title: Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant.
abstract: Zinc concentrations in breast milk are considerably higher than those of the maternal serum, to meet the infant's requirements for normal growth and development. Thus, effective mechanisms ensuring secretion of large amounts of zinc into the milk operate in mammary epithelial cells during lactation. ZnT2 was recently found to play an essential role in the secretion of zinc into milk. Heterozygous mutations of human ZnT2 (hZnT2), including H54R and G87R, in mothers result in low (>75% reduction) secretion of zinc into the breast milk, and infants fed on the milk develop transient neonatal zinc deficiency. We identified two novel missense mutations in the SLC30A2/ZnT2 gene in a Japanese mother with low milk zinc concentrations (>90% reduction) whose infant developed severe zinc deficiency; a T to C transition (c.454T>C) at exon 4, which substitutes a tryptophan residue with an arginine residue (W152R), and a C to T transition (c.887C>T) at exon 7, which substitutes a serine residue with a leucine residue (S296L). Biochemical characterization using zinc-sensitive DT40 cells indicated that the W152R mutation abolished the abilities to transport zinc and to form a dimer complex, indicating a loss-of-function mutation. The S296L mutation retained both abilities but was extremely destabilized. The two mutations were found on different alleles, indicating that the genotype of the mother with low milk zinc was compound heterozygous. These results show novel compound heterozygous mutations in the SLC30A2/ZnT2 gene causing zinc deficiency in a breast-fed infant.
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Itsumura
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Inamo
authors.forename: Fumiko
authors.initials: F
authors.lastname: Okazaki
authors.forename: Fumie
authors.initials: F
authors.lastname: Teranishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Narita
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kodama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D001942:Breast Feeding; D027682:Cation Transport Proteins / Q000235:genetics*; D002413:Cations, Divalent; D002460:Cell Line; D002645:Chickens; D005091:Exons; D005260:Female; D006130:Growth Disorders; D006579:Heterozygote; D006801:Humans; D007223:Infant; D017136:Ion Transport; D007774:Lactation; D008664:Metal Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008895:Milk, Human / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D015032:Zinc / Q000378:metabolism* / Q000172:deficiency
chemical_list: D027682:Cation Transport Proteins; D002413:Cations, Divalent; C486299:SLC30A2 protein, human; D015032:Zinc