High proportion of transient neonatal zinc deficiency causing alleles in the general population

Abstract

Loss of function (LoF) mutations in the zinc transporter SLC30A2/ZnT2 result in impaired zinc secretion into breast milk consequently causing transient neonatal zinc deficiency (TNZD) in exclusively breastfed infants. However, the frequency of TNZD causing alleles in the general population is yet unknown. Herein, we investigated 115 missense SLC30A2/ZnT2 mutations from the ExAC database, equally distributed in the entire coding region, harboured in 668 alleles in 60 706 healthy individuals of diverse ethnicity. To estimate the frequency of LoF SLC30A2/ZnT2 mutations in the general population, we used bioinformatics tools to predict the potential impact of these mutations on ZnT2 functionality, and corroborated these predictions by a zinc transport assay in human MCF‐7 cells. We found 14 missense mutations that were markedly deleterious to zinc transport. Together with two conspicuous LoF mutations in the ExAC database, 26 SLC30A2/ZnT2 alleles harboured deleterious mutations, suggesting that at least 1 in 2334 newborn infants are at risk to develop TNZD. This high frequency of TNZD mutations combined with the World Health Organization‐promoted increase in the rate of exclusive breastfeeding highlights the importance of genetic screening for inactivating SLC30A2/ZnT2 mutations in the general population for the early diagnosis and prevention of TNZD.

ZnT2 is an electroneutral proton-coupled vesicular antiporter displaying an apparent stoichiometry of two protons per zinc ion

“…ZnT2 was previously shown [9,21,44] to mediate the accumulation of zinc in intracellular vesicles in MCF-7 cells as indicated by the specific zinc probe FluoZin3 (Fig 6A). Furthermore, ZnT2 was previously shown to play a role in lysosomal zinc accumulation in both mouse mammary gland cells and in human HeLa cells [15,45,46].…”

Milk-derived miRNA profiles elucidate molecular pathways that underlie breast dysfunction in women with common genetic variants in SLC30A2

“…While to our knowledge ZnT heterodimerization has only been shown in transfected cell systems, these studies suggest an intriguing level of zinc transporter complementation that needs further exploration. Moreover, the idea that variants in ZnT2 may alter heterodimer location and function is an additional avenue that warrants investigation, given how common non-synonymous variants in ZnT2 are in the population 22 .…”

“…In humans, seven missense mutations have thus far been identified in SLC30A2 that are associated with a 50–90% reduction in milk zinc concentration and result in severe neonatal zinc deficiency in exclusively breastfed infants 18–21 . However, ZnT2 variants are likely quite common, as Golan and colleagues recently estimated the frequency of loss-of-function mutations to be 1 in 2334 22 . Indeed, we recently reported that non-synonymous ZnT2 variants are quite common in humans; 36% of a random population of breastfeeding women harbored non-synonymous ZnT2 variants.…”

Genetic and Physiological Factors Affecting Human Milk Production and Composition

“…We have recently proposed that a haploinsufficiency state occurs in women harboring heterozygous mutations in SLC30A2/ZnT2, which implies that a single gene copy of the wild type (WT) allele is not sufficient for the secretion of zinc into the milk to meet the infant's nutritional needs [32]. We have further reported that the frequency of individuals harboring TNZD causing alleles was as high as 1 in 2334 individuals from various ethnic groups [34]. Furthermore, the frequency of the specific founder p.G87R mutation in the Ashkenazi Jewish population was even higher and attained a striking frequency of 1 in 576 individuals (unpublished data); this frequent mutation is known to cause TNZD [29].…”

“…If these findings also reflect the function of ZnT2 in women's mammary gland, it may negatively affect not only human milk composition, but also the actual breastfeeding ability. Importantly, these findings might explain the relatively low number of TNZD cases that were reported in the literature in contrast to the high frequency of TNZD causing alleles in the general population [34]. If women harboring loss of function (LoF) mutations in SLC30A2/ZnT2 also suffered from low milk supply, supplementary foods must be provided to the infant relatively early (i.e., baby formula) which will therefore mask the zinc deficiency in the milk.…”