Hepatic HIF2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency

Prajapati, Milankumar; Zhang, Jared Z.; Chiu, Lauren; Chong, Grace S.; Mercadante, Courtney J.; Kowalski, Heather L.; Delaney, Bradley; Anderson, Jessica A.; Guo, Shuling; Aghajan, Mariam; Bartnikas, Thomas B.

doi:10.1172/jci.insight.169738

Cited by 1 publication

(2 citation statements)

References 56 publications

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“…1h, S2-9). This was not unexpected given that Slc30a10 -/mice have increased dietary Fe absorption 8,28 . However, the relevance of intestinal Dmt1 and Fpn to Mn absorption in mutant mice remained to be determined.…”

Section: Slc30a10 -/Mice Have Increased Mn Absorptionmentioning

confidence: 82%

“…To examine the impact of intestinal Dmt1 deficiency on the brain, an organ prominently impacted in SLC30A10 deficiency, we performed bulk RNA-sequencing (RNA-seq). We previously demonstrated using this approach that ~300 genes were differentially expressed in brains of two-month-old Slc30a10 -/mice 8,28 . Here we detected 76 genes impacted by Slc30a10 deficiency and 16 genes impacted by intestinal Dmt1 deficiency in female Slc30a10 -/mice (Fig.…”

Section: Intestinal Dmt1 Deficiency Attenuates Mn Absorption and Exce...mentioning

confidence: 99%

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Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption

Prajapati,

Zhang,

Chong

et al. 2024

Preprint

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SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.

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Section: Slc30a10 -/Mice Have Increased Mn Absorptionmentioning

confidence: 82%

Section: Intestinal Dmt1 Deficiency Attenuates Mn Absorption and Exce...mentioning

confidence: 99%

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption

Prajapati,

Zhang,

Chong

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Hepatic HIF2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency

Cited by 1 publication

References 56 publications

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption

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