Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice

Xin, Yongjuan; Gao, Hong; Wang, Jia; Qiang, Yuzhen; Imam, Mustapha Umar; Li, Yang; Wang, Jianyao; Zhang, Ruochen; Zhang, Huizhen; Yu, Yingying; Wang, Hao; Luo, Hui; Shi, Changhe; Xu, Yuming; Hojyo, Shintaro; Fukada, Toshiyuki; Min, Junxia; Wang, Fudi

doi:10.1038/celldisc.2017.25

Cited by 106 publications

(118 citation statements)

References 56 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…In our Mn supplementation study, we fed mice with 300 ppm Mn and found a slight protective effect against DSS‐induced colitis. Previous mouse studies have shown that oral supplementation with Mn even at levels of ~2400 ppm does not cause toxicity . This finding suggests that Mn toxicity would be less of a concern in the design of dietary Mn supplementation for this IBD mouse model.…”

Section: Resultsmentioning

confidence: 58%

“…Previous mouse studies have shown that oral supplementation with Mn even at levels of ~2400 ppm does not cause toxicity. 51,52 This finding suggests that Mn toxicity would be less of a concern in the design of dietary Mn supplementation for this IBD mouse model. Future studies will be needed to determine the dietary Mn levels that would be most beneficial for human patient populations.…”

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

Impact of dietary manganese on experimental colitis in mice

et al. 2019

View full text Add to dashboard Cite

Diet plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). A recent epidemiological study has shown an inverse relationship between nutritional manganese (Mn) status and IBD patients. Mn is an essential micronutrient required for normal cell function and physiological processes. To date, the roles of Mn in intestinal homeostasis remain unknown and the contribution of Mn to IBD has yet to be explored. Here, we provide evidence that Mn is critical for the maintenance of the intestinal barrier and that Mn deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in mice. Specifically, when treated with DSS, Mn-deficient mice showed increased morbidity, weight loss, and colon injury, with a concomitant increase in inflammatory cytokine levels and oxidative and DNA damage. Even without DSS treatment, dietary Mn deficiency alone increased intestinal permeability by impairing intestinal tight junctions. In contrast, mice fed a Mn-supplemented diet showed slightly increased tolerance to DSS-induced experimental colitis, as judged by the colon length. Despite the well-appreciated roles of intestinal microbiota in driving inflammation in IBD, the gut microbiome composition was not altered by changes in dietary Mn. We conclude that Mn is necessary for proper maintenance of the intestinal barrier and provides protection against DSS-induced colon injury. K E Y W O R D Scolitis, gut microbiota, inflammatory bowel disease, manganese, tight junction 2930 | CHOI et al. | RNA isolation and RT-PCR

show abstract

Section: Resultsmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 81%

Impact of dietary manganese on experimental colitis in mice

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Thus, Mn accumulation due to ZIP14 mutations in humans was initially believed to be associated with impaired hepatobiliary Mn elimination (35). However, liver-specific Zip14 KO mice do not show systemic Mn accumulation or motor deficits (37), suggesting that Mn is eliminated by an alternative route. In enterocytes, ZIP14 has a basolateral orientation (BL) (3, 14).…”

Section: Introductionmentioning

confidence: 99%

Intestine-specific deletion of metal transporterZip14 (Slc39a14)causes brain manganese overload and locomotor defects of manganism

