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Zinc transporter ZIP12 is a protein that is encoded by the solute carrier 39 member 12 (SLC39A12) gene.<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Eide DJ | title = The SLC39 family of metal ion transporters | journal = Pflugers Archiv | volume = 447 | issue = 5 | pages = 796–800 | date = February 2004 | pmid = 12748861 | doi = 10.1007/s00424-003-1074-3 }}</ref> ZIP12 is part of a family of Zrt-like, IRT-like proteins (ZIPs) that transport metals. ZIP12 is most closely related to a similar transporter, ZIP4, which is mutated in the genetic disorder acrodermatitis enteropathica.<ref>{{Cite journal|last=Küry|first=Sébastien|last2=Dréno|first2=Brigitte|last3=Bézieau|first3=Stéphane|last4=Giraudet|first4=Stéphanie|last5=Kharfi|first5=Monia|last6=Kamoun|first6=Ridha|last7=Moisan|first7=Jean-Paul|date=2002-07|title=Identification of SLC39A4, a gene involved in acrodermatitis enteropathica|url=https://pubmed.ncbi.nlm.nih.gov/12068297|journal=Nature Genetics|volume=31|issue=3|pages=239–240|doi=10.1038/ng913|issn=1061-4036|pmid=12068297}}</ref><ref>{{Cite journal|last=Wang|first=Kun|last2=Zhou|first2=Bing|last3=Kuo|first3=Yien-Ming|last4=Zemansky|first4=Jason|last5=Gitschier|first5=Jane|date=2002-07|title=A novel member of a zinc transporter family is defective in acrodermatitis enteropathica|url=https://pubmed.ncbi.nlm.nih.gov/12032886|journal=American Journal of Human Genetics|volume=71|issue=1|pages=66–73|doi=10.1086/341125|issn=0002-9297|pmc=PMC419995|pmid=12032886}}</ref> Human ZIP12 shares 31 percent of its amino acids with human ZIP4 between their conserved regions.<ref name=":2">{{Cite journal|last=Chowanadisai|first=Winyoo|date=2014|title=Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development|url=https://pubmed.ncbi.nlm.nih.gov/25375179|journal=PloS One|volume=9|issue=11|pages=e111535|doi=10.1371/journal.pone.0111535|issn=1932-6203|pmc=4222902|pmid=25375179}}</ref> There are two main splice variants of ZIP12 in humans, which are 691 and 654 amino acids long.<ref name=":2" /> The difference in the lengths of these 2 variants of ZIP12 are due to the inclusion or exclusion of an in-frame exon.<ref name=":2" />
Zinc transporter ZIP12 is a protein that is encoded by the solute carrier 39 member 12 (SLC39A12) gene.<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Eide DJ | title = The SLC39 family of metal ion transporters | journal = Pflugers Archiv | volume = 447 | issue = 5 | pages = 796–800 | date = February 2004 | pmid = 12748861 | doi = 10.1007/s00424-003-1074-3 }}</ref> ZIP12 is part of a family of Zrt-like, IRT-like proteins (ZIPs) that transport metals. ZIP12 is most closely related to a similar transporter, ZIP4, which is mutated in the genetic disorder acrodermatitis enteropathica.<ref>{{Cite journal|last=Küry|first=Sébastien|last2=Dréno|first2=Brigitte|last3=Bézieau|first3=Stéphane|last4=Giraudet|first4=Stéphanie|last5=Kharfi|first5=Monia|last6=Kamoun|first6=Ridha|last7=Moisan|first7=Jean-Paul|date=2002-07|title=Identification of SLC39A4, a gene involved in acrodermatitis enteropathica|url=https://pubmed.ncbi.nlm.nih.gov/12068297|journal=Nature Genetics|volume=31|issue=3|pages=239–240|doi=10.1038/ng913|issn=1061-4036|pmid=12068297}}</ref><ref>{{Cite journal|last=Wang|first=Kun|last2=Zhou|first2=Bing|last3=Kuo|first3=Yien-Ming|last4=Zemansky|first4=Jason|last5=Gitschier|first5=Jane|date=2002-07|title=A novel member of a zinc transporter family is defective in acrodermatitis enteropathica|url=https://pubmed.ncbi.nlm.nih.gov/12032886|journal=American Journal of Human Genetics|volume=71|issue=1|pages=66–73|doi=10.1086/341125|issn=0002-9297|pmc=PMC419995|pmid=12032886}}</ref> Human ZIP12 shares 31 percent of its amino acids with human ZIP4 between their conserved regions.<ref name=":2">{{Cite journal|last=Chowanadisai|first=Winyoo|date=2014|title=Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development|url=https://pubmed.ncbi.nlm.nih.gov/25375179|journal=PloS One|volume=9|issue=11|pages=e111535|doi=10.1371/journal.pone.0111535|issn=1932-6203|pmc=4222902|pmid=25375179}}</ref> There are two main splice variants of ZIP12 in humans, which are 691 and 654 amino acids long.<ref name=":2" /> The difference in the lengths of these 2 variants of ZIP12 are due to the inclusion or exclusion of an in-frame exon.<ref name=":2" />


