Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant

• Published in: PloS one Vol. 8; no. 5; p. e64045
• Main Authors: Itsumura, Naoya, Inamo, Yasuji, Okazaki, Fumiko, Teranishi, Fumie, Narita, Hiroshi, Kambe, Taiho, Kodama, Hiroko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.05.2013; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Alzheimers disease; Amino Acid Sequence; Animals; Arginine; Asian Continental Ancestry Group; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Babies; Baldness; Base Sequence; Biology; Breast; Breast Feeding; Breast milk; Breastfeeding & lactation; Cation Transport Proteins - genetics; Cations, Divalent; Cell Line; Chickens; Congenital diseases; Dermatitis; Diabetes; Epithelial cells; Exons; Family medical history; Female; Food science; Genomes; Growth Disorders; Heterozygote; Humans; Infant; Infants; Ion Transport; Lactation; Leucine; Life sciences; Mammary gland; Medicine; Metal Metabolism, Inborn Errors - genetics; Metal Metabolism, Inborn Errors - metabolism; Metal Metabolism, Inborn Errors - pathology; Milk; Milk, Human - chemistry; Milk, Human - metabolism; Missense mutation; Molecular Sequence Data; Mutation; Neonates; Newborn babies; Nutrient deficiency; Pediatrics; Reduction; Review boards; Rodents; Secretion; Serine; Substitutes; Tryptophan; Womens health; Zinc; Zinc - metabolism; Zinc compounds; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0064045

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.