Human Genetics

, Volume 113, Issue 3, pp 202–210

Analysis of zinc transporter, hZnT4 (Slc30A4), gene expression in a mammary gland disorder leading to reduced zinc secretion into milk

  • Agnes Michalczyk
  • George Varigos
  • Anthony Catto-Smith
  • Rachael C. Blomeley
  • M. Leigh Ackland
Original Investigation

Abstract

Zinc deficiency, causing impaired growth and development, may have a nutritional or genetic basis. We investigated two cases of inherited zinc deficiency found in breast-fed neonates, caused by low levels of zinc in the maternal milk. This condition is different from acrodermatitis enteropathica but has similarities to the "lethal milk" mouse, where low levels of zinc in the milk of lactating dams leads to zinc deficiency in pups. The mouse disorder has been attributed to a defect in the ZnT4 gene. Little is known about the expression of the human orthologue, hZnT4 (Slc30A4). Sequence analysis of cDNA, real-time PCR and Western blot analysis of hZnT4, carried out on control cells and cells from unrelated mothers of two infants with zinc deficiency, showed no differences. The hZnT4 gene was highly expressed in mouthwash buccal cells compared with lymphoblasts and fibroblasts. The hZnT4 protein did not co-localise with intracellular free zinc pools, suggesting that hZnT4 is not involved in transport of zinc into vesicles destined for secretion into milk. This observation, combined with phenotypic differences between the "lethal milk" mouse and the human disorder, suggests that the "lethal milk" mouse is not the corresponding model for the human zinc deficiency condition.

