Inherited Disorders of Manganese Metabolism

  • Charles E. Zogzas
  • Somshuvra MukhopadhyayEmail author
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 18)


While the neurotoxic effects of manganese were recognized in 1837, the first genetic disorder of manganese metabolism was described only in 2012 when homozygous mutations in SLC30A10 were reported to cause manganese-induced neurotoxicity. Two other genetic disorders of manganese metabolism have now been described – mutations in SLC39A14 cause manganese toxicity, while mutations in SLC39A8 cause manganese and zinc deficiency. Study of rare genetic disorders often provides unique insights into disease pathobiology, and the discoveries of these three inherited disorders of manganese metabolism are already transforming our understanding of manganese homeostasis, detoxification, and neurotoxicity. Here, we review the mechanisms by which mutations in SLC30A10, SLC39A14, and SLC39A8 impact manganese homeostasis to cause human disease.


Manganese SLC30A10 SLC39A14 SLC39A8 Homeostasis Transporter 



Supported by R00-ES020844 and R01-ES024812 from NIH/NIEHS (to S. M.).


  1. Aschner M, Erikson KM, Herrero Hernandez E, Tjalkens R. Manganese and its role in Parkinson's disease: from transport to neuropathology. NeuroMolecular Med. 2009;11:252–66.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aydemir TB, Sitren HS, Cousins RJ. The zinc transporter Zip14 influences c-met phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology. 2012;142:1536–46.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bosomworth HJ, Thornton JK, Coneyworth LJ, Ford D, Valentine RA. Efflux function, tissue-specific expression and intracellular trafficking of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis. Metallomics. 2012;4:771–9.CrossRefPubMedGoogle Scholar
  4. Bowman AB, Aschner M. Considerations on manganese (Mn) treatments for in vitro studies. Neurotoxicology. 2014;41:141–2.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Boycott KM, Beaulieu CL, Kernohan KD, Gebril OH, Mhanni A, Chudley AE, Redl D, Qin W, Hampson S, Kury S, Tetreault M, Puffenberger EG, Scott JN, Bezieau S, Reis A, Uebe S, Schumacher J, Hegele RA, Mcleod DR, Galvez-Peralta M, Majewski J, Ramaekers VT, Care4Rare Canada Consortium, Nebert DW, Innes AM, Parboosingh JS, Abou Jamra R. Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8. Am J Hum Genet. 2015;97:886–93.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Butterworth RF. Parkinsonism in cirrhosis: pathogenesis and current therapeutic options. Metab Brain Dis. 2013;28:261–7.CrossRefPubMedGoogle Scholar
  7. Chen P, Bowman AB, Mukhopadhyay S, Aschner M. SLC30A10: A novel manganese transporter. WormBook. 2015;4:e1042648.Google Scholar
  8. Culotta VC, Yang M, Hall MD. Manganese transport and trafficking: lessons learned from Saccharomyces cerevisiae. Eukaryot Cell. 2005;4:1159–65.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dokmanic I, Sikic M, Tomic S. Metals in proteins: correlation between the metal-ion type, coordination number and the amino-acid residues involved in the coordination. Acta Crystallogr D Biol Crystallogr. 2008;64:257–63.CrossRefPubMedGoogle Scholar
  10. Ebert BL, Bunn HF. Regulation of the erythropoietin gene. Blood. 1999;94:1864–77.PubMedGoogle Scholar
  11. Freeland-Graves JH, Mousa TY, Kim S. International variability in diet and requirements of manganese: causes and consequences. J Trace Elem Med Biol. 2016;Google Scholar
  12. Girijashanker K, He L, Soleimani M, Reed JM, Li H, Liu Z, Wang B, Dalton TP, Nebert DW. Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol Pharmacol. 2008;73:1413–23.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gospe SM Jr, Caruso RD, Clegg MS, Keen CL, Pimstone NR, Ducore JM, Gettner SS, Kreutzer RA. Paraparesis, hypermanganesaemia, and polycythaemia: a novel presentation of cirrhosis. Arch Dis Child. 2000;83:439–42.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hennet T. The galactosyltransferase family. Cell Mol Life Sci. 2002;59:1081–95.CrossRefPubMedGoogle Scholar