The ZIP12 protein contains many elements that are conserved across other ZIP transporters in vertebrates (including mammals and humans).<ref name=":2" /> ZIP12 has eight transmembrane domains and contains histidine residues within transmembrane regions four and five that are believed to be necessary for zinc transport across cellular membranes.<ref name=":0" /><ref name=":1" /><ref name=":2" /> ZIP12 is present at the plasma membrane and can transport zinc ions from the outside of the cell to the inside.<ref name=":3">{{Cite journal|last=Chowanadisai|first=Winyoo|last2=Graham|first2=David M.|last3=Keen|first3=Carl L.|last4=Rucker|first4=Robert B.|last5=Messerli|first5=Mark A.|date=2013-06-11|title=Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12)|url=https://pubmed.ncbi.nlm.nih.gov/23716681|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=24|pages=9903–9908|doi=10.1073/pnas.1222142110|issn=1091-6490|pmc=3683776|pmid=23716681}}</ref><ref>{{Cite journal|last=Scarr|first=Elizabeth|last2=Udawela|first2=Madhara|last3=Greenough|first3=Mark A.|last4=Neo|first4=Jaclyn|last5=Suk Seo|first5=Myoung|last6=Money|first6=Tammie T.|last7=Upadhyay|first7=Aradhana|last8=Bush|first8=Ashley I.|last9=Everall|first9=Ian P.|last10=Thomas|first10=Elizabeth A.|last11=Dean|first11=Brian|date=2016|title=Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia|url=https://pubmed.ncbi.nlm.nih.gov/27336053|journal=NPJ schizophrenia|volume=2|pages=16002|doi=10.1038/npjschz.2016.2|issn=2334-265X|pmc=4898896|pmid=27336053}}</ref>
The ZIP12 protein contains many elements that are conserved across other ZIP transporters in vertebrates (including mammals and humans).<ref name=":2" /> ZIP12 has eight transmembrane domains and contains histidine residues within transmembrane regions four and five that are believed to be necessary for zinc transport across cellular membranes.<ref name=":0" /><ref name=":1" /><ref name=":2" /> ZIP12 is present at the plasma membrane and can transport zinc ions from the outside of the cell to the inside.<ref name=":3">{{Cite journal|last=Chowanadisai|first=Winyoo|last2=Graham|first2=David M.|last3=Keen|first3=Carl L.|last4=Rucker|first4=Robert B.|last5=Messerli|first5=Mark A.|date=2013-06-11|title=Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12)|url=https://pubmed.ncbi.nlm.nih.gov/23716681|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=24|pages=9903–9908|doi=10.1073/pnas.1222142110|issn=1091-6490|pmc=3683776|pmid=23716681}}</ref><ref name=":6">{{Cite journal|last=Scarr|first=Elizabeth|last2=Udawela|first2=Madhara|last3=Greenough|first3=Mark A.|last4=Neo|first4=Jaclyn|last5=Suk Seo|first5=Myoung|last6=Money|first6=Tammie T.|last7=Upadhyay|first7=Aradhana|last8=Bush|first8=Ashley I.|last9=Everall|first9=Ian P.|last10=Thomas|first10=Elizabeth A.|last11=Dean|first11=Brian|date=2016|title=Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia|url=https://pubmed.ncbi.nlm.nih.gov/27336053|journal=NPJ schizophrenia|volume=2|pages=16002|doi=10.1038/npjschz.2016.2|issn=2334-265X|pmc=4898896|pmid=27336053}}</ref>


The SLC39A12 gene is conserved across vertebrates, including humans, non-human primates like rhesus monkeys, cats, dogs, rodents including rats and mice, birds such as chickens, and frogs such as Xenopus laevis and Xenopus tropicalis.<ref name=":2" /> The SLC39A12 gene is present in some fish such as Japanese medaka, Nile tilapia, and European seabass, but the SLC39A12 gene is not present in zebrafish.<ref name=":2" /> ZIP12 has been shown to transport zinc, and there is currently no evidence that ZIP12 can transport metals other than zinc. ZIP12 is expressed in many tissues and is particularly high in the brain and eye.<ref name=":2" /><ref name=":3" /> In mice, ZIP12 mRNA is not detected in pancreas.<ref name=":3" />
