Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease.
Animals
CRISPR-Cas Systems
/ genetics
Cation Transport Proteins
/ genetics
Colitis
/ chemically induced
Crohn Disease
/ genetics
Dextran Sulfate
/ toxicity
Genetic Predisposition to Disease
Genome-Wide Association Study
Homeostasis
/ genetics
Humans
Kidney
/ metabolism
Liver
/ metabolism
Male
Manganese
/ blood
Mice
Polymorphism, Single Nucleotide
/ genetics
Gastroenterology
Genetic variation
Genetics
Glycobiology
Inflammatory bowel disease
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
11
06
2020
accepted:
26
08
2020
pubmed:
9
9
2020
medline:
19
5
2021
entrez:
8
9
2020
Statut:
epublish
Résumé
ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn's disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn's disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.
Identifiants
pubmed: 32897876
pii: 140978
doi: 10.1172/jci.insight.140978
pmc: PMC7605523
doi:
pii:
Substances chimiques
Cation Transport Proteins
0
Slc39a8 protein, mouse
0
Manganese
42Z2K6ZL8P
Dextran Sulfate
9042-14-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R24 DK099803
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK089502
Pays : United States
Organisme : NIA NIH HHS
ID : U54 AG062333
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK114478
Pays : United States
Organisme : NIH HHS
ID : S10 OD025244
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116352
Pays : United States
Références
Curr Protoc Immunol. 2014 Feb 04;104:15.25.1-15.25.14
pubmed: 24510619
Biochem Biophys Res Commun. 2019 Jul 23;515(2):325-331
pubmed: 31151823
Gastroenterology. 2016 Oct;151(4):724-32
pubmed: 27492617
Blood. 2008 Sep 15;112(6):2390-9
pubmed: 18566325
Am J Hum Genet. 2015 Dec 3;97(6):886-93
pubmed: 26637978
Am J Clin Nutr. 1994 Dec;60(6):949-55
pubmed: 7985639
Nature. 2014 Jul 24;511(7510):421-7
pubmed: 25056061
Nat Genet. 2016 Jul;48(7):709-17
pubmed: 27182965
Gastroenterology. 2018 Sep;155(3):829-843
pubmed: 29792883
Hum Mol Genet. 2016 Sep 15;25(18):4117-4126
pubmed: 27466201
Glycobiology. 2019 Nov 20;29(12):817-821
pubmed: 31410450
Gastroenterology. 2019 Sep;157(3):777-792.e14
pubmed: 31078624
Glycobiology. 2015 Oct;25(10):1125-33
pubmed: 26088564
Nat Commun. 2018 Oct 9;9(1):4171
pubmed: 30301978
Nat Commun. 2019 Apr 2;10(1):1499
pubmed: 30940813
Mol Carcinog. 2018 Aug;57(8):1017-1029
pubmed: 29637628
Immunity. 2013 Jan 24;38(1):41-52
pubmed: 23290522
J Clin Invest. 2019 Dec 2;129(12):5442-5461
pubmed: 31527311
Environ Health. 2014 Oct 24;13:87
pubmed: 25342305
Nature. 2017 Dec 7;552(7683):110-115
pubmed: 29160304
Int J Mol Sci. 2016 Jul 30;17(8):
pubmed: 27483259
Nat Genet. 2010 Nov;42(11):937-48
pubmed: 20935630
Environ Int. 2019 Sep;130:104908
pubmed: 31233999
Front Genet. 2018 Dec 20;9:664
pubmed: 30619481
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1769-E1778
pubmed: 29437953
Sci Rep. 2020 Aug 4;10(1):13162
pubmed: 32753748
Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2264-76
pubmed: 20864672
PLoS One. 2012;7(5):e36055
pubmed: 22563477
Anal Bioanal Chem. 2010 Sep;398(2):845-55
pubmed: 20617306
Nutrients. 2019 Sep 04;11(9):
pubmed: 31487869
FASEB J. 2020 Feb;34(2):2929-2943
pubmed: 31908045
Glycoconj J. 2016 Jun;33(3):309-43
pubmed: 26555091
Hum Mol Genet. 2015 Aug 15;24(16):4739-45
pubmed: 26025379
Sci Adv. 2020 Feb 19;6(8):eaax0301
pubmed: 32128391
J Nutr. 1996 Feb;126(2):489-98
pubmed: 8632223
Nat Genet. 2016 Oct;48(10):1171-1184
pubmed: 27618452
Front Biosci (Landmark Ed). 2018 Mar 1;23:1655-1679
pubmed: 29293455
Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1127-36
pubmed: 18390834
Curr Protein Pept Sci. 2019;20(6):505-524
pubmed: 30950347
Am J Hum Genet. 2015 Dec 3;97(6):894-903
pubmed: 26637979
Cell. 2014 Feb 13;156(4):730-43
pubmed: 24529376
Science. 2015 May 8;348(6235):660-5
pubmed: 25954002
Cell. 2019 Jul 25;178(3):714-730.e22
pubmed: 31348891
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Hum Mol Genet. 2014 Dec 20;23(25):6746-61
pubmed: 25080502
Schizophr Bull. 2016 Jan;42(1):178-90
pubmed: 26006263
J Clin Invest. 2017 Jun 1;127(6):2407-2417
pubmed: 28481222
J Inherit Metab Dis. 2017 Mar;40(2):261-269
pubmed: 27995398
Cell. 2019 Sep 5;178(6):1493-1508.e20
pubmed: 31474370
Hum Mol Genet. 2019 Jun 15;28(12):2062-2077
pubmed: 31163085
Gastroenterology. 2018 Apr;154(5):1320-1333.e10
pubmed: 29309774
Cell Rep. 2013 Feb 21;3(2):386-400
pubmed: 23403290
Biochem Biophys Res Commun. 2011 Jul 1;410(2):289-94
pubmed: 21658371