  15. Hoch E, Lin W, Chai J, Hershfinkel M, Fu D, Sekler I. Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity. Proc Natl Acad Sci U S A. 2012;109:7202–7.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Huang L, Tepaamorndech S. The SLC30 family of zinc transporters - a review of current understanding of their biological and pathophysiological roles. Mol Asp Med. 2013;34:548–60.CrossRefGoogle Scholar
  17. Jenkitkasemwong S, Wang CY, Mackenzie B, Knutson MD. Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals. 2012;25:643–55.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jensen LT, Carroll MC, Hall MD, Harvey CJ, Beese SE, Culotta VC. Down-regulation of a manganese transporter in the face of metal toxicity. Mol Biol Cell. 2009;20:2810–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Jeong J, Eide DJ. The SLC39 family of zinc transporters. Mol Asp Med. 2013;34:612–9.CrossRefGoogle Scholar
  20. Kambe T, Tsuji T, Hashimoto A, Itsumura N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol Rev. 2015;95:749–84.CrossRefPubMedGoogle Scholar
  21. Kolaj-Robin O, Russell D, Hayes KA, Pembroke JT, Soulimane T. Cation diffusion facilitator family: structure and function. FEBS Lett. 2015;589:1283–95.CrossRefPubMedGoogle Scholar
  22. Lechpammer M, Clegg MS, Muzar Z, Huebner PA, Jin LW, Gospe SM Jr. Pathology of inherited manganese transporter deficiency. Ann Neurol. 2014;75:608–12.CrossRefPubMedGoogle Scholar
  23. Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S. SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J Neurosci. 2014;34:14079–95.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci U S A. 2006;103:13612–7.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Lu M, Fu D. Structure of the zinc transporter YiiP. Science. 2007;317:1746–8.CrossRefPubMedGoogle Scholar
  26. Lu M, Chai J, Fu D. Structural basis for autoregulation of the zinc transporter YiiP. Nat Struct Mol Biol. 2009;16:1063–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lucchini RG, Guazzetti S, Zoni S, Donna F, Peter S, Zacco A, Salmistraro M, Bontempi E, Zimmerman NJ, Smith DR. Tremor, olfactory and motor changes in Italian adolescents exposed to historical ferro-manganese emission. Neurotoxicology. 2012;33:687–96.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lucchini RG, Guazzetti S, Zoni S, Benedetti C, Fedrighi C, Peli M, Donna F, Bontempi E, Borgese L, Micheletti S, Ferri R, Marchetti S, Smith DR. Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese. Neurotoxicology. 2014;45:309–17.CrossRefPubMedGoogle Scholar
  29. Martin JE, Giedroc DP. Functional determinants of metal ion transport and selectivity in paralogous cation diffusion facilitator transporters CzcD and MntE in Streptococcus Pneumoniae. J Bacteriol. 2016;198:1066–76.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Montanini B, Blaudez D, Jeandroz S, Sanders D, Chalot M. Phylogenetic and functional analysis of the cation diffusion facilitator (CDF) family: improved signature and prediction of substrate specificity. BMC Genomics. 2007;8:107.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Mukhopadhyay S, Linstedt AD. Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity. Proc Natl Acad Sci U S A. 2011;108:858–63.CrossRefPubMedGoogle Scholar
  32. Ng BG, Buckingham KJ, Raymond K, Kircher M, Turner EH, He M, Smith JD, Eroshkin A, Szybowska M, Losfeld ME, Chong JX, Kozenko M, Li C, Patterson MC, Gilbert RD, Nickerson DA, Shendure J, Bamshad MJ, University of Washington Center for Mendelian Genomics, Freeze HH. Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet. 2013;92:632–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Nishito Y, Tsuji N, Fujishiro H, Takeda TA, Yamazaki T, Teranishi F, Okazaki F, Matsunaga A, Tuschl K, Rao R, Kono S, Miyajima H, Narita H, Himeno S, Kambe T. Direct comparison of manganese detoxification/efflux proteins and molecular characterization of ZnT10 protein as a manganese transporter. J Biol Chem. 2016;291:14773–87.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Ohana E, Hoch E, Keasar C, Kambe T, Yifrach O, Hershfinkel M, Sekler I. Identification of the Zn2+ binding site and mode of operation of a mammalian Zn2+ transporter. J Biol Chem. 2009;284:17677–86.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Olanow CW. Manganese-induced parkinsonism and Parkinson's disease. Ann N Y Acad Sci. 2004;1012:209–23.CrossRefPubMedGoogle Scholar
