Zinc Deficiency in Murine Milk Underlies Expression of the Lethal Milk ( lm ) Mutation

Abstract

The inability of nursing pups to survive on milk of mice homozygous for the recessive mutation, lethal milk (lm), is correlated with a reduction in zinc levels of both milk and pup carcass. Administration of zinc to pups nursing on lmlm dams reduces the observed mortality and morbidity. It is suggested that lm alters zinc transport from maternal blood to milk and that its study may provide useful information for understanding the rare human disease, acrodermatitis enteropathica.

A Dominant Negative Heterozygous G87R Mutation in the Zinc Transporter, ZnT-2 (SLC30A2), Results in Transient Neonatal Zinc Deficiency

“…Dams homozygous for a ZnT-4 mutation are known as lethal milk mice because they produce less milk and milk that is zinc-deficient (OMIM 602095). Consequently, pups nursed by lethal milk mice died in neonatal life unless they received oral zinc supplementation (12). The third was found to be associated with a mutation in SLC30A2/ZnT-2 (NP_001004434.1), which resulted in transient neonatal zinc deficiency (TNZD) (OMIM 608118) in breast-fed infants; TNZD was described in some previous reports (13)(14)(15).…”

Functional Characterization of a Novel Mammalian Zinc Transporter, ZnT6

“…In addition, ZnT4 is deficient in the lethal milk mouse mutant in which pups of any genotype suckled on homozygous lethal milk mothers die of zinc deficiency before weaning (12,13). The zinc level in the milk of homozygous lethal milk animals is about 50% that of normal animals (14,15) demonstrating that ZnT4 plays a crucial role in depositing the cytoplasmic zinc into the secretory vesicles in the lactating mammary glands.…”

The Znt4 mutation inlethal milk mice affects intestinal zinc homeostasis through the expression of other Zn transporters

“…However, it is interesting to note that the lm pups nursed by foster mothers of genetically unrelated background (the outbred strain CD1) grew much faster than pups of the isogenic wild type C57BL/6J strain nursed by their own mothers. The only difference between lm milk and that of the isogenic wild type was reported to reside in lower zinc content (Piletz & Ganschow, 1978), therefore such different growth rates are probably due to other nutrient components in CD1 milk. As expected, the surviving lm mice developed signs of mild zinc deficiency by the age of 8-10 months, including alopecia (Fig.…”

“…Higher intracellular zinc concentration have been shown to induce ZnT1 transcription by the Zn-dependent transcription factor MTF1 (Lichtlen & Schaffner, 2001;Langmade et al, 2000) which also regulates transcription of the metallothionein genes. Zinc concentration in the milk of lm mutant dams is decreased by 34% with respect to wild type (Piletz & Ganschow, 1978;Ackland & Mercer, 1992;Lee et al, 1992), therefore zinc secretion is mediated by other transporters, other than ZnT4, also in mammary epithelial cells.…”