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.

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

“…Women harboring T 288 S, the most common variant we previously identified (16% frequency) 23 , had biomarkers of oxidative and ER stress evident in their breast milk 29 and an elevated milk Na/K ratio 23 , strongly suggesting breast dysfunction. In vitro studies determined T 288 S is mislocalized to the ER and lysosomes, and leads to accumulation of ER and lysosomal zinc, and activation of STAT3 signaling; however, the molecular and clinical implications of these observations are not currently understood.…”

“…Women who harbor T 288 S also have ~30% less zinc in their milk, concurrent with significantly elevated milk sodium levels 23 . Further characterization of T 288 S recently showed their milk also contains molecules indicative of increased oxidative and ER stress, and mammary gland remodeling 29 . Studies in vitro showed T 288 S is retained in the ER and lysosomes leading to zinc accumulation, ER and oxidative stress, and the activation of STAT3 signaling, a hallmark of mammary gland remodeling during involution 29 .…”

“…Further characterization of T 288 S recently showed their milk also contains molecules indicative of increased oxidative and ER stress, and mammary gland remodeling 29 . Studies in vitro showed T 288 S is retained in the ER and lysosomes leading to zinc accumulation, ER and oxidative stress, and the activation of STAT3 signaling, a hallmark of mammary gland remodeling during involution 29 . This provides compelling evidence that expression of genetic variants in ZnT2 may compromise breast function; however, the molecular pathways that underpin these consequences are not understood.…”

Transient symptomatic zinc deficiency in a breastfed infant associated with low zinc levels in maternal serum and breast milk improving after zinc supplementation: An uncommon phenotype?

“…[ 15 16 ] Recently, Lee et al . [ 17 ] demonstrated that genetic variants in SLC30A2 (ZnT-2) mutation have profound consequences on zinc pools. This affects key cellular functions in mammary epithelial cells that may lead to breast dysfunction and decreased secretion of zinc into breast milk which otherwise contains adequate zinc for infantile requirements up to 6 months.…”

Transient symptomatic zinc deficiency in a breast‐fed African infant: case report and literature review

“…In particular Lee et al., in 2018, studied SLC30A2 mutation in mice and demonstrated that genetic variants in ZnT2 may have profound consequences on Zinc pools affecting key cellular functions in MECs, which may lead to breast dysfunction and poor lactation performance in women …”