- Published:
Zinc deficiency and its inherited disorders -a review
Genes & Nutrition volume 1, pages 41–49 (2006)
Abstract
Zinc is an essential trace element required by all living organisms because of its critical roles both as a structural component of proteins and as a cofactor in enzyme catalysis. The importance of zinc in human metabolism is illustrated by the effects of zinc deficiency, which include a diminished immune response, reduced healing and neurological disorders. Furthermore, nutritional zinc deficiency can be fatal in newborn or growing animals. While zinc deficiency is commonly caused by dietary factors, several inherited defects of zinc deficiency have been identified. Acrodermatitis enteropathica is the most commonly described inherited condition found in humans. In several of the few cases that have been reported, this disorder is associated with mutations in the hZIP4 gene, a member of the SLC39 family, whose members encode membranebound putative zinc transporters. Mutations in other members of this family or in different genes may account for other cases of acrodermatitis in which defects in hZIP4 have not been detected. Another inherited form of zinc deficiency occurs in the lethal milk mouse, where a mutation in ZnT4 gene, a member of the SLC30 family of transmembrane proteins results in impaired secretion of zinc into milk from the mammary gland. A similar disorder to the lethal milk mouse occurs in humans. In the few cases studied, no changes in ZnT4 orthologue, hZnT4, were detected. This, and the presence of several minor phenotypic differences between the zinc deficiency in humans and mice, suggests that the human condition is caused by defects in genes that are yet to be identified. Taking into account the fact that there are no definitive tests for zinc deficiency and that this disorder can go undiagnosed, plus the recent identification of multiple members of the SCL30 and SLC39, it is likely that mutations in other genes may underlie additional inherited disorders of zinc deficiency.
References
Ackland, M. L., Danks, D. M. and McArdle, H. J. (1989) Zinc transport by fibroblasts from patients with acrodermatitis enteropathica.Biological Trace Element Research 22, 257–263.
Ackland, M. L. and Mercer, J. F. (1992) The murine mutation, lethal milk, results in production of zinc-deficient milk.Journal of Nutrition 122, 1214–1218.
Aggett, P. J. (1983) Acrodermatitis enteropathica.Journal of Inherited Metabolic Disease 1, 39–43.
Aggett, P. J. (1991) The assessment of zinc status: a personal view.Proceedings of the Nutrition Society 50, 9–17.
Aggett, P. J., Atherton, D. J., Delves, H. T., Thorn, J. M., Bangham, A., Clayton, B. E. and Harries, J.T. (1978) Studies in acrodermatitis enteropathica. In: Kirchgessner, M. (Eds), Trace element metabolism in man and animals, Vol. 3 (Technische Universtat Munchen, Freising-Weihenstephan), pp. 418–422.
Aggett, P. J., Atherton, D. J., More, J., Davey, J., Delves, H. T. and Harries, J. T. (1980) Symptomatic zinc deficiency in a breast-fed preterm infant.Archives of Disease in Childhood 55, 547–550.
Aggett, P. J. and Comerford, J. G. (1995)Zinc and human health. Nutrition Reviews 53, S16–22.
Aggett, P. J., Delves, H. T., Thorn, J. M., Atherton, D. J., Harries, J. T. and Bangham, A. D. (1981) The therapeutic effect of amphotericin in acrodermatitis enteropathica.European Journal of Pediatrics 137, 23–25.
Anttila, P., Simell, O., Salmela, S. and Vuori, E. (1984) Serum and hair zinc as predictors of clinical symptoms in acrodermatitis enteropathica.Journal of Inherited Metabolic Disease 7, 46–8.
Arnaud, J. and Favier, A. (1992) Determination of ultrafiltrable zinc in human milk by electrothermal atomic absorption spectrometry.Analyst 117, 1593–1598.
Atherton, D. J., Muller, D. P. R., Aggett, P. J. and Harries, J. T. (1979) A defect in zinc uptake by jejunal biopsies in acrodermatitis enteropathica.Clinical Science 56, 505–507.
