upregulated in iron overload and inflammation, and is downregulated in iron deficiency/hypoxia. The transmembrane serine protease matriptase-2 (TMPRSS6) inhibits the hepcidin response and its mutational inactivation causes iron-deficient anemia in mice and humans. Here we confirm the inhibitory effect of matriptase-2 on hepcidin promoter; we show that matriptase-2 lacking the serine protease domain, identified in the anemic Mask mouse (matriptase-2(MASK)), is fully inactive and that mutant R774C found in patients with genetic iron deficiency has decreased inhibitory activity. Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma membrane; matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity. Matriptase-2 interacts with HJV through the ectodomain since the interaction is conserved in matriptase-2(MASK). The expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and its interaction with HJV.
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PMID:The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. 1897 66

Maintaining the body's levels of iron within precise boundaries is essential for normal physiological function. Alterations of these levels below or above the healthy limit lead to a systemic deficiency or overload in iron. The type-two transmembrane serine protease (TTSP), matriptase-2 (also known as TMPRSS6), is attracting significant amounts of interest due to its recently described role in iron homeostasis. The finding of this regulatory role for matriptase-2 was originally derived from the observation that mice deficient in this protease present with anemia due to elevated levels of hepcidin and impaired intestinal iron absorption. Further in vitro analysis has demonstrated that matriptase-2 functions to suppress bone morphogenetic protein stimulation of hepcidin transcription through cell surface proteolytic processing of the bone morphogenetic protein co-receptor hemojuvelin. Consistently, the anemic phenotype of matriptase-2 knockout mice is mirrored in humans with matripase-2 mutations. Currently, 14 patients with iron-refractory iron deficiency anemia (IRIDA) have been reported to harbor various genetic mutations that abrogate matriptase-2 proteolytic activity. In this review, after overviewing the membrane anchored serine proteases, in particular the TTSP family, we summarize the identification and characterization of matriptase-2 and describe its functional relevance in iron metabolism.
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PMID:Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. 1937 77

Matriptase-2 is a recently identified membrane-bound, cell-surface serine protease expressed primarily in liver. Mutations in matriptase-2 in mice and humans cause iron-deficiency anemia that responds poorly to iron therapy. The poor response results from an inability to decrease hepcidin production during iron deficiency. Cell culture studies reveal that matriptase-2 inhibits hepcidin induction by cleaving membrane hemojuvelin, a potent activator of hepcidin transcription. As a novel suppressor of hepcidin expression, matriptase-2 emerges as a possible candidate for therapeutic interventions aimed at treating disorders of iron metabolism.
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PMID:Into the matrix: regulation of the iron regulatory hormone hepcidin by matriptase-2. 1938 32

Iron-refractory, iron-deficiency anemia (IRIDA) is a familial disorder characterized by iron deficiency anemia unresponsive to oral iron treatment but partially responsive to intravenous iron therapy. Previously, we showed that IRIDA patients harbor loss-of-function mutations in TMPRSS6, a type II transmembrane serine protease primarily expressed by the liver. Both humans and mice with TMPRSS6 mutations show inappropriately elevated levels of the iron-regulatory hormone hepcidin, suggesting that TMPRSS6 acts to negatively regulate hepcidin expression. Here we investigate the relationship between Tmprss6 and the bone morphogenetic protein (BMP)-Smad signaling pathway, a key pathway promoting hepcidin transcription in hepatocytes. We show that livers from mice deficient for Tmprss6 have decreased iron stores and decreased Bmp6 mRNA, but markedly increased mRNA for Id1, a target gene of Bmp6 signaling. In contrast, mice deficient for both Tmprss6 and hemojuvelin (Hjv), a BMP coreceptor that augments hepcidin expression in hepatocytes, showed markedly decreased hepatic levels of hepcidin and Id1 mRNA, markedly increased hepatic Bmp6 mRNA levels, and systemic iron overload similar to mice deficient for Hjv alone. These findings suggest that down-regulation of Bmp/Smad signaling by Tmprss6 is required for regulation of hepcidin expression and maintenance of systemic iron homeostasis.
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PMID:Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. 2068 66

IRIDA (iron-refractory iron-deficiency anaemia) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anaemia, low transferrin saturation and high levels of the iron-regulated hormone hepcidin. The disease is caused by mutations in the transmembrane serine protease TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of HJV (haemojuvelin), an activator of hepcidin transcription. In the present paper, we describe a patient with IRIDA who carries a novel mutation (Y141C) in the SEA domain of the TMPRSS6 gene. Functional characterization of the TMPRSS6(Y141C) mutant protein in cultured cells showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. As a consequence, hepcidin mRNA expression is increased, causing the clinical symptoms observed in this IRIDA patient. The present study provides important mechanistic insight into how TMPRSS6 is activated.
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PMID:A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA. 2070 62

Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6(-/-) mice (characterized by increased hepcidin levels and anemia) and Bmp6(-/-) mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6(-/-) mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.
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PMID:Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6. 2094 Apr 20

Current treatment for genotype 1 HCV infection with pegylated interferon (PEG IFN) and ribavirin (RBV) is effective in less than 50% of patients. The advent of direct-acting antiviral agents that target replication of HCV promises to improve therapy for the disease. Telaprevir is a new peptidomimetic serine protease inhibitor that specifically targets the NS3/4a HCV serine protease to cause rapid reduction in HCV RNA levels. Three Phase II Protease Inhibition for Viral Evaluation (PROVE) studies have assessed the efficacy and safety of telaprevir in genotype 1 patients. The studies examined sustained virological response (SVR) rates and also the adverse events related to the use of this drug in different groups. The results of these studies suggested that the addition of this specific protease inhibitor to PEG IFN alfa-2a and RBV can significantly improve the results of treatment in patients affected with chronic HCV infection with genotype 1, when compared with the standard treatment, PEG IFN alfa-2a and RBV alone. The key observations in these Phase II trials of telaprevir were higher rate of SVR above current standard of care (61-69% for T12PR24 treatment-naive patients compared with 46-48% for standard of care in naive patients). Low rates of relapse were observed in T12PR24-treated patients (2-14% vs 22-23%). The studies suggest that the duration of treatment could be reduced for rapidly responsive naive patients from 48 to 24 weeks while maintaining improved SVR rates. RBV remains an essential component of treatment with protease inhibitors combined with PEG IFN. The main adverse reactions of note with its use were rashes, anemia and nausea.
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PMID:Overview of the PROVE studies evaluating the use of telaprevir in chronic hepatitis C genotype 1 patients. 2114 41

The iron hormone hepcidin is inhibited by matriptase-2 (MT2), a liver serine protease encoded by the TMPRSS6 gene. Cleaving the bone morphogenetic protein (BMP) coreceptor hemojuvelin (HJV), MT2 impairs the BMP/son of mothers against decapentaplegic homologs (SMAD) signaling pathway, down-regulates hepcidin, and facilitates iron absorption. TMPRSS6 inactivation causes iron-deficiency anemia refractory to iron administration both in humans and mice. Genome-wide association studies have shown that the SNP rs855791, which causes the MT2 V736A amino acid substitution, is associated with variations of serum iron, transferrin saturation, hemoglobin, and erythrocyte traits. In the present study, we show that, in vitro, MT2 736(A) inhibits hepcidin more efficiently than 736(V). Moreover, in a genotyped population, after exclusion of samples with iron deficiency and inflammation, hepcidin, hepcidin/transferrin saturation, and hepcidin/ferritin ratios were significantly lower and iron parameters were consistently higher in homozygotes 736(A) than in 736(V). Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen the idea that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.
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PMID:TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. 2187 47

Novel roles for the serine protease plasmin have been implicated recently in physiological and pathological processes. However, whether plasmin is involved in erythropoiesis is not known. In the present study, we studied the consequences of plasminogen deficiency on erythropoiesis in plasminogen-deficient (Plg knockout [KO]) mice. Erythroid differentiation was attenuated in male Plg KO mice and resulted in erythroblastic accumulation within the spleen and bone marrow, with increased apoptosis in the former, erythrocytosis, and splenomegaly, whereas similar erythropoietic defect was less prominent in female Plg KO mice. In addition, erythrocyte lifespan was shorter in both male and female Plg KO mice. Erythropoietin levels were compensatory increased in both male and female Plg KO mice, and resulted in a higher frequency of burst-forming units-erythroid within the spleen and bone marrow. Surprisingly, we found that male Plg KO mice, but not their female counterparts, exhibited normochromic normocytic anemia. The observed sex-linked erythropoietic defect was attributed to decreased serum testosterone levels in Plg KO mice as a consequence of impaired secretion of the pituitary luteinizing hormone (LH) under steady-state condition. Surgical castration causing testosterone deficiency and stimulating LH release attenuated erythroid differentiation and induced anemia in wild-type animals, but did not further decrease the hematocrit levels in Plg KO mice. In addition, complementation of LH using human choriogonadotropin, which increases testosterone production, improved the erythropoietic defect and anemia in Plg KO mice. The present results identify a novel role for plasmin in the hormonal regulation of postnatal erythropoiesis by the LH-testosterone axis.
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PMID:Plasminogen deficiency attenuates postnatal erythropoiesis in male C57BL/6 mice through decreased activity of the LH-testosterone axis. 2205 79


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