A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia

Juneja, Monica; Shamim, Uzma; Joshi, Aditi; Mathur, Anurag; Uppili, Bharathram; Sairam, Smitha; Ambawat, Sakshi; Dixit, Rashmi; Faruq, Mohammed

doi:10.1002/jgm.3012

Cited by 30 publications

(35 citation statements)

References 18 publications

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“…Post-mortem analyses of one patient showed evidence of neuronal degeneration in the globus pallidus (159). Additional descriptions of patients suffering from Mn toxicity due to mutations in SLC39A14 were reported in 2018 (161,162).…”

Section: Slc39a14mentioning

confidence: 89%

Brain manganese and the balance between essential roles and neurotoxicity

Balachandran

Mukhopadhyay

McBride

et al. 2020

Journal of Biological Chemistry

206

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Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity.

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Section: Slc39a14mentioning

confidence: 89%

Brain manganese and the balance between essential roles and neurotoxicity

Balachandran

Mukhopadhyay

McBride

et al. 2020

Journal of Biological Chemistry

206

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“…The physiological function of ZIP14 became clear with the identification of human mutations. Patients carrying ZIP14 mutations developed manganese toxicity and early-onset dystonia [32,[58][59][60][61]. These patients did not accumulate manganese in the liver and had normal liver function.…”

Section: Zip14mentioning

confidence: 99%

The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis

Winslow

Limesand

Zhao

2020

IJMS

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As an essential nutrient, manganese is required for the regulation of numerous cellular processes, including cell growth, neuronal health, immune cell function, and antioxidant defense. However, excess manganese in the body is toxic and produces symptoms of neurological and behavioral defects, clinically known as manganism. Therefore, manganese balance needs to be tightly controlled. In the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been identified to cause dysregulated manganese homeostasis in humans, highlighting the critical roles of these genes in manganese metabolism. This review focuses on the most recent advances in the understanding of physiological functions of these three identified manganese transporters and summarizes the molecular mechanisms underlying how the loss of functions in these genes leads to impaired manganese homeostasis and human diseases.

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“…Mutations in the SLC39A14 gene encoding the ZIP14 transporter were found in patients with childhood-onset parkinsonism and dystonia with systemic and brain Mn accumulation (35). Since that discovery, there have been a number of case reports of similar symptoms in humans with ZIP14 mutations (17, 23, 31, 38). Whole-body Zip14 KO mice display phenotypes similar to those of human carriers of ZIP14 mutations, including spontaneous systemic and brain Mn overload, specifically in the globus pallidus, and motor dysfunction (3).…”

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

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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.

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A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia

Abstract: We conclude that the mutation identified in SLC39A14 in our case is a novel variation linked to recessive disorders of hypermaganesemia and dystonia.

Cited by 30 publications

References 18 publications

Brain manganese and the balance between essential roles and neurotoxicity

Brain manganese and the balance between essential roles and neurotoxicity

The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis

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

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