Beach, R. S., Gershwin, M. E., Makishima, R. K. and Hurley, L. S. (1980) Impaired immunologic ontogeny in postnatal zinc deprivation.Journal of Nutrition 110, 805–815.
Bettger, W. J. and O’Dell, B. L. (1981) A critical physiological role of zinc in the structure and function of biomembranes.Life Science 28, 1425–38.
Bohane, T. D., Cutz, E., Hamilton, J. R. and Gall, D. G. (1977) Acrodermatitis enteropathica, zinc, and the Paneth cell. A case report with family studies.Gastroenterology 73, 587–92.
Bronson, D. M., Barsky, R. and Barsky, S. (1983) Acrodermatitis enteropathica.Journal of American Academy of Dermatology 9, 140–4.
Brown, R. S., Sander, C. and Argos, P. (1985) The primary structure of transcription factor IIIA has 12 consecutive repeats.FEBS Letters 186, 271–274.
Bye, A. M., Goodfellow, A. and Atherton, D. J. (1985) Transient zinc deficiency in a full-term breast-fed infant of normal birth weight.Pediatric Dermatology 2, 308–11.
Chandra, R. K. (1980) Acrodermatitis enteropathica: zinc levels and cell-mediated immunity.Pediatrics 66, 789–91.
Connors, T. J., Czarnecki, D. B. and Haskett, M. I. (1983) Acquired zinc deficiency in a breast-fed premature infant.Archives of Dermatology 119, 319–21.
Cunnane, S. C. (1988) Role of zinc in lipid and fatty acid metabolism and in membranes.Progress in Food and Nutrition Science 12, 151–88.
Danbolt, N. and Closs, K. (1942) Acrodermatitis entheropathica.American Dermatology and Venerology 23, 127–169.
Dauncey, M. J., Shaw, J. C. and Urman, J. (1977) The absorption and retention of magnesium, zinc, and copper by low birth weight infants fed pasteurized human breast milk.Pediatric Research 11, 1033–9.
Dorea, J. (2000) Zinc in human milk.Nutrition Research 20, 1645–1687.
Dufner-Beattie, J., Langmade, S. J., Wang, F., Eide, D. and Andrews, G. K. (2003a) Structure, function, and regulation of a subfamily of mouse zinc transporter genes.Journal of Biological Chemistry 278, 50142–50150.
Dufner-Beattie, J., Wang, F., Kuo, Y.-M., Gitschier, J., Eide, D. and Andrews, G. K. (2003b) The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice.Journal of Biological Chemistry 278, 33474–33481.
Endre, L., Katona, Z. and Gyurkovits, K. (1975) Zinc deficiency and cellular immune deficiency in acrodermatitis enteropathica.Lancet 2, 119–6.
Erway, L. C. and Grider, A., Jr. (1984) Zinc metabolism in lethalmilk mice. Otolith, lactation, and aging effects.Journal of Heredity 75, 480–4.
Gaither, L. A. and Eide, D. J. (2001) The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells.Journal of Biological Chemistry 276, 22258–64.
Garretts, M. and Molokhia, M. (1977) Acrodermatitis enteropathica without hypozincemia.Journal of Pediatrics 91, 492–4.
Glover, M. T. and Atherton, D.J.(1988) Transient zinc deficiency in two full-term breast-fed siblings associated with low maternal breast milk zinc concentration.Pediatric Dermatology 5, 10–3.
Graves, K., Kestenbaum, T. and Kalivas, J. (1980) Hereditary acrodermatitis enteropathica in an adult.Archives of Dermatology 116, 562–4.
Green, M. C., Sweet, H. O. (1973) Linkages and chromosomes.Mouse News Letter,33.
Grider, A., Lin, Y. F. and Muga, S. J. (1998) Differences in the cellular zinc content and 5’-nucleotidase activity of normal and acrodermatitis enteropathica (AE) fibroblasts.Biological Trace Element Research 61, 1–8.