References

  1. Ackland ML, Mercer JF (1992) The murine mutation, lethal milk, results in production of zinc-deficient milk. J Nutr 122:1214–1218PubMedGoogle Scholar
  2. Aggett PJ (1983) Acrodermatitis enteropathica. J Inherit Metab Dis 1:39–43Google Scholar
  3. Aggett PJ, Harries JT (1979) Current status of zinc in health and disease states. Arch Dis Child 54:909–917PubMedGoogle Scholar
  4. Aggett PJ, Atherton DJ, More J, Davey J, Delves HT, Harries JT (1980) Symptomatic zinc deficiency in a breast-fed preterm infant. Arch Dis Child 55:547–550PubMedGoogle Scholar
  5. Ambrosini L, Mercer JF (1999) Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease. Hum Mol Genet 8:1547–1555CrossRefPubMedGoogle Scholar
  6. Atherton DJ, Muller DPR, Aggett PJ, Harries JT (1979) A defect in zinc uptake by jejunal biopsies in acrodermatitis enteropathica. Clin Sci 56:505–507PubMedGoogle Scholar
  7. Berg JM (1986) Potential metal-binding domains in nucleic acid binding proteins. Science 232:485–487PubMedGoogle Scholar
  8. Bettger WJ, Fernandez MS, O'Dell BL (1980) Effect of zinc deficiency on the content of rat cell membranes. Fed Proc 39:3309:896Google Scholar
  9. Bye AM, Goodfellow A, Atherton DJ (1985) Transient zinc deficiency in a full-term breast-fed infant of normal birth weight. Pediatr Dermatol 2:308–311PubMedGoogle Scholar
  10. Connors TJ, Czarnecki DB, Haskett MI (1983) Acquired zinc deficiency in a breast-fed premature infant. Archiv Dermatol 119:319–321CrossRefGoogle Scholar
  11. Cunnane SC (1988) Role of zinc in lipid and fatty acid metabolism and in membranes. Prog Food Nutr Sci 12:151–88PubMedGoogle Scholar
  12. Dauncey MJ, Shaw JC, Urman J (1977) The absorption and retention of magnesium, zinc, and copper by low birth weight infants fed pasteurized human breast milk. Pediatr Res 11:1033–1039PubMedGoogle Scholar
  13. Dorea J (2000) Zinc in human milk. Nutr Res 20:1645–1687CrossRefGoogle Scholar
  14. Erway LC, Grider A Jr (1984) Zinc metabolism in lethal-milk mice. Otolith, lactation, and aging effects. J Hered 75:480–484PubMedGoogle Scholar
  15. Fowler KJ (1984) Storage of skin biopsies at −70 degrees C for future fibroblast culture. J Clin Pathol 37:1191–1193PubMedGoogle Scholar
  16. Frederickson CJ, Suh SW, Silva D, Thompson RB (2000) Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr 130:1471S-1483SPubMedGoogle Scholar
  17. Glover MT, Atherton DJ (1988) Transient zinc deficiency in two full-term breast-fed siblings associated with low maternal breast milk zinc concentration. Pediatr Dermatol 5:10–13PubMedGoogle Scholar
  18. Grider A, Young EM (1996) The acrodermatitis enteropathica mutation transiently affects zinc metabolism in human fibroblasts. J Nutr 126:219–224PubMedGoogle Scholar
  19. Guhaniyogi J, Brewer G (2001) Regulation of mRNA stability in mammalian cells. Gene 265:11–23CrossRefPubMedGoogle Scholar
  20. Heinen F, Matern D, Pringsheim W, Leititis JU, Brandis M (1995) Zinc deficiency in an exclusively breast-fed preterm infant. Eur J Pediatr 154:71–75PubMedGoogle Scholar
  21. Huang L, Gitschier J (1997) A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet 17:292–297PubMedGoogle Scholar
  22. Khoshoo V, Kjarsgaard J, Krafchick B, Zlotkin SH (1992) Zinc deficiency in a full-term breast-fed infant: unusual presentation. Pediatr 89:1094–1095Google Scholar
  23. Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M, Kamoun R, Moisan J-P (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 31:239–240CrossRefPubMedGoogle Scholar
  24. La-Fontaine S, Theophilos MB, Firth SD, Gould R, Parton RG, Mercer JF (2001) Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase. Hum Mol Genet 10:361–370CrossRefPubMedGoogle Scholar
  25. Lee DY, Shay NF, Cousins RJ (1992) Altered zinc metabolism occurs in murine lethal milk syndrome. J Nutr 122:2233–2238PubMedGoogle Scholar
  26. Michalczyk A-A, Allen J, Blomeley R-C, Ackland ML (2002) Constitutive expression of hZnT4 zinc transporter in human breast epithelial cells. Biochem J 364:105–113PubMedGoogle Scholar
  27. Moynahan EJ (1974) Letter: Acrodermatitis enteropathica: a lethal inherited human zinc-deficiency disorder. Lancet 2:399–400PubMedGoogle Scholar
  28. Murgia C, Vespignani I, Cerase J, Nobili F, Perozzi G (1999) Cloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4 in intestinal tissue and cells. Am J Physiol 277: G1231–1239PubMedGoogle Scholar
  29. Nakano A, Nakano H, Hanada K, Nomura K, Uitto J (2002) ZNT4 gene is not responsible for acrodermatitis enteropathica in Japanese families. Hum Genet 110:201–202CrossRefPubMedGoogle Scholar
  30. Parker PH, Helinek GL, Meneely RL, Stroop S, Ghishan FK, Greene HL (1982) Zinc deficiency in a premature infant fed exclusively human milk. Am J Dis Child 136:77–78PubMedGoogle Scholar
  31. Piletz JE, Ganschow RE (1978) Zinc deficiency in murine milk underlies expression of the lethal milk (lm) mutation. Science 199:181–183PubMedGoogle Scholar
  32. Prasad AS (1985) Clinical manifestations of zinc deficiency. Annu Rev Nutr 5:341–363CrossRefPubMedGoogle Scholar
  33. Sharma NL, Sharma RC, Gupta KR, Sharma RP (1988) Self-limiting acrodermatitis enteropathica. A follow-up study of three interrelated families. Int J Dermatol 27:485–486PubMedGoogle Scholar
  34. Stevens J, Lubitz L (1998) Symptomatic zinc deficiency in breast-fed term and premature infants. J Paed Child Health 34:97–100Google Scholar
  35. Truong-Tran AQ, Ruffin R, Zalewski PD (2000) Visualization of labile zinc and its role in apoptosis of primary airway epithelial cells and cell lines. Am J Physiol Lung Cell Mol Physiol 279: L1172-L1183PubMedGoogle Scholar
  36. Vallee BL, Auld DS (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochem 29:5647–5659PubMedGoogle Scholar
  37. Vileisis RA, Deddish RB, Fitzsimons E, Hunt CE (1981) Serial serum zinc levels in preterm infants during parenteral and enteral feedings. Am J Clin Nutr 34:2653–2657PubMedGoogle Scholar
  38. Wang K, Zhou B, Kuo Y-M, Zemansky J, Gitschier J (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71:66–73CrossRefPubMedGoogle Scholar
  39. Weismann K, Hoe S, Knudsen L, Sorensen SS (1979) 65Zinc absorption in patients suffering from acrodermatits enteropathica and in normal adults assessed by whole-body counting technique. Br J Dermatol 101:573–579PubMedGoogle Scholar
  40. Weymouth RD, Kelley R, Lansdell BJ (1982) Symptomatic zinc deficiency in a premature infant. Aust J Paediatr 18:208–210Google Scholar
  41. Widdowson E, Dauncey J, Shaw J (1974) Trace elements in foetal and early postnatal development. Proc Nutr Soc 33:275–284PubMedGoogle Scholar
  42. Xie XM, Smart TG (1991) A physiological role for endogenous zinc in rat hippocampal synaptic neurotransmission. Nature 349:521–524PubMedGoogle Scholar
  43. Zalewski PD, Millard SH, Forbes IJ, Kapaniris O, Slavotinek A, Betts WH, Ward AD, Lincoln SF, Mahadevan I (1994) Video image analysis of labile zinc in viable pancreatic islet cells using a specific fluorescent probe for zinc. J Histochem Cytochem 42:877–884PubMedGoogle Scholar
  44. Zimmerman AW, Hambidge KM, Lepow ML, Greenberg RD, Stover ML, Casey CE (1982) Acrodermatitis in breast-fed premature infants: evidence for a defect of mammary zinc secretion. Pediatr 69:176–183PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Agnes Michalczyk
    • 1
  • George Varigos
    • 2
  • Anthony Catto-Smith
    • 3
  • Rachael C. Blomeley
    • 1
  • M. Leigh Ackland
    • 1
  1. 1.Centre for Cellular and Molecular Biology, School of Biological and Chemical SciencesDeakin University, Burwood CampusBurwoodAustralia
  2. 2.Department of DermatologyRoyal Children's HospitalAustralia
  3. 3.Department of Gastroenterology and Clinical NutritionRoyal Children's HospitalAustralia

Personalised recommendations