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1.
Biology of the iron efflux transporter, ferroportin.
Rishi, G, Subramaniam, VN
Advances in protein chemistry and structural biology. 2021;:1-16
Abstract
Iron, the most common metal in the earth, is also an essential component for almost all living organisms. While these organisms require iron for many biological processes, too much or too little iron itself poses many issues; this is most easily recognized in human beings. The control of body iron levels is thus an important metabolic process which is regulated essentially by controlling the expression, activity and levels of the iron transporter ferroportin. Ferroportin is the only known iron exporter. The function and activity of ferroportin is influenced by its interaction with the iron-regulatory peptide hepcidin, which itself is regulated by many factors. Here we review the current state of understanding of the mechanisms that regulate ferroportin and its function.
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2.
Analysis of the relationship between the mutation site of the SLC39A4 gene and acrodermatitis enteropathica by reporting a rare Chinese twin: a case report and review of the literature.
Zhong, W, Yang, C, Zhu, L, Huang, YQ, Chen, YF
BMC pediatrics. 2020;(1):34
Abstract
BACKGROUND Acrodermatitis enteropathica (AE) is a rare autosomal recessive hereditary skin disease caused by mutations in the SLC39A4 gene and is characterized by periorificial dermatitis, alopecia and diarrhoea due to insufficient zinc absorption. Only one of the three known sets of twins with AE has genetic information. This case reports the discovery of new mutation sites in rare twin patients and draws some interesting conclusions by analysing the relationship between genetic information and clinical manifestations. CASE PRESENTATION Here, we report a pair of 16-month-old twin boys with AE exhibiting periorificial and acral erythema, scales and blisters, while subsequent laboratory examination showed normal plasma zinc and alkaline phosphatase levels. Further Sanger sequencing demonstrated that the patients were compound heterozygous for two unreported SLC39A4 mutations: a missense mutation in exon 5 (c.926G > T), which led to a substitution of the 309th amino acid residue cysteine with phenylalanine, a splice site mutation occurring in the consensus donor site of intron 5 (c.976 + 2 T > A). A family study revealed that the boys' parents were heterozygous carriers of these two mutations. CONCLUSION We identified a new compound heterozygous mutation in Chinese twins with AE, which consisted of two previous unreported variants in exon 5 and intron 5 of SLC39A4. We propose an up-to-date review that different mutations in SLC39A4 may exhibit different AE manifestations. In conjunction with future research, our work may shed light on genotype-phenotype correlations in AE patients and provide knowledge for genetic counselling and treatment for AE patients.
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3.
Molecular identification of the magnesium transport gene family in Brassica napus.
Zhang, L, Wen, A, Wu, X, Pan, X, Wu, N, Chen, X, Chen, Y, Mao, D, Chen, L, Luan, S
Plant physiology and biochemistry : PPB. 2019;:204-214
Abstract
Magnesium (Mg2+) is an essential element for plant growth. Its transport and homeostasis in plants is mainly maintained by the MRS2/MGT of Mg2+ transporters. Little is known about the MRS2/MGT gene family in Brassica napus L. (B. napus), one of the most important oil grains. In our present study, we identified 36 putative MRS2/MGT genes (BnMGTs) from B. napus and investigated their phylogeny, expression pattern and function. These BnMGT genes were sorted into five distinguished groups by the phylogenetic analysis, and they were clearly homologous with the MRS2/MGT genes in Arabidopsis and rice. Complementation assays using the Salmonella typhimurium mutant MM281 demonstrated that the BnMGT genes were capable of mediating Mg2+ uptake and transport, with varied affinities to Mg2+. The expression pattern analysis showed that the expression of BnMGTs were tissue-specific and varied in different tissues. This work provides the molecular basis to discover the function of BnMGT gene family in plant growth and development.
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4.
Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes.
Adulcikas, J, Sonda, S, Norouzi, S, Sohal, SS, Myers, S
Nutrients. 2019;(2)
Abstract
Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the "gate-keeper" of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.
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5.
Genetic Disorders of Manganese Metabolism.
