Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10 , a Manganese Transporter in Man

Tuschl, Karin; Clayton, Peter T.; Gospe, Sídney M.; Gulab, Shamshad; Ibrahim, Shahnaz; Singhi, Pratibha; Aulakh, Roosy; Ribeiro, Reinaldo Teixeira; Barsottini, Orlando Graziani Póvoas; Zaki, Maha S.; Rosario, Maria Luz Del; Dyack, Sarah; Price, Victoria; Rideout, Andrea L.; Gordon, Ken; Wevers, Ron A.; Chong, WK; Mills, Philippa B.

doi:10.1016/j.ajhg.2012.01.018

Cited by 327 publications

(379 citation statements)

References 55 publications

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“…Recent genetic studies identified mutations in the human gene that were associated with hypermanganesemia. Loading of this metal is observed in both tissues, resulting in cirrhosis of the liver and Parkinson-like motor impairments (94,95). Due to the roles of manganese (and zinc) in combating infection, one speculation is that this transporter may also participate in the host immune response.…”

Section: Roles Of Other Transportersmentioning

confidence: 99%

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

Wessling‐Resnick

2015

Journal of Biological Chemistry

112

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During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review.The rationale for host metal withholding against invading pathogens seems intuitive; restriction of any nutrient required for pathogen survival should combat infection. But why metals? The answer to this question becomes crystal clear when one recognizes that iron is required for nearly all life forms, including pathogenic bacteria, with a few rare exceptions that rely on manganese instead (1-7). Iron is essential for ATP production and other metabolic pathways, but its concentration is limited to avoid production of ROS 2 catalyzed by excess levels of this redox-active metal (8). In some organisms, manganese can substitute for redox-active iron to protect against oxidative stress (9, 10). Moreover, most pathogens require manganese to produce their own superoxide dismutase activity to thwart oxidative killing mechanisms exerted by the host (11-13). Iron and manganese have similar ionic radii, have a divalent charge state under physiological conditions, have similar coordination chemistries, and have cellular concentrations in the micromolar range. Consequently, it comes as no surprise that these two metals also share membrane transporters, despite their different cellular functions and distributions. Restriction of iron and/or manganese provides a broad-spectrum metabolic "antidote" against all pathogenic infections, and the common transport pathways used by these metals present selective targets to limit their availability. Although many other immune responses contribute to the fight against infection, metal withholding represents a major force in host defense with combat controlled through transport.The concept of nutritional immunity through metal withholding is largely based on the observations that the iron content of the human diet profoundly affects infectious diseases such as malaria, brucellosis, and tuberculosis (14, 15). Iron overload states such as sickle cell anemia and ␤-thalassemia increase the risk of infection (16 -18). Hereditary hemochromatosis, an inherited disorder of iron metabolism, is also linked to susceptibility to some pathogens (17, 19 -22). Iron deficiency, on the other hand, is associated with decreased survival of individuals infected with HIV and other agents (23). Still, high iron is positively associated with viral load and mortality in HIV (24 -26), suggesting that an optimal balance of iron is necessary. In general terms, low iron status is protective, whereas elevated iron levels promote infection (27, 28). The complexity of host-pathogen interact...

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Section: Roles Of Other Transportersmentioning

confidence: 99%

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

Wessling‐Resnick

2015

Journal of Biological Chemistry

112

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“…Homozygous mutations of the ZnT10 gene cause Parkinsonism and dystonia with hypermanganesemia, polycythemia, and hepatic cirrhosis (OMIM 613280) (341,417). In these patients, not zinc, but systemic and cellular manganese homeostasis was disturbed (341,417), suggesting that the primary function of ZnT10 is manganese transport (see sect. IIIA).…”

Section: Znt10mentioning

confidence: 99%

“…Homozygous loss-of-function mutations of the ZnT10/ SLC30A10 gene cause Parkinsonism and dystonia with hypermanganesemia, which are ameliorated by metal chelation therapy (341,417).…”

Section: B Genetic Diseases Of Zinc Transporters and Therapeutic Appmentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

873

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…For example, toxic effects of hypermanganesemia are seen in an inherited Mn overload syndrome associated with genetic defects in SLC30A10 (15,16). Recent studies have shown that SLC30A10 is a cell surfacelocalized Mn efflux transporter that reduces cellular Mn levels and protects against Mn toxicity (17,18).…”

mentioning

confidence: 99%

Ferroportin deficiency impairs manganese metabolism in flatiron mice

Seo

Wessling‐Resnick

2015

FASEB j.

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We examined the physiologic role of ferroportin (Fpn) in manganese (Mn) export using flatiron (ffe/+) mice, a genetic model of Fpn deficiency. Blood (0.0123 vs. 0.0107 mg/kg; P = 0.0003), hepatic (1.06 vs. 0.96 mg/kg; P = 0.0125), and bile Mn levels (79 vs. 38 mg/kg; P = 0.0204) were reduced in ffe/+ mice compared to +/+ controls. Erythrocyte Mn-superoxide dismutase was also reduced at 6 (0.154 vs. 0.096, P = 0.0101), 9 (0.131 vs. 0.089, P = 0.0162), and 16 weeks of age (0.170 vs. 0.090 units/mg protein/min; P < 0.0001). 54 Mn uptake after intragastric gavage was markedly reduced in ffe/+ mice (0.0187 vs. 0.0066% dose; P = 0.0243), while clearance of injected isotope was similar in ffe/+ and +/+ mice. These values were compared to intestinal absorption of 59 Fe, which was significantly reduced in ffe/+ mice (8.751 vs. 3.978% dose; P = 0.0458). The influence of the ffe mutation was examined in dopaminergic SH-SY5Y cells and human embryonic HEK293T cells. While expression of wild-type Fpn reversed Mn-induced cytotoxicity, ffe mutant H32R failed to confer protection. These combined results demonstrate that Fpn plays a central role in Mn transport and that flatiron mice provide an excellent genetic model to explore the role of this exporter in Mn homeostasis.-Seo, Y. A., Wessling-Resnick, M. Ferroportin deficiency impairs manganese metabolism in flatiron mice. FASEB J. 29, 2726-2733 (2015). www.fasebj.org

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Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10 , a Manganese Transporter in Man

Cited by 327 publications

References 55 publications

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Ferroportin deficiency impairs manganese metabolism in flatiron mice

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