  36. Park JH, Hogrebe M, Gruneberg M, Duchesne I, von der Heiden AL, Reunert J, Schlingmann KP, Boycott KM, Beaulieu CL, Mhanni AA, Innes AM, Hortnagel K, Biskup S, Gleixner EM, Kurlemann G, Fiedler B, Omran H, Rutsch F, Wada Y, Tsiakas K, Santer R, Nebert DW, Rust S, Marquardt T. SLC39A8 deficiency: a disorder of manganese transport and glycosylation. Am J Hum Genet. 2015;97:894–903.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Perl DP, Olanow CW. The neuropathology of manganese-induced parkinsonism. J Neuropathol Exp Neurol. 2007;66:675–82.CrossRefPubMedGoogle Scholar
  38. Pinilla-Tenas JJ, Sparkman BK, Shawki A, Illing AC, Mitchell CJ, Zhao N, Liuzzi JP, Cousins RJ, Knutson MD, Mackenzie B. Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol. 2011;301:C862–71.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, Severijnen LA, di Toro Mammarella L, Mignarri A, Monti L, Sanna A, Lu P, Punzo F, Cossu G, Willemsen R, Rasi F, Oostra BA, van de Warrenburg BP, Bonifati V. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90:467–77.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Ramos-Castaneda J, Park YN, Liu M, Hauser K, Rudolph H, Shull GE, Jonkman MF, Mori K, Ikeda S, Ogawa H, Arvan P. Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress. J Biol Chem. 2005;280:9467–73.CrossRefPubMedGoogle Scholar
  41. Rentschler G, Kippler M, Axmon A, Raqib R, Skerfving S, Vahter M, Broberg K. Cadmium concentrations in human blood and urine are associated with polymorphisms in zinc transporter genes. Metallomics. 2014;6:885–91.CrossRefPubMedGoogle Scholar
  42. Schachter H, Mcguire EJ, Roseman S. Sialic acids. 13. A uridine diphosphate D-galactose: mucin galactosyltransferase from porcine submaxillary gland. J Biol Chem. 1971;246:5321–8.PubMedGoogle Scholar
  43. Shusterman E, Beharier O, Shiri L, Zarivach R, Etzion Y, Campbell CR, Lee IH, Okabayashi K, Dinudom A, Cook DI, Katz A, Moran A. ZnT-1 extrudes zinc from mammalian cells functioning as a Zn(2+)/H(+) exchanger. Metallomics. 2014;6:1656–63.CrossRefPubMedGoogle Scholar
  44. Taylor KM, Morgan HE, Johnson A, Nicholson RI. Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett. 2005;579:427–32.CrossRefPubMedGoogle Scholar
  45. Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz M, Clayton PT. Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia--a new metabolic disorder. J Inherit Metab Dis. 2008;31:151–63.CrossRefPubMedGoogle Scholar
  46. Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, del Rosario ML, Dyack S, Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012;90:457–66.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada A, Hung CY, Simpson MA, Chong WK, Jacques TS, Woltjer RL, Eaton S, Gregory A, Sanford L, Kara E, Houlden H, Cuno SM, Prokisch H, Valletta L, Tiranti V, Younis R, Maher ER, Spencer J, Straatman-Iwanowska A, Gissen P, Selim LA, Pintos-Morell G, Coroleu-Lletget W, Mohammad SS, Yoganathan S, Dale RC, Thomas M, Rihel J, Bodamer OA, Enns CA, Hayflick SJ, Clayton PT, Mills PB, Kurian MA, Wilson SW. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun. 2016;7:11601.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Wagner RR, Cynkin MA. Glycoprotein metabolism: a UDP-galactose-glycoprotein galactosyltransferase of rat serum. Biochem Biophys Res Commun. 1971;45:57–62.CrossRefPubMedGoogle Scholar
  49. Wahlberg K, Kippler M, Alhamdow A, Rahman SM, Smith DR, Vahter M, Lucchini RG, Broberg K. Common polymorphisms in the solute carrier SLC30A10 are associated with blood manganese and neurological function. Toxicol Sci. 2016;149:473–83.CrossRefPubMedGoogle Scholar
  50. Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A, Mackenzie B, Knutson MD. ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem. 2012;287:34032–43.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Zogzas CE, Aschner M, Mukhopadhyay S. Structural elements in the transmembrane and cytoplasmic domains of the metal transporter SLC30A10 are required for its manganese efflux activity. J Biol Chem. 2016;291:15940–57.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Pharmacology & ToxicologyCollege of Pharmacy; Institute for Cellular & Molecular Biology; and Institute for Neuroscience, The University of Texas at AustinAustinUSA

Personalised recommendations