Grider, A. and Young, E. M. (1996) The acrodermatitis enteropathica mutation transiently affects zinc metabolism in human fibroblasts.Journal of Nutrition 126, 219–24.
Halsted, J. A., Ronaghy, H.A. and Abadi, R. (1972) Zinc deficiency in man.American Journal of Medicine 53, 277–284.
Hambidge, M. (2000) Human zinc deficiency.Journal of Nutrition 130, 1344S-1349S.
Heinen, F., Matern, D., Pringsheim, W., Leititis, J. U. and Brandis, M. (1995) Zinc deficiency in an exclusively breast-fed preterm infant.European Journal of Pediatrics 154, 71–5.
Huang, L. and Gitschier, J. (1997) A novel gene involved in zinc transport is deficient in the lethal milk mouse.Nature Genetics 17, 292–297.
Jackson, M. J., Jones, D. A., Edwards, R. H. T., Swainbank, I. G. and Coleman, M. L. (1984) Zinc homeostasis in man: studies using a new stable isotope dilution technique.British Journal of Nutrition 51, 199–208.
Jones, J. G., Elmes, M. E., Aggett, P. J. and Harries, J. T. (1983) The effect of zinc therapy on lysosomal inclusion bodies in intestinal epithelial cells in acrodermatitis enteropathica.Pediatric Research 17, 354–7.
Julius, R., Schulkind, M., Sprinkle, T. and Rennert, O. (1973) Acrodermatitis enteropathica with immune deficiency.Journal of Pediatrics 83, 1007–1011.
Kelly, R., Davidson, G. P., Townley, R. R. and Campbell, P. E. (1976) Reversible intestinal mucosal abnormality in acrodermatitis enteropathica.Archives of Diseases in Childhood 51, 219–22.
Khoshoo, V., Kjarsgaard, J., Krafchick, B. and Zlotkin, S. H. (1992) Zinc deficiency in a full-term breast-fed infant: unusual presentation.Pediatrics 89, 1094–5.
Kim, B. E., Wang, F., Dufner-Beattie, J., Andrews, G. K., Eide, D. J. and Petris, M. J. (2004) Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane.Journal of Biological Chemistry 279, 4523–4530.
King, J. C. (2000) Determinants of maternal zinc status during pregnancy.American Journal of Clinical Nutrition 71, 1334S-43S.
Krebs, N. F. and Hambidge, K. M. (2001) Zinc metabolism and homeostasis: the application of tracer techniques to human zinc physiology.Biometals 14, 397–412.
Kury, S., Dreno, B., Bezieau, S., Giraudet, S., Kharfi, M., Kamoun, R. and Moisan, J.-P. (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica.Nature Genetics 31, 239–40.
Kury, S., Kharfi, M., Kamoun, R., Taieb, A., Mallet, E., Baudon, J. J., Glastre, C., Michel, B., Sebag, F., Brooks, D., Schuster, V., Scoul, C., Dreno, B., Bezieau, S. and Moisan, J.-P. (2003) Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica.Human Mutation 22, 337–338.
Lee, D. Y., Shay, N. F. and Cousins, R. J. (1992) Altered zinc metabolism occurs in murine lethal milk syndrome.Journal of Nutrition 122, 2233–2238.
Liuzzi, J. P., Bobo, J. A., Lichten, L. A., Samuelson, D. A. and Cousins, R. J. (2004) Responsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis.Proceedings of the National Academy of Sciences of the United States of America 101, 14355–14360.
Lonnerdal, B., Hoffman, B. and Hurley, L. S. (1982) Zinc and copper binding proteins of human milk.American Journal of Clinical Nutrition 36, 1170–1176.
Mack, D., Koletzko, B., Cunnane, S., Cutz, E. and Griffiths, A. (1989) Acrodermatitis enteropathica with normal serum zinc levels: diagnostic value of small bowel biopsy and essential fatty acid determination.Gut 30, 1426–9.
Maze, P. (1914) Influences respectives des elements de la solution mineral du mais.Annales de l’Institut Pasteur (Paris) 28, 21–69.
