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...

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Autores principales:	Sooyeon Lee, Yandong Zhou, Donald L. Gill, Shannon L. Kelleher
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7442bfde707e4e3ebdaa7b0c56fea71b
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spelling	oai:doaj.org-article:7442bfde707e4e3ebdaa7b0c56fea71b2021-12-02T15:08:00ZA genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects10.1038/s41598-018-21505-82045-2322https://doaj.org/article/7442bfde707e4e3ebdaa7b0c56fea71b2018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21505-8https://doaj.org/toc/2045-2322Abstract 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.Sooyeon LeeYandong ZhouDonald L. GillShannon L. KelleherNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sooyeon Lee Yandong Zhou Donald L. Gill Shannon L. Kelleher A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects
description	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.
format	article
author	Sooyeon Lee Yandong Zhou Donald L. Gill Shannon L. Kelleher
author_facet	Sooyeon Lee Yandong Zhou Donald L. Gill Shannon L. Kelleher
author_sort	Sooyeon Lee
title	A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects
title_short	A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects
title_full	A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects
title_fullStr	A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects
title_full_unstemmed	A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects
title_sort	genetic variant in slc30a2 causes breast dysfunction during lactation by inducing er stress, oxidative stress and epithelial barrier defects
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/7442bfde707e4e3ebdaa7b0c56fea71b
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A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects

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