A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron

Melis, Maria Paola; Cau, Milena; Congiu, Rita; Sole, Gabriella; Barella, Susanna; Cao, Antonio; Westerman, Mark; Cazzola, Mario; Galanello, Renzo

doi:10.3324/haematol.13342

Cited by 174 publications

(154 citation statements)

References 26 publications

(25 reference statements)

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“…C-reactive protein mRNA levels are similar in Tmprss6 ϩ/Ϫ and wild-type mice (data not shown), ruling out a potential contribution of inflammation to hepcidin expression. In agreement with the observation of a more severe anemia in young versus adult patients in a large iron-refractory iron deficiency anemia (IRIDA) pedigree, 6 our results show that young Tmprss6 ϩ/Ϫ mice, which have increased iron demands, are indeed more iron-deficient than adult mice.…”

Section: Horny Hp Akin C Metcalfe Dd Et Al Mastocytosis (Mast Celsupporting

confidence: 78%

Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

Nai

Pagani

Silvestri

et al. 2010

Blood

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Section: Horny Hp Akin C Metcalfe Dd Et Al Mastocytosis (Mast Celsupporting

confidence: 78%

Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

Nai

Pagani

Silvestri

et al. 2010

Blood

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“…Contrariwise, overexpression of wild-type matriptase-2 in human hepatoblastoma (HepG2) cells has been observed to result in suppression of hepcidin gene promoter activation (Du et al 2008). Mutations in the TMPRSS6 gene have also been implicated in iron deficiency anaemia refractory to oral iron therapy within Caucasian populations (Finberg et al 2008;Guillem et al 2008;Melis et al 2008). Further evidence of the association of TMPRSS6 polymorphisms with iron status in persons not affected by overt genetic disorders of iron metabolism have been observed in several GWAS though not all findings are consistent across studies (Benyamin et al 2009;Chambers et al 2009;Ganesh et al 2009;Tanaka et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses

et al. 2014

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Transmembrane protease, serine 6 (TMPRSS6), is likely to be involved in iron metabolism through its pleiotropic effect on hepcidin concentrations. Recently, genome-wide association studies have identified common variants in the TMPRSS6 gene to be linked to anaemia and low iron status. To get a more precise evaluation of identified TMPRSS6 single nucleotide polymorphism associations with iron status in cohorts of differing continental ancestry, we conducted a systematic review with metaanalyses. We searched the literature using HuGE Navigator, Pubmed and Scopus databases for primarily genomewide association studies using TMPRSS6 as a free term. Fixed-effects meta-analysis was used to obtain summary estimates of associations. Eleven studies comprised Caucasian populations, four included an Asian population and one study included an African-American population. Differences in minor allele frequencies of 8 TMPRSS6 SNPs (rs855791, rs4820268, rs2111833, rs1421312, rs228921, rs228918, rs228919 and rs575620) across ethnic groups were observed, with the MAF of rs855791 significantly higher in Asian populations than in Caucasians (0.55 vs 0.42, P \ 0.0001). In the meta-analysis, the A allele of rs855791 was associated with lower Hb and ferritin concentrations in all populations. This allele was also associated with increased serum transferrin receptor and transferrin concentrations. We observed similar associations for the G allele in rs4820268. Clear disparities in associations were found for the African-American population, although not statistically significant. Associations between TMPRSS6 SNPs and anaemia are consistent across Caucasian and Asian populations. This study highlights the need to conduct studies in African populations where iron deficiency is of utmost public health significance.

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“…99 Conversely, elevated hepcidin levels have been described in iron deficiency anemia patients that are insensitive to oral iron therapy and display an incomplete hematologic recovery with parenteral iron administrations, a condition termed iron refractory iron deficiency anemia (IRIDA). 94,100 Heterozygous and homozygous biallelic human matriptase-2 mutations have been identified by 3 independent studies in 14 IRIDA patients from Northern European, African and Afro-American, 94 Mediterranean 100 and English ancestries. 101 Further, 2 additional IRIDA patients who harbored a single mutated allele have been described, 94 although as only exon/intron boundaries and coding regions were sequenced, deep intronic mutations of the second allele may exist.…”

Section: Matriptase-2 Mutations In Human Iron Disordersmentioning

confidence: 99%

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Ramsay¹,

Hooper²,

Folgueras³

et al. 2009

Haematologica

107

104

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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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A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron

Abstract: BackgroundHepcidin plays a key role in body iron metabolism by preventing the release of iron from macrophages and intestinal cells. Defective hepcidin synthesis causes iron loading, while overproduction results in defective reticuloendothelial iron release and iron absorption.

Cited by 174 publications

References 26 publications

Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

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