McNulty, T. J. and Taylor, C. W. (1999) Extracellular heavymetal ions stimulate Ca2+ mobilization in hepatocytes.Biochemical Journal 339 (Pt 3), 555–561.
Michalczyk, A., Varigos, G., Catto Smith, A., Blomeley, R. and Ackland, L. (2003) Analysis of zinc transporter, hZnT4 (Slc30A4) gene expression in a mammary gland disorder leading to reduced zinc secretion into milk.Human Genetics 113, 202–210.
Miller, W. J., Blackmon, D. M., Gentry, R. P., Pitts, W. J. and Powell, G. W. (1967) Absorption, excretion, and retention of orally administered zinc-65 in various tissues of zinc-deficient and normal goats and calves.Journal of Nutrition 92, 71–8.
Moynahan, E. J. (1974) Letter: Acrodermatitis enteropathica: a lethal inherited human zinc-deficiency disorder.Lancet 2, 399–400.
Murgia, C., Vespignani, I., Cerase, J., Nobili, F. and Perozzi, G. (1999) Cloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4 in intestinal tissue and cells.American Journal of Physiology 277, G1231–1239.
Nakano, A., Nakano, H., Hanada, K., Nomura, K. and Uitto, J. (2002) ZNT4 gene is not responsible for acrodermatitis enteropathica in Japanese families.Human Genetics 110, 201–2.
Neldner, K. H. and Hambidge, K. M. (1975) Zinc therapy of acrodermatitis enteropathica.New England Journal of Medicine 292, 879–882.
Oleske, J. M., Westphal, M. L., Shore, S., Gorden, D., Bogden, J. D. and Nahmias, A. (1979) Zinc therapy of depressed cellular immunity in acrodermatitis enteropathica. Its correction.American Journal of Disease in Childhood 133, 915–8.
Ozkan, S., Ozkan, H., Fetil, E., Corapcioglu, F., Yilmaz, S. and Ozer, E. (1999) Acrodermatitis enteropathica with Pseudomonas aeruginosa sepsis.Pediatric Dermatology 16, 444–7.
Parker, P. H., Helinek, G. L., Meneely, R. L., Stroop, S., Ghishan, F. K. and Greene, H. L. (1982) Zinc deficiency in a premature infant fed exclusively human milk.American Journal of Disease in Childhood 136, 77–8.
Piletz, J. E. and Ganschow, R. E. (1978) Zinc deficiency in murine milk underlies expression of the lethal milk (lm) mutation.Science 199, 181–183.
Prasad, A. S. (1985) Clinical manifestations of zinc deficiency.Annual Review of Nutrition 5, 341–363.
Prasad, A. S. (1991) Role of zinc in human health.Boletin de la Asociacion Medica de Puerto Rico 83, 558–560.
Prasad, A. S., Halsted, J. A. and Nadimi, M. (1961) Syndrome of iron deficiency anaemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia.American Journal of Medicine 31, 532–546.
Prasad, A. S., Miale, A., Farid, Z., Sandstead, H. H. and Darby, W. (1963b) Biochemical studies on dwarfism, hypogonadism and anemia.Archives of Internal Medicine 111, 407–28.
Prasad, A. S., Miale, A. J., Farid, Z., Sandstead, H. H. and Schulert, A. R. (1963a) Zinc metabolism in patients with the symptoms of iron deficiency, anaemia, hepatosplenomegaly, dwarfism and hypogonadism.Journal of Laboratory and Clinical Medicine 61, 537–549.
Ramakrishnan, U. (2002) Prevalence of micronutrient malnutrition worldwide.Nutrition Reviews 60, S46–52.
Raulin, J. (1869) Etudes clinique sur la vegetation.Annales des Scienceas Naturelle: Botanique 11, 93–299.
Rodin, A. E. and Goldman, A. S. (1969) Autopsy findings in acrodermatitis enteropathica.American Journal of Clinical Pathology 51, 315–322.
