Analysis of SLC40A1 gene at the mRNA level reveals rapidly the causative mutations in patients with hereditary hemochromatosis type IV

Speletas, Matthaios; Kioumi, Anna; Loules, Gedeon; Hytiroglou, Prodromos; Tsitouridis, John; Christakis, John; Germenis, Anastasios E.

doi:10.1016/j.bcmd.2007.09.011

Cited by 22 publications

(8 citation statements)

References 26 publications

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“…Fpn may function as a monomer or a dimer in Fe and Mn efflux [45,50]. Mutations in Fpn ( SCL40A1 ) lead to Fe accumulation called haemochromatosis type 4, also known as Ferroportin disease [53,54,55]. No neurological symptoms are reported from Fpn mutation.…”

Section: Ferroportin: Fe and Mn Effluxmentioning

confidence: 99%

Manganese efflux in Parkinsonism: Insights from newly characterized SLC30A10 mutations

DeWitt

Chen

Aschner

2013

Biochemical and Biophysical Research Communications

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Although manganese (Mn) is required for normal cellular function, overexposure to this metal may cause an extrapyramidal syndrome resembling Parkinson’s disease (PD). Notably, high whole-blood Mn levels have been reported in patients with idiopathic PD. Because Mn is both essential at low dose and toxic at higher dose; its transport and homeostasis are tightly regulated. Previously, the only protein known to be operant in cellular Mn export was the iron-regulating transporter, ferroportin (Fpn). The causal role for Mn in PD has yet to be fully understood, but evidence of a familial predisposition to PD associated with Mn toxicity is mounting. A recently discovered mutation in SLC30A10 identified its gene product as putatively involved in Mn efflux. Patients with the SLC30A10 mutation display Parkinsonian-like gate disturbances and hypermanganesemia. This review will address Mn transport proteins, the newly discovered SLC30A10 mutations and their implications to Parkinsonism and Mn regulation.

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Section: Ferroportin: Fe and Mn Effluxmentioning

confidence: 99%

Manganese efflux in Parkinsonism: Insights from newly characterized SLC30A10 mutations

DeWitt

Chen

Aschner

2013

Biochemical and Biophysical Research Communications

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“…Although the amount of iron effluxed by ferroportin from the enterocyte in mammals is quantitatively minuscule under normal physiologic conditions, a breach in its regulation is fraught with disastrous consequences. Several mutations have been described in the Fpn gene (39)(40)(41)(42) and associated with these is a loss-offunction phenotype that results in iron-loading specifically in macrophages, a niche that favors the growth and proliferation of a number of pathogens. (39,42,43) Fpn regulation, remotely controlled by hepcidin, is discussed below.…”

Section: Ferroportinmentioning

confidence: 99%

Iron metabolism: microbes, mouse, and man

Latunde-Dada

2009

BioEssays

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Recent advances in research on iron metabolism have revealed the identity of a number of genes, signal transduction pathways, and proteins involved in iron regulation in mammals. The emerging paradigm is a coordination of homeostasis within a network of classical iron metabolic pathways and other cellular processes such as cell differentiation, growth, inflammation, immunity, and a host of physiologic and pathologic conditions. Iron, immunity, and infection are intricately linked and their regulation is fundamental to the survival of mammals. The mutual dependence on iron by the host and invading pathogenic organisms elicits competition for the element during infection. While the host maintains mechanisms to utilize iron for its own metabolism exclusively, pathogenic organisms are armed with a myriad of strategies to circumvent these measures. This review explores iron metabolism in mammalian host, defense mechanisms against pathogenic microbes and the competitive devices of microbes for access to iron.

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“…2 In contrast, a reduced iron export function as previously reported for A77D and R178Q could explain increased iron storage in macrophages and low transferrin saturation, but does not explain total body iron overload. 20 The R178Q mutation has been first identified in in France and Greece where affected patients had FD [21][22][23] and further characterized in a cohort of 22 patients from six unrelated pedigrees in France, Belgium and Iraq. 24 In vitro experiments also showed a reduced iron export capacity and high serum hepcidin concentration.…”

Section: Introductionmentioning

confidence: 99%

Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease

Viveiros

Panzer

Baumgartner

et al. 2020

Liver International

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Background & Aims: Ferroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin-encoding gene SLC40A1. Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidininduced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant. Methods: The ferroportin disease variants R178Q andA77D and the HH4-variant C326Y were overexpressed in HEK-293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin-ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases. Results: In the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D-variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD. Conclusions: These results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin-mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.

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Analysis of SLC40A1 gene at the mRNA level reveals rapidly the causative mutations in patients with hereditary hemochromatosis type IV

Cited by 22 publications

References 26 publications

Manganese efflux in Parkinsonism: Insights from newly characterized SLC30A10 mutations

Manganese efflux in Parkinsonism: Insights from newly characterized SLC30A10 mutations

Iron metabolism: microbes, mouse, and man

Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease

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