A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects

Sooyeon Lee, Yandong Zhou, Donald Gill, Shannon L. Kelleher

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

SLC30A2 encodes a zinc (Zn) transporter (ZnT2) that imports Zn into vesicles in highly-specialized secretory cells. Numerous mutations and non-synonymous variants in ZnT2 have been reported in humans and in breastfeeding women; ZnT2 variants are associated with abnormally low milk Zn levels and can lead to severe infantile Zn deficiency. However, ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and vesicle secretion, indicating that normal ZnT2 function is critical for MEC function. Here we report that women who harbor a common ZnT2 variant (T288S) present with elevated levels of several oxidative and endoplasmic reticulum (ER) stress markers in their breast milk. Functional studies in vitro suggest that substitution of threonine for serine at amino acid 288 leads to hyperphosphorylation retaining ZnT2 in the ER and lysosomes, increasing ER and lysosomal Zn accumulation, ER stress, the generation of reactive oxygen species, and STAT3 activation. These changes were associated with decreased abundance of zona occludens-1 and increased tight junction permeability. This study confirms that ZnT2 is important for normal breast function in women during lactation, and suggests that women who harbor defective variants in ZnT2 may be at-risk for poor lactation performance.

Original languageEnglish (US)
Article number3542
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Endoplasmic Reticulum Stress
Lactation
Zinc
Oxidative Stress
Breast
Endoplasmic Reticulum
Epithelial Cells
Cell Polarity
Tight Junctions
Herpes Zoster
Human Milk
Threonine
Lysosomes
Breast Feeding
Serine
Permeability
Reactive Oxygen Species
Milk
Amino Acids

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects",
abstract = "SLC30A2 encodes a zinc (Zn) transporter (ZnT2) that imports Zn into vesicles in highly-specialized secretory cells. Numerous mutations and non-synonymous variants in ZnT2 have been reported in humans and in breastfeeding women; ZnT2 variants are associated with abnormally low milk Zn levels and can lead to severe infantile Zn deficiency. However, ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and vesicle secretion, indicating that normal ZnT2 function is critical for MEC function. Here we report that women who harbor a common ZnT2 variant (T288S) present with elevated levels of several oxidative and endoplasmic reticulum (ER) stress markers in their breast milk. Functional studies in vitro suggest that substitution of threonine for serine at amino acid 288 leads to hyperphosphorylation retaining ZnT2 in the ER and lysosomes, increasing ER and lysosomal Zn accumulation, ER stress, the generation of reactive oxygen species, and STAT3 activation. These changes were associated with decreased abundance of zona occludens-1 and increased tight junction permeability. This study confirms that ZnT2 is important for normal breast function in women during lactation, and suggests that women who harbor defective variants in ZnT2 may be at-risk for poor lactation performance.",
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A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects. / Lee, Sooyeon; Zhou, Yandong; Gill, Donald; Kelleher, Shannon L.

In: Scientific reports, Vol. 8, No. 1, 3542, 01.12.2018.

Research output: Contribution to journalArticle

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