The SLC39A12 gene is conserved across vertebrates, including humans, non-human primates like rhesus monkeys, cats, dogs, rodents including rats and mice, birds such as chickens, and frogs such as Xenopus laevis and Xenopus tropicalis.<ref name=":2" /> The SLC39A12 gene is present in some fish such as Japanese medaka, Nile tilapia, and European seabass, but the SLC39A12 gene is not present in zebrafish.<ref name=":2" /> ZIP12 has been shown to transport zinc, and there is currently no evidence that ZIP12 can transport metals other than zinc. ZIP12 is expressed in many tissues and is particularly high in the brain and eye.<ref name=":2" /><ref name=":3" /> In mice, ZIP12 mRNA is not detected in pancreas.<ref name=":3" />
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== Role in neurite extension and mitochondria in mouse neural cells ==
== Role in neurite extension and mitochondria in mouse neural cells ==


In mouse Neuro-2a neuroblastoma cells and primary mouse neurons, ZIP12 is necessary for neurite extension.<ref name=":3" /> Neurites are projections from the cell body of a neural cell during differentiation, and neurites can be either axons or dendrites. To study how ZIP12 is important for a neural cell to extend neurites out from the cell body, researchers used short hairpin RNA (shRNA) to induce RNA interference to degrade ZIP12 mRNA and reduce ZIP12 protein.<ref name=":3" /> In Neuro-2a cells and primary mouse neurons transfected with shRNA specifically targeting ZIP12, the neural cells have shorter neurites.<ref name=":3" /> Increasing intracellular zinc with a zinc ionophore that can cross the cellular membrane while bypassing ZIP12 can restore neurite extension in cells with targeted ZIP12 depletion.<ref name=":3" />
In mouse Neuro-2a neuroblastoma cells and primary mouse neurons, ZIP12 is necessary for neurite extension.<ref name=":3" /> Neurites are projections from the cell body of a neural cell during differentiation, and neurites can refer to either axons or dendrites. To study how ZIP12 is important for a neural cell to extend neurites out from the cell body, researchers used short hairpin RNA (shRNA) to induce RNA interference to degrade ZIP12 mRNA and reduce ZIP12 protein.<ref name=":3" /> In Neuro-2a cells and primary mouse neurons transfected with shRNA specifically targeting ZIP12, the neural cells have shorter neurites.<ref name=":3" /> Increasing intracellular zinc with a zinc ionophore that can cross the cellular membrane while bypassing ZIP12 can restore neurite extension in cells with targeted ZIP12 depletion.<ref name=":3" />


In a subsequent study, Neuro-2a cells with targeted ZIP12 mutations using CRISPR-mediated genome editing also have shorter neurites during differentiation and impaired mitochondrial function.<ref name=":4">{{Cite journal|last=Strong|first=Morgan D.|last2=Hart|first2=Matthew D.|last3=Tang|first3=Tony Z.|last4=Ojo|first4=Babajide A.|last5=Wu|first5=Lei|last6=Nacke|first6=Mariah R.|last7=Agidew|first7=Workneh T.|last8=Hwang|first8=Hong J.|last9=Hoyt|first9=Peter R.|last10=Bettaieb|first10=Ahmed|last11=Clarke|first11=Stephen L.|date=2020-09|title=Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function|url=https://pubmed.ncbi.nlm.nih.gov/32716562|journal=FASEB journal: official publication of the Federation of American Societies for Experimental Biology|volume=34|issue=9|pages=10702–12725|doi=10.1096/fj.202000772R|issn=1530-6860|pmid=32716562}}</ref> In addition, ZIP12-deleted cells have reduced cellular respiration,<ref name=":4" /> which is a measure of mitochondrial function. Neurite extension of Neuro-2a is more affected by rotenone and sodium azide,<ref name=":4" /> which are inhibitors of the electron transport chain of the mitochondria, in cells without ZIP12. ZIP12-deleted cells also have increased superoxide generation and higher oxidative damage<ref name=":4" />, which are consistent with mitochondrial dysfunction. Exposing ZIP12-deleted cells to antioxidants such as alpha-tocopherol (vitamin E), MitoQ, or MitoTEMPO can restore neurite length, which indicates that the oxidative damage present in cells without ZIP12 leads to stunted neurites.<ref name=":4" />
