A missense variant in
            <i>SLC39A8</i>
            confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity

Nakata, Toru; Creasey, Elizabeth A.; Kadoki, Motohiko; Lin, Helen Lee; Selig, Martin K.; Yao, Junmei; Lefkovith, Ariel; Daly, Mark J.; Graham, Daniel B.; Xavier, Ramnik J.

doi:10.1073/pnas.2014742117

Cited by 33 publications

(31 citation statements)

References 62 publications

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“…SLC39A8: the SLC39A8 A391T variant was not reported in the fine-mapping paper, as its genetic region was not included in the ImmunoChip design. Because this variant has been published in several papers as an IBD variant with genetic and functional evidence [58][59][60] , we assign this variant as "Known causal candidate". TYK2: the TYK2 A928V was not reported in the fine-mapping paper 5 , likely due to a lack of power.…”

Section: Conditional Analysismentioning

confidence: 99%

Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

Sazonovs¹,

Stevens²,

Venkataraman³

et al. 2021

Preprint

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Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD); however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequence data from more than 30,000 CD cases and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

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Section: Conditional Analysismentioning

confidence: 99%

Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

Sazonovs¹,

Stevens²,

Venkataraman³

et al. 2021

Preprint

Self Cite

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“…The choice of the most suitable assay is not only dictated by the characteristics of a particular SLC, but also by the goal of the screening. While many biological questions related to the role of individual transporters in biological processes can be answered only in animal models ( Jiménez-Valerio et al, 2016 ; Pisarsky et al, 2016 ; Nakata et al, 2020 ), or with different approaches, such as genetic screens ( Fauster et al, 2018 ; Kory et al, 2018 ; Sedlyarov et al, 2018 ; Girardi et al, 2020a ), this review will focus on target-based cellular technologies for chemical screening in drug discovery campaigns or mechanistic transport studies. Most presented assays are best suited for in vitro applications, which may limit physiological relevance.…”

Section: Cell-based Assay Technologies For Solute Carrier Oriented Screeningmentioning

confidence: 99%

An Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters

et al. 2021

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The solute carrier (SLC) superfamily represents the biggest family of transporters with important roles in health and disease. Despite being attractive and druggable targets, the majority of SLCs remains understudied. One major hurdle in research on SLCs is the lack of tools, such as cell-based assays to investigate their biological role and for drug discovery. Another challenge is the disperse and anecdotal information on assay strategies that are suitable for SLCs. This review provides a comprehensive overview of state-of-the-art cellular assay technologies for SLC research and discusses relevant SLC characteristics enabling the choice of an optimal assay technology. The Innovative Medicines Initiative consortium RESOLUTE intends to accelerate research on SLCs by providing the scientific community with high-quality reagents, assay technologies and data sets, and to ultimately unlock SLCs for drug discovery.

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“…Correspondingly, missense mutation A391T of the SLC39A8 gene, which is known as a Mn transporter, was associated with profound Mn deficiency and altered the intestinal mucus barrier function in mice. The latter is expected to be related to altered glycoprotein structures, including glycocalyx, through the modulation of Mn-dependent glycosyltransferases [ 84 ]. In multivariate models, this mutation was also shown to be associated with a predominant increase in the abundance of Firmicutes [ 85 ].…”

Section: Mn and Gut Wall Permeabilitymentioning

confidence: 99%

Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity

et al. 2021

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Manganese (Mn) is an essential metal, which at high exposures causes neurotoxic effects and neurodegeneration. The neurotoxic effects of Mn are mediated by neuroinflammation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, and other mechanisms. Recent findings have demonstrated the potential impact of Mn overexposure on gut microbiota dysbiosis, which is known to contribute to neurodegeneration via secretion of neuroactive and proinflammatory metabolites. Therefore, in this review, we discuss the existing data on the impact of Mn exposure on gut microbiota biodiversity, bacterial metabolite production, and gut wall permeability regulating systemic levels. Recent data have demonstrated that Mn exposure may affect gut microbiota biodiversity by altering the abundance of Shiegella, Ruminococcus, Dorea, Fusicatenibacter, Roseburia, Parabacteroides, Bacteroidetes, Firmicutes, Ruminococcaceae, Streptococcaceae, and other bacterial phyla. A Mn-induced increase in Bacteroidetes abundance and a reduced Firmicutes/Bacteroidetes ratio may increase lipopolysaccharide levels. Moreover, in addition to increased systemic lipopolysaccharide (LPS) levels, Mn is capable of potentiating LPS neurotoxicity. Due to the high metabolic activity of intestinal microflora, Mn-induced perturbations in gut microbiota result in a significant alteration in the gut metabolome that has the potential to at least partially mediate the biological effects of Mn overexposure. At the same time, a recent study demonstrated that healthy microbiome transplantation alleviates Mn-induced neurotoxicity, which is indicative of the significant role of gut microflora in the cascade of Mn-mediated neurotoxicity. High doses of Mn may cause enterocyte toxicity and affect gut wall integrity through disruption of tight junctions. The resulting increase in gut wall permeability further promotes increased translocation of LPS and neuroactive bacterial metabolites to the systemic blood flow, ultimately gaining access to the brain and leading to neuroinflammation and neurotransmitter imbalance. Therefore, the existing data lead us to hypothesize that gut microbiota should be considered as a potential target of Mn toxicity, although more detailed studies are required to characterize the interplay between Mn exposure and the gut, as well as its role in the pathogenesis of neurodegeneration and other diseases.

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A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity

Cited by 33 publications

References 62 publications

Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

An Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters

Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity

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