The role of TMPRSS6/matriptase-2 in iron regulation and anemia

Wang, Chia-Yu; Meynard, Delphine; Lin, Herbert Y.

doi:10.3389/fphar.2014.00114

Cited by 59 publications

(39 citation statements)

References 76 publications

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“…These enzymes possess an intracellular, cytoplasmic domain giving an excellent opportunity to mediate signal transduction between the cell and its extracellular environment and to regulate various cellular responses. [11,12] Hepcidin, encoded by the Hamp gene and expressed primarily in the liver, acts as a negative regulator of iron absorption. [3] It was shown that its expression correlates with a suppression of the migration and invasiveness of breast and prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Design and chemical syntheses of potent matriptase‐2 inhibitors based on trypsin inhibitor SFTI‐1 isolated from sunflower seeds

et al. 2017

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Matriptase-2 plays a pivotal role in keeping iron concentrations within a narrow physiological range in humans. The opportunity to reduce matriptase-2 proteolytic activity may open a novel possibility to treat iron overload diseases, such as hereditary hemochromatosis and thalassemia. Here, we present 23 new analogues of trypsin inhibitor SFTI-1 designed to inhibit human matriptase-2. Influence of the modifications Gly1Lys, Ile10Arg, and Phe12His, as well as the introduction of Narg in P1 or P1 and P4 positions were examined. Selected peptides were further analyzed, together with previously reported peptides, for their inhibitory activity against related human proteases, that are, matriptase-1, plasmin, thrombin and trypsin. A highly potent inhibitor of matriptase-2, the bicycylic [Arg , Arg , His ]SFTI-1, with a K value of 15 nm was obtained.

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Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] The importance of matriptase-2 in iron homeostasis is reflected in both mouse models and human patients suffering from iron-refractory iron deficiency anemia. hemojuvelin (HJV), which is a bone morphogenetic protein (BMP) coreceptor.…”

Section: Introductionmentioning

confidence: 99%

Design and chemical syntheses of potent matriptase‐2 inhibitors based on trypsin inhibitor SFTI‐1 isolated from sunflower seeds

et al. 2017

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“…6,7 In addition to these SNPs, a novel mutation corresponding to a substitution (A>T) in the beginning of intron 11 (c.1396+4 A>T) of the TMPRSS6 gene was also observed. In silico studies (using the Human Splicing Finder software) revealed that this mutation disturbs the intron 11 consensus dador splicing site (wt sequence score = 82.12; mutant sequence score = 73.32; variation −10.72%; MaxEnt −67.34).…”

Section: Case Reportmentioning

confidence: 99%

Iron Refractory Iron Deficiency Anemia in Dizygotic Twins Due to a Novel TMPRSS6 Gene Mutation in Addition to Polymorphisms Associated With High Susceptibility to Develop Ferropenic Anemia

Pinto

Jesus

Anselmo

et al. 2017

Journal of Investigative Medicine High Impact Case Reports

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Iron refractory iron deficiency anemia (IRIDA) is an autosomal recessive ferropenic anemia. Its hypochromic microcytic pattern is associated with low transferrin saturation, normal-high ferritin, and inappropriately high hepcidin level. This entity is caused by mutants of the TMPRSS6 gene that encodes the protein matriptase II, which influences hepcidin expression, an iron metabolism counterregulatory protein. We report two 29-year-old dizygotic female twins with ferropenic, hypochromic microcytic anemia with 20 years of evolution, refractory to oral iron therapy. After exclusion of gastrointestinal etiologies, IRIDA diagnosis was suspected and a novel mutation in the TMPRSS6 gene was identified. It was found in intron 11 (c.1396+4 A>T) and seems to affect the gene expression. In addition, 3 polymorphisms already associated with a higher risk of developing iron deficiency anemia were also found (D521D, V736A, and Y739Y). Our case reports an undescribed mutation causing IRIDA and supports the hypothesis that this clinical syndrome may be more common than previously thought and its genetics more heterogeneous than initially described.

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“…In the case of deficient matriptase-2 activity, the resulting absence of negative regulation of hepcidin leads to decreased iron bioavailability and an iron deficiency state. [3][4][5][6] In this article, we report a new case of IRIDA for which we explore the functional consequences, including neurocognitive impact.…”

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confidence: 99%

Iron-Refractory Iron Deficiency Anemia May Not Lead to Neurocognitive Dysfunction: A Case Report

et al. 2016

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Iron deficiency is a common cause of anemia (IDA) in infancy and can be associated with neurocognitive impairments. Iron-refractory IDA (IRIDA) has recently been described as an inherited cause of IDA due to loss-of-function mutations in the TMPRSS6 gene. IRIDA is characterized by a lack of response to iron replacement. Here we report a new case of IRIDA with its biological parameters and its functional consequences, including neuropsychological impact. The latter was evaluated by the Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition and subtests. We report a 5-year-old French Canadian boy who was incidentally diagnosed with a severe microcytic anemia at 2 years of age (hemoglobin 52 g/L, mean corpuscular volume 50 fL). Except mild pallor, he was asymptomatic of his anemia. Although he had a slight response to intravenous iron therapy, his hemoglobin remained <92 g/L, with persistent microcytosis, low serum iron, but normal ferritin levels. Blood hepcidin level was higher than those of his parents and control (patient 11.2 nM, father 9.06 nM, mother 4.07 nM). Compound heterozygosity for TMPRSS6 paternally inherited c.1324G>A and maternally inherited c.1807G>C mutations were eventually identified. The patient had normal development and growth. Neuropsychological evaluation revealed excellent performance, with high Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition scores (ie, 82nd percentile for both global intelligence and general ability index). In conclusion, TMPRSS6 c.1807G>C in conjunction with c.1324G>A results in IRIDA. In contrast to the usual form of IDA, IRIDA may not be associated with neuropsychological deficits.

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The role of TMPRSS6/matriptase-2 in iron regulation and anemia

Cited by 59 publications

References 76 publications

Design and chemical syntheses of potent matriptase‐2 inhibitors based on trypsin inhibitor SFTI‐1 isolated from sunflower seeds

Design and chemical syntheses of potent matriptase‐2 inhibitors based on trypsin inhibitor SFTI‐1 isolated from sunflower seeds

Iron Refractory Iron Deficiency Anemia in Dizygotic Twins Due to a Novel TMPRSS6 Gene Mutation in Addition to Polymorphisms Associated With High Susceptibility to Develop Ferropenic Anemia

Iron-Refractory Iron Deficiency Anemia May Not Lead to Neurocognitive Dysfunction: A Case Report

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