Anagianni, S, Tuschl, K
Current neurology and neuroscience reports. 2019;(6):33
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Abstract
PURPOSE OF REVIEW This article provides an overview of the pathogenesis, clinical presentation and treatment of inherited manganese transporter defects. RECENT FINDINGS Identification of a new group of manganese transportopathies has greatly advanced our understanding of how manganese homeostasis is regulated in vivo. While the manganese efflux transporter SLC30A10 and the uptake transporter SLC39A14 work synergistically to reduce the manganese load, SLC39A8 has an opposing function facilitating manganese uptake into the organism. Bi-allelic mutations in any of these transporter proteins disrupt the manganese equilibrium and lead to neurological disease: Hypermanganesaemia with dystonia 1 (SLC30A10 deficiency) and hypermanganesaemia with dystonia 2 (SLC39A14 deficiency) are characterised by manganese neurotoxicity while SLC39A8 mutations cause a congenital disorder of glycosylation type IIn due to Mn deficiency. Inherited manganese transporter defects are an important differential diagnosis of paediatric movement disorders. Manganese blood levels and MRI brain are diagnostic and allow early diagnosis to avoid treatment delay.
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6.
A case of dystonia with polycythemia and hypermanganesemia caused by SLC30A10 mutation: a treatable inborn error of manganese metabolism.
Tavasoli, A, Arjmandi Rafsanjani, K, Hemmati, S, Mojbafan, M, Zarei, E, Hosseini, S
BMC pediatrics. 2019;(1):229
Abstract
BACKGROUND Manganese is a critical trace element that not only has antioxidant properties, but also is essential for various metabolic pathways and neurotransmitters production. However, it can be toxic at high levels, particularly in the central nervous system. Manganese intoxication can be acquired, but an inherited form due to autosomal-recessive mutations in the SLC30A10 gene encoding a Mn transporter protein has also been reported recently. These mutations are associated with significant failure of manganese excretion and its storage in the liver, brain (especially basal ganglia), and other peripheral tissues, resulting in toxicity. CASE PRESENTATION A 10-year-old boy from consanguineous parents presented with a history of progressive truncal instability, gait difficulty, and frequent falls for 2 months. He had dystonia, rigidity, ataxia, dysarthria, bradykinesia and a plethoric skin. Investigations showed polycythemia, low serum iron and ferritin levels, and increased total iron binding capacity. A brain MRI revealed symmetric hyperintensities in the basal ganglia and dentate nucleuses on TI images that were suggestive of brain metal deposition together with clinical manifestations. Serum calcium and copper levels were normal, while the manganese level was significantly higher than normal values. There was no history of environmental overexposure to manganese. Genetic testing showed a homozygous missense mutation in SLC30A10 (c.C1006T, p.His336Tyr) and Sanger sequencing confirmed a homozygous state in the proband and a heterozygous state in the parents. Regular treatment with monthly infusions of disodium calcium edetate and oral iron compounds resulted in decreased serum manganese and hemoglobin levels to normal values, significant resolution of MRI lesions, and partial improvement of neurological symptoms during 6 months of follow-up. CONCLUSION The syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by SLC30A10 mutation is a treatable inherited metal deposition syndrome. The patient may only have pure neurological without hepatic manifestations. Although this is a rare and potentially fatal inborn error of metabolism, early diagnosis and continuous chelation therapy might improve the symptoms and prevent disease progression.
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7.
The bifunctional transporter-receptor IRT1 at the heart of metal sensing and signalling.
Cointry, V, Vert, G
The New phytologist. 2019;(3):1173-1178
Abstract
Transporters are at the centre of regulatory modules allowing optimal assimilation, distribution or efflux of substrate molecules. The IRT1 root metal transporter represents a textbook example in which detailed regulatory networks have been shown to integrate several endogenous and exogenous cues at various levels to regulate its expression and to fine tune iron uptake. Here, we summarise recent advances in the dissection of the transcriptional and posttranslational control of IRT1 by its various metals substrates and discuss the emerging role of IRT1 in the direct sensing of non-iron metals flowing through IRT1 to drive its degradation. We propose that transporters that also act as receptors are likely to be a common theme in the regulation of nutrient transport by sensing local nutrient concentrations.
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8.
Zinc and Skin Disorders.