In a subsequent study, Neuro-2a cells with targeted ZIP12 mutations using CRISPR-mediated genome editing also have shorter neurites during differentiation and impaired mitochondrial function.<ref name=":4">{{Cite journal|last=Strong|first=Morgan D.|last2=Hart|first2=Matthew D.|last3=Tang|first3=Tony Z.|last4=Ojo|first4=Babajide A.|last5=Wu|first5=Lei|last6=Nacke|first6=Mariah R.|last7=Agidew|first7=Workneh T.|last8=Hwang|first8=Hong J.|last9=Hoyt|first9=Peter R.|last10=Bettaieb|first10=Ahmed|last11=Clarke|first11=Stephen L.|date=2020-09|title=Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function|url=https://pubmed.ncbi.nlm.nih.gov/32716562|journal=FASEB journal: official publication of the Federation of American Societies for Experimental Biology|volume=34|issue=9|pages=10702–12725|doi=10.1096/fj.202000772R|issn=1530-6860|pmid=32716562}}</ref> In addition, ZIP12-deleted cells have reduced cellular respiration,<ref name=":4" /> which is a measure of mitochondrial function. Neurite extension of Neuro-2a is more affected by rotenone and sodium azide,<ref name=":4" /> which are inhibitors of the electron transport chain of the mitochondria, in cells without ZIP12. ZIP12-deleted cells also have increased superoxide generation and higher oxidative damage<ref name=":4" />, which are consistent with mitochondrial dysfunction. Exposing ZIP12-deleted cells to antioxidants such as alpha-tocopherol (vitamin E), MitoQ, or MitoTEMPO can restore neurite length, which indicates that the oxidative damage present in cells without ZIP12 leads to stunted neurites.<ref name=":4" />
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== Role in hypoxia-induced pulmonary hypertension ==
== Role in hypoxia-induced pulmonary hypertension ==


Hypoxia induces the expression of ZIP12 in the endothelium of mammalian pulmonary vessels. The induction of ZIP12 results in the proliferation and thickening of pulmonary vascular smooth muscle cells, which leads to pulmonary hypertension. Zhao et al. identified ZIP12 as the responsible gene through a congenic breeding program between Fisher 344 (F344) rats, which are resistant to hypoxia-induced pulmonary hypertension, and susceptible Wistar Kyoto (WKY) rats. Resistant F344 rats crossed with non-resistant WKY rats produce subcongenic strains, and quantitative trait loci (QTL) analysis was used to determine which genes co-segregate with the hypoxic response by the pulmonary vessels and sensitivity to pulmonary hypertension. A ZIP12 frameshift mutation in F344 rats truncates the protein and reduces cellular zinc uptake by pulmonary endothelial smooth muscle cells. Additional support for ZIP12 as the responsible gene was shown when a similar resistance to hypoxia-induced pulmonary hypertension was observed in rats with targeted deletion of the SLC39A12 (ZIP12) gene by zinc finger nucleases. In addition to rats, cattle and humans also show increased ZIP12 protein when housed in hypoxic environments, which implies that response of increased ZIP12 protein to hypoxia is found across different mammals. A hypoxia response element (HRE) is present within a SLC39A12 intron, which can increase ZIP12 expression under hypoxic conditions. In a separate study using human vascular endothelial and smooth muscle cells, ZIP12 expression increased after intracellular zinc chelation.
