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

Scientific Reports
Sooyeon LeeShannon L Kelleher

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 defecti...Continue Reading

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Citations

Sep 25, 2018·International Journal of Dermatology·Stefania BarruscottiValeria Brazzelli
Mar 5, 2019·Digestive Diseases and Sciences·Wakana OhashiToshiyuki Fukada
Mar 12, 2021·Endocrine Reviews·Amir AjoolabadyJun Ren

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Methods Mentioned

BETA
ubiquitination
ELISA
confocal microscopy
FRET
immunoprecipitation
fluorescence resonance energy transfer

Software Mentioned

Slidebook
NetPhos
AlphaView
Prism GraphPad
Adobe Photoshop

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