Ogawa, Y, Kinoshita, M, Shimada, S, Kawamura, T
Nutrients. 2018;(2)
Abstract
The skin is the third most zinc (Zn)-abundant tissue in the body. The skin consists of the epidermis, dermis, and subcutaneous tissue, and each fraction is composed of various types of cells. Firstly, we review the physiological functions of Zn and Zn transporters in these cells. Several human disorders accompanied with skin manifestations are caused by mutations or dysregulation in Zn transporters; acrodermatitis enteropathica (Zrt-, Irt-like protein (ZIP)4 in the intestinal epithelium and possibly epidermal basal keratinocytes), the spondylocheiro dysplastic form of Ehlers-Danlos syndrome (ZIP13 in the dermal fibroblasts), transient neonatal Zn deficiency (Zn transporter (ZnT)2 in the secretory vesicles of mammary glands), and epidermodysplasia verruciformis (ZnT1 in the epidermal keratinocytes). Additionally, acquired Zn deficiency is deeply involved in the development of some diseases related to nutritional deficiencies (acquired acrodermatitis enteropathica, necrolytic migratory erythema, pellagra, and biotin deficiency), alopecia, and delayed wound healing. Therefore, it is important to associate the existence of mutations or dysregulation in Zn transporters and Zn deficiency with skin manifestations.
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9.
Ferroportin disease: pathogenesis, diagnosis and treatment.
Pietrangelo, A
Haematologica. 2017;(12):1972-1984
Abstract
Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (FPN) gene. It represents one of the commonest causes of genetic hyperferritinemia, regardless of ethnicity. FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting. The hallmark of FD is marked iron accumulation in hepatic Kupffer cells. Numerous FD-associated mutations have been reported worldwide, with a few occurring in different populations and some more commonly reported (e.g. Val192del, A77D, and G80S). FPN1 polymorphisms also represent the gene variants most commonly responsible for hyperferritinemia in Africans. Differential diagnosis includes mainly hereditary hemochromatosis, the syndrome commonly due to either HFE or TfR2, HJV, HAMP, and, in rare instances, FPN1 itself. Here, unlike FD, hyperferritinemia associates with high transferrin saturation, iron-spared macrophages, and progressive parenchymal cell iron load. Abdominal magnetic resonance imaging (MRI), the key non-invasive diagnostic tool for the diagnosis of FD, shows the characteristic iron loading SSL triad (spleen, spine and liver). A non-aggressive phlebotomy regimen is recommended, with careful monitoring of transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation.
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10.
The role of the zinc transporter SLC30A2/ZnT2 in transient neonatal zinc deficiency.
Golan, Y, Kambe, T, Assaraf, YG
Metallomics : integrated biometal science. 2017;(10):1352-1366
Abstract
Breast milk is the optimal nutrient mix for infants until the age of 6 months. However, in some cases, due to genetic alterations as well as nutrient deficiencies in nursing mothers, infants may suffer from inadequate levels of micronutrients upon exclusive breastfeeding. In this respect, transient neonatal zinc deficiency (TNZD) is caused by loss-of-function mutations in the zinc transporter SLC30A2/ZnT2 gene, resulting in poor secretion of zinc into the breast milk. Consequently, infants exclusively breastfed with zinc-deficient breast milk develop severe zinc deficiency. The main initial symptoms of zinc deficiency are dermatitis, diarrhea, alopecia, and loss of appetite. Importantly, zinc supplementation of these zinc-deficient infants effectively and rapidly resolves these TNZD symptoms. In the current review, we present the major steps towards the identification of the molecular mechanisms underlying TNZD and propose novel approaches that could be implemented in order to achieve an early diagnosis of TNZD towards the prevention of TNZD morbidity. We also discuss the importance of assessing the prevalence of TNZD in the general population, while taking into consideration its autosomal dominant inheritance that was recently established, also supported by a large number of SLC30A2/ZnT2 variants recently identified in American lactating mothers. These findings indicating that TNZD is more frequent than initially thought, along with the increasing number of TNZD cases that were recently reported worldwide, prompted us here to highlight the importance of early diagnosis of SLC30A2/ZnT2 variants in order to supplement zinc-deficient infants in real-time, thus preventing TNZD morbidity and enhancing newborn health. This early genetic diagnosis of zinc deficiency could possibly prove to be a useful platform for the identification of other micronutrient deficiencies, which could be readily resolved by proper real-time supplementation of the infant's diet.