The homozygous mutation <scp>G</scp>75<scp>R</scp> in the human <scp><i>SLC11A2</i></scp> gene leads to microcytic anaemia and iron overload

Prieto‐Barrios, Marta; Moreno-Carralero, María-Isabel; Cuadrado-Grande, Nuria; Baró, María del Rosario González; Vivanco, José-Luis; Morán-Jiménez, María-Josefa

doi:10.1111/j.1365-2141.2012.09043.x

Cited by 10 publications

(5 citation statements)

References 8 publications

(10 reference statements)

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“…(Barrios et al, 2012) and (Blanco, Kannengiesser, Grandchamp, Tasso, and Beaumont 2009) reported the same homozygous mutation in DMT1 in a 7-year-old boy and a 10-year-old boy, respectively. The mutation is located in the first transmembrane domain and leads to a glycine to arginine substitution (G75R).…”

Section: Iron Import Across the Plasma Membranementioning

confidence: 82%

Iron Transport Machinery of Human Cells

Zhao

Enns

2012

Metal Transporters

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Organisms, like cells, maintain tight control of iron. In humans as well as other mammals, control is achieved through the regulation of iron uptake into the body rather than through the excretion of iron. The mechanisms by which humans and mice regulate both iron uptake and the distribution of iron within the body and cells are reviewed. Special emphasis is given to the iron transporters involved in this process.

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Section: Iron Import Across the Plasma Membranementioning

confidence: 82%

Iron Transport Machinery of Human Cells

Zhao

Enns

2012

Metal Transporters

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“…To observe additional conformational states of a transport cycle in a single Nramp homolog at high resolution, we developed two complementary conformationally-locked constructs for crystallization. Adding steric bulk along TM1a—for example a G45R mutation, which mimics a human anemia-causing mutation of a conserved glycine (Barrios et al, 2012)—prevented the opening of the extracellular vestibule and eliminated metal transport, emphasizing the importance of the alternating-access mechanism to DraNramp function (Bozzi et al, 2016b). Based on these findings we pursued the G45R mutant as a new inward-locked crystallization construct.…”

Section: Resultsmentioning

confidence: 99%

Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter

Bozzi

Zimanyi

Nicoludis

et al. 2019

eLife

121

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Nramp family transporters—expressed in organisms from bacteria to humans—enable uptake of essential divalent transition metals via an alternating-access mechanism that also involves proton transport. We present high-resolution structures of Deinococcus radiodurans (Dra)Nramp in multiple conformations to provide a thorough description of the Nramp transport cycle by identifying the key intramolecular rearrangements and changes to the metal coordination sphere. Strikingly, while metal transport requires cycling from outward- to inward-open states, efficient proton transport still occurs in outward-locked (but not inward-locked) DraNramp. We propose a model in which metal and proton enter the transporter via the same external pathway to the binding site, but follow separate routes to the cytoplasm, which could facilitate the co-transport of two cationic species. Our results illustrate the flexibility of the LeuT fold to support a broad range of substrate transport and conformational change mechanisms.

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“…In addition, SNPs in the TF gene, also important in iron transport to cells, have also been reported to affect iron status and lead to low iron status [ 24 – 26 ]. Furthermore, SNPs in the divalent metal transporter 1 ( DMT1 ), the duodenal apical iron transporter encoded by the SLC11A2 gene have been associated with an unusual syndrome characterized by microcytic anaemia and a paradoxical iron overload [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Differences in the frequency of genetic variants associated with iron imbalance among global populations

et al. 2020

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Iron deficiency anaemia is a major health problem affecting approximately 1.2 billion people worldwide. Young children, women of reproductive age and pregnant women living in sub-Saharan Africa are the most vulnerable. It is estimated that iron deficiency accounts for half of anaemia cases. Apart from nutritional deficiency, infection, inflammation and genetic factors are the major drivers of anaemia. However, the role of genetic risk factors has not been thoroughly investigated. This is particularly relevant in African populations, as they carry high genetic diversity and have a high prevalence of anaemia. Multiple genetic variations in iron regulatory genes have been linked to impaired iron status. Here we conducted a literature review to identify genetic variants associated with iron imbalance among global populations. We compare their allele frequencies and risk scores and we investigated populationspecific selection among populations of varying geographic origin using data from the Keneba Biobank representing individuals in rural Gambia and the 1000 Genomes Project. We identified a significant lack of data on the genetic determinants of iron status in sub-Saharan Africa. Most of the studies on genetic determinants of iron status have been conducted in Europeans. Also, we identified population differences in allele frequencies in candidate putative genetic risk factors. Given the disproportionately high genetic diversity in African populations coupled with their high prevalence of iron deficiency, there is need to investigate the genetic influences of low iron status in Sub-Saharan Africa. The resulting insights may inform the future implementation of iron intervention strategies.

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The homozygous mutation G75R in the human SLC11A2 gene leads to microcytic anaemia and iron overload

Cited by 10 publications

References 8 publications

Iron Transport Machinery of Human Cells

Iron Transport Machinery of Human Cells

Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter

Differences in the frequency of genetic variants associated with iron imbalance among global populations

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