Aydemir

Thorn

Ruggiero

et al. 2020

Preprint

View full text Add to dashboard Cite

Impaired manganese (Mn) homeostasis can result in excess Mn accumulation in specific brain regions and neuropathology. Maintaining Mn homeostasis and detoxification is dependent on effective Mn elimination. Specific metal transporters control Mn homeostasis. Human carriers of mutations in the metal transporter ZIP14 and whole-body Zip14 KO (WB-KO) mice display similar phenotypes, including spontaneous systemic and brain Mn overload, and motor dysfunction. Initially, it was believed that Mn accumulation due to ZIP14 mutations caused by impaired hepatobiliary Mn elimination. However, liver-specific Zip14 KO mice (L-KO) did not show systemic Mn accumulation or motor deficits. ZIP14 is highly expressed in the small intestine and is localized to the basolateral surface of enterocytes. Thus we hypothesized that basolaterally-localized ZIP14 in enterocytes provides another route for elimination of Mn. Using wild type and intestine-specific ZIP14 KO (I-KO) mice, we have shown that ablation of intestinal Zip14 is sufficient to cause systemic and brain Mn accumulation. The lack of intestinal ZIP14- mediated Mn excretion was compensated for by the hepatobiliary system; however, it was not sufficient to maintain Mn homeostasis. When supplemented with extra dietary Mn, I-KO mice displayed some motor dysfunctions, brain Mn accumulation based on both MRI imaging and chemical analysis, thus demonstrating the importance of intestinal ZIP14 as a route of Mn excretion. A defect in intestinal Zip14 expresssion likely could contribute to the Parkinson-like Mn accumulation of manganism.New & NoteworthyMn-induced parkinsonism is recognized as rising in frequency due to both environmental factors and genetic vulnerability, yet currently, there is no cure. We provide evidence in an integrative animal model that basolaterally localized ZIP14 regulates Mn excretion and detoxification and that deletion of intestinal ZIP14 leads to systemic and brain Mn accumulation, providing robust evidence for the indispensable role of intestinal ZIP14 on Mn excretion.

show abstract

“…Even more recently, a syndrome of infantile‐ or childhood‐onset dystonia with hypermanganesemia (OMIM #617013) has been linked to biallelic mutations in yet another divalent cation transporter gene, SLC39A14 , responsible for manganese elimination . This disorder presents in infancy or early childhood with developmental delay, dystonia, and bulbar dysfunction .…”

Section: The “Top Ten” Of Treatable Iems Presenting With Movement Dismentioning

confidence: 99%

“…Even more recently, a syndrome of infantile-or childhood-onset dystonia with hypermanganesemia (OMIM #617013) has been linked to biallelic mutations in yet another divalent cation transporter gene, SLC39A14, 47 responsible for manganese elimination. 47,[93][94][95] This disorder presents in infancy or early childhood with developmental delay, dystonia, and bulbar dysfunction. 47,96 The course is progressive, and most children develop generalized dystonia, spasticity, contractures, and severe scoliosis within the first 10 years of life.…”

Section: #09 Slc30a10-and Slc39a14-associated Hypermanganesemiamentioning

confidence: 99%

Movement Disorders in Treatable Inborn Errors of Metabolism

Ebrahimi‐Fakhari

Karnebeek²,

Münchau

2018

Movement Disorders

View full text Add to dashboard Cite

There are several hundred single‐gene disorders that we classify as inborn errors of metabolism. Inborn errors of metabolism are often rare and highly heterogeneous multisystem diseases with non‐neurological and neurological manifestations, commonly with onset during childhood. Movement disorders are among the most common neurological problems in inborn errors of metabolism, but, in many cases, remain poorly defined. Although movement disorders are usually not the only and often not the presenting symptom, their recognition can facilitate a diagnosis. Movement disorders contribute substantially to the morbidity in inborn errors of metabolism and can have a significant impact on quality of life. Common metabolic movement disorders include the monoamine neurotransmitter disorders, disorders of amino and organic acid metabolism, metal storage disorders, lysosomal storage disorders, congenital disorders of autophagy, disorders of creatine metabolism, vitamin‐responsive disorders, and disorders of energy metabolism. Importantly, disease‐modifying therapies exist for a number of inborn errors of metabolism, and early recognition and treatment can prevent irreversible CNS damage and reduce morbidity and mortality. A phenomenology‐based approach, based on the predominant movement disorder, can facilitate a differential diagnosis and can guide biochemical, molecular, and imaging testing. The complexity of metabolic movement disorders demands an interdisciplinary approach and close collaboration of pediatric neurologists, neurologists, geneticists, and experts in metabolism. In this review, we develop a general framework for a phenomenology‐based approach to movement disorders in inborn errors of metabolism and discuss an approach to identifying the “top ten” of treatable inborn errors of metabolism that present with movement disorders—diagnoses that should never be missed. © 2018 International Parkinson and Movement Disorder Society

show abstract

Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice

Cited by 106 publications

References 56 publications

Impact of dietary manganese on experimental colitis in mice

Impact of dietary manganese on experimental colitis in mice

Intestine-specific deletion of metal transporterZip14 (Slc39a14)causes brain manganese overload and locomotor defects of manganism

Movement Disorders in Treatable Inborn Errors of Metabolism

Contact Info

Product

Resources

About