Genetic Disorders Associated with Metal Metabolism

Umair, Muhammad; Alfadhel, Majid

doi:10.3390/cells8121598

Cited by 37 publications

(26 citation statements)

References 130 publications

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“…Stress caused by toxic levels of copper ions results in overproduction of ROS, which can alter energy production and metabolism ( Uriu-Adams and Keen 2005 ; Tchounwou et al 2008 ; Quijano et al 2016 ). Negative effects of the misregulation of or overexposure to copper and other heavy metals such as zinc, lead, mercury, and arsenic through disease ( Giacoppo et al 2014 ; Liddell and White 2018 ; Umair and Alfadhel 2019 ) or because of pollution have been associated with impaired or altered mitochondrial function ( Belyaeva et al 2011 , 2012 ; Jia et al 2015 ). It is therefore possible that variation in metabolic function among the DSPR strains is one of the underlying contributors to variation in copper resistance.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the genetic basis of copper toxicity in Drosophila reveals a complex pattern of allelic, regulatory, and behavioral variation

2020

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A range of heavy metals are required for normal cell function and homeostasis. However, the anthropogenic release of metal compounds into soil and water sources presents a pervasive health threat. Copper is one of many heavy metals that negatively impacts diverse organisms at a global scale. Using a combination of quantitative trait locus (QTL) mapping and RNA sequencing in the Drosophila Synthetic Population Resource, we demonstrate that resistance to the toxic effects of ingested copper in D. melanogaster is genetically complex and influenced by allelic and expression variation at multiple loci. QTL mapping identified several QTL that account for a substantial fraction of heritability. Additionally, we find that copper resistance is impacted by variation in behavioral avoidance of copper and may be subject to life-stage specific regulation. Gene expression analysis further demonstrated that resistant and sensitive strains are characterized by unique expression patterns. Several of the candidate genes identified via QTL mapping and RNAseq have known copper-specific functions (e.g., Ccs, Sod3, CG11825), and others are involved in the regulation of other heavy metals (e.g., Catsup, whd). We validated several of these candidate genes with RNAi suggesting they contribute to variation in adult copper resistance. Our study illuminates the interconnected roles that allelic and expression variation, organism life stage, and behavior play in copper resistance, allowing a deeper understanding of the diverse mechanisms through which metal pollution can negatively impact organisms.

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Section: Discussionmentioning

confidence: 99%

Characterizing the genetic basis of copper toxicity in Drosophila reveals a complex pattern of allelic, regulatory, and behavioral variation

2020

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“…Unlike iron, zinc is a divalent cation and does not require a redox reaction during the membrane transport process [122]. From more than twenty Zn transporters, Irt-related protein 4 is essential for the uptake of dietary zinc at the apical membrane in intestinal epithelial cells, and thus, the SLC39A4 gene mutation is associated with zinc deficiency and results in a rare inherited recessive disease (Acrodermatitis enteropathica) [123,124]. The Zn 2+ efflux from enterocytes is secured by ZnT1 transporter (also known as SLC30A1), which may operate as Zn 2+ /H + exchanger [125].…”

Section: Association Between Zinc and Gut Microbiotamentioning

confidence: 99%

Bioaccessibility and Bioavailability of Minerals in Relation to a Healthy Gut Microbiome

Bielik

Kolísek

2021

IJMS

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Adequate amounts of a wide range of micronutrients are needed by body tissues to maintain health. Dietary intake must be sufficient to meet these micronutrient requirements. Mineral deficiency does not seem to be the result of a physically active life or of athletic training but is more likely to arise from disturbances in the quality and quantity of ingested food. The lack of some minerals in the body appears to be symbolic of the modern era reflecting either the excessive intake of empty calories or a negative energy balance from drastic weight-loss diets. Several animal studies provide convincing evidence for an association between dietary micronutrient availability and microbial composition in the gut. However, the influence of human gut microbiota on the bioaccessibility and bioavailability of trace elements in human food has rarely been studied. Bacteria play a role by effecting mineral bioavailability and bioaccessibility, which are further increased through the fermentation of cereals and the soaking and germination of crops. Moreover, probiotics have a positive effect on iron, calcium, selenium, and zinc in relation to gut microbiome composition and metabolism. The current literature reveals the beneficial effects of bacteria on mineral bioaccessibility and bioavailability in supporting both the human gut microbiome and overall health. This review focuses on interactions between the gut microbiota and several minerals in sport nutrition, as related to a physically active lifestyle.

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“…ATP7B is the only gene known to cause WD. The phenotype of WD is clinically distinct from other disorders of copper metabolism such as Menkes disease and MEDNIK syndrome (Umair and Alfadhel 2019). Considering this, as well as the fact that the SNP ROH encompassed the ATP7B gene, a hidden variant involving ATP7B was suspected.…”

Section: Discussionmentioning

confidence: 99%

Early-onset Wilson disease caused by ATP7B exon skipping associated with intronic variant

Koboldt

Hickey

Chaudhari

et al. 2020

Cold Spring Harb Mol Case Stud

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Wilson disease is a medically actionable rare autosomal recessive disorder of defective copper excretion caused by mutations in ATP7B, one of two highly evolutionarily conserved copper-transporting ATPases. Hundreds of disease-causing variants in ATP7B have been reported to public databases; more than half of these are missense changes, and a significant proportion are presumed unequivocal loss-of-function variants (nonsense, frameshift, and canonical splice site). Current molecular genetic testing includes sequencing all coding exons (±10 bp) as well as deletion/duplication testing, with reported sensitivity of >98%. We report a proband from a consanguineous family with a biochemical phenotype consistent with early-onset Wilson disease who tested negative on conventional molecular genetic testing. Using a combination of whole-genome sequencing and transcriptome sequencing, we found that the proband's disease is due to skipping of exons 6-7 of the ATP7B gene associated with a novel intronic variant (NM_000053.4:c.1947-19T > A) that alters a putative splicing enhancer element. This variant was also homozygous in the proband's younger sister, whose subsequent clinical evaluations revealed biochemical evidence of Wilson disease. Our work adds to emerging evidence that ATP7B exon skipping from deep intronic variants outside typical splice junctions is an important mechanism of Wilson disease; the variants responsible may elude standard genetic testing.

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Genetic Disorders Associated with Metal Metabolism

Cited by 37 publications

References 130 publications

Characterizing the genetic basis of copper toxicity in Drosophila reveals a complex pattern of allelic, regulatory, and behavioral variation

Characterizing the genetic basis of copper toxicity in Drosophila reveals a complex pattern of allelic, regulatory, and behavioral variation

Bioaccessibility and Bioavailability of Minerals in Relation to a Healthy Gut Microbiome

Early-onset Wilson disease caused by ATP7B exon skipping associated with intronic variant

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