Sandstead, H. H. (1991) Zinc deficiency. A public health problem?American Journal of Disease in Childhood 145, 853–9.
Sharma, N. L., Sharma, R. C., Gupta, K. R. and Sharma, R. P. (1988) Self-limiting acrodermatitis enteropathica. A follow-up study of three interrelated families.International Journal of Dermatology 27, 485–6.
Stevens, J. and Lubitz, L. (1998) Symptomatic zinc deficiency in breast-fed term and premature infants.Journal of Paediatrics and Child Health 34, 97–100.
Todd, W. R., Elvehjem, C. A. and Hart, E. B. (1934) Zinc in the nutrition of the rat.American Journal of Physiology 107, 146–156.
Vallee, B. L. and Auld, D. S. (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins.Biochemistry 29, 5647–59.
Vallee, B. L. and Falchuk, K. H. (1993) The biochemical basis of zinc physiology.Physiological Reviews 73, 79–118.
Vileisis, R. A., Deddish, R. B., Fitzsimons, E. and Hunt, C. E. (1981) Serial serum zinc levels in preterm infants during parenteral and enteral feedings.American Journal of Clinical Nutrition 34, 2653–7.
Walravens, P. A., Hambidge, K. M., Neldner, K. H., Silverman, A., van Doorninck, W. J., Mierau, G. and Favara, B. (1978) Zinc metabolism in acrodermatitis enteropathica.Journal of Pediatrics 93, 71–3.
Wang, F., Kim, B.-E., Dufner-Beattie, J., Petris, M. J., Andrews, G. and Eide, D. J. (2004) Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter.Human Molecular Genetics 13, 563–571.
Wang, K., Zhou, B., Kuo, Y.-M., Zemansky, J. and Gitschier, J. (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica.American Journal of Human Genetics 71, 66–73.
Wang, Y. and Walsh, S. W. (2001) Increased superoxide generation is associated with decreased superoxide dismutase activity and mRNA expression in placental trophoblast cells in pre-eclampsia.Placenta 22, 206–12.
Weismann, K., Christophersen, J. and Kobayasi, T. (1980) Ultrastructural changes of zinc deficient rat epidermis: an electron microscopic study.Acta Dermato-Venereologica 60, 197–202.
Weismann, K., Hoe, S., Knudsen, L. and Sorensen, S. S. (1979) 65Zinc absorption in patients suffering from acrodermatits enteropathica and in normal adults assessed by whole-body counting technique.British Journal of Dermatology 101, 573–579.
Weismann, K., Kvist, N. and Kobayasi, T. (1983) Bullous acrodermatitis due to zinc deficiency during total parenteral nutrition: an ultrustructural study of the epidermal changes.Acta Dermatovener (Stockholm) 63, 143–146.
Wende, G. W. (1902) Epidermolysis bullosa hereditaria. Journal of Cutaneous Disease20, 532.
Weymouth, R. D., Kelly, R. and Lansdell, B. J. (1982) Symptomatic zinc deficiency in a premature infant.Australian paediatric journal 18, 208–10.
Widdowson, E., Dauncey, J. and Shaw, J. (1974) Trace elements in foetal and early postnatal development.Proceedings of the Nutrition Society 33, 275–284.
Zalewski, P. D., Forbes, I. J. and Betts, W. H. (1993) Correlation of apoptosis with change in intracellular labile Zn(II) using zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetic acid], a new specific fluorescent probe for Zn(II).Biochemical Journal 296, 403–408.
Zimmerman, A. W., Hambidge, K. M., Lepow, M. L., Greenberg, R. D., Stover, M. L. and Casey, C. E. (1982) Acrodermatitis in breast-fed premature infants: evidence for a defect of mammary zinc secretion.Pediatrics 69, 176–83.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ackland, M.L., Michalczyk, A. Zinc deficiency and its inherited disorders -a review. Genes Nutr 1, 41–49 (2006). https://doi.org/10.1007/BF02829935
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02829935