Hypoxia induces the expression of ZIP12 in the endothelium of mammalian pulmonary vessels. The induction of ZIP12 results in the proliferation and thickening of pulmonary vascular smooth muscle cells, which leads to pulmonary hypertension. Zhao et al.<ref name=":7">{{Cite journal|last=Zhao|first=Lan|last2=Oliver|first2=Eduardo|last3=Maratou|first3=Klio|last4=Atanur|first4=Santosh S.|last5=Dubois|first5=Olivier D.|last6=Cotroneo|first6=Emanuele|last7=Chen|first7=Chien-Nien|last8=Wang|first8=Lei|last9=Arce|first9=Cristina|last10=Chabosseau|first10=Pauline L.|last11=Ponsa-Cobas|first11=Joan|date=2015-08-20|title=The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia|url=https://pubmed.ncbi.nlm.nih.gov/26258299|journal=Nature|volume=524|issue=7565|pages=356–360|doi=10.1038/nature14620|issn=1476-4687|pmc=6091855|pmid=26258299}}</ref> identified ZIP12 as the responsible gene through a congenic breeding program between Fisher 344 (F344) rats, which are resistant to hypoxia-induced pulmonary hypertension, and susceptible Wistar Kyoto (WKY) rats. Resistant F344 rats crossed with non-resistant WKY rats produce subcongenic strains, and quantitative trait loci (QTL) analysis was used to determine which genes co-segregate with the hypoxic response by the pulmonary vessels and sensitivity to pulmonary hypertension<ref name=":7" />. A ZIP12 frameshift mutation in F344 rats truncates the protein and reduces cellular zinc uptake by pulmonary endothelial smooth muscle cells.<ref name=":7" /> Additional support for ZIP12 as the responsible gene was shown when a similar resistance to hypoxia-induced pulmonary hypertension was observed in rats with targeted deletion of the SLC39A12 (ZIP12) gene by zinc finger nucleases.<ref name=":7" /> In addition to rats, cattle and humans also show increased ZIP12 protein when housed in hypoxic environments, which implies that response of increased ZIP12 protein to hypoxia is found across different mammals.<ref name=":7" /> A hypoxia response element (HRE) is present within a SLC39A12 intron, which can increase ZIP12 expression under hypoxic conditions.<ref name=":7" /> In a separate study using human vascular endothelial and smooth muscle cells, ZIP12 expression increased after intracellular zinc chelation.<ref>{{Cite journal|last=Abdo|first=Adrian I.|last2=Tran|first2=Hai Bac|last3=Hodge|first3=Sandra|last4=Beltrame|first4=John F.|last5=Zalewski|first5=Peter D.|date=2021-06|title=Zinc Homeostasis Alters Zinc Transporter Protein Expression in Vascular Endothelial and Smooth Muscle Cells|url=https://pubmed.ncbi.nlm.nih.gov/32776265|journal=Biological Trace Element Research|volume=199|issue=6|pages=2158–2171|doi=10.1007/s12011-020-02328-z|issn=1559-0720|pmid=32776265}}</ref>


== Association with schizophrenia ==
== Association with schizophrenia ==


Associations between ZIP12 and schizophrenia have been reported. A non-coding polymorphism in ZIP12 has been described as being more prevalent in patients with schizophrenia, although this finding has not yet been replicated in other studies. In another study using genome-wide microarrays and post-mortem brain tissue, researchers found higher abundance of ZIP12 mRNA in frontal lobe, superior frontal gyrus, and inferior frontal gyrus of brains from schizophrenic subjects. Higher expression of both splice variants of ZIP12 was detected in the brains of patients with schizophrenia.
Associations between ZIP12 and schizophrenia have been reported. A non-coding polymorphism in ZIP12 has been described as being more prevalent in patients with schizophrenia,<ref>{{Cite journal|last=Bly|first=Mike|date=2006-01-31|title=Examination of the zinc transporter gene, SLC39A12|url=https://pubmed.ncbi.nlm.nih.gov/16311021|journal=Schizophrenia Research|volume=81|issue=2-3|pages=321–322|doi=10.1016/j.schres.2005.07.039|issn=0920-9964|pmid=16311021}}</ref> although this finding has not yet been replicated in other studies. In another study using genome-wide microarrays and post-mortem brain tissue, researchers found higher abundance of ZIP12 mRNA in frontal lobe, superior frontal gyrus, and inferior frontal gyrus of brains from schizophrenic subjects.<ref name=":6" /> Higher expression of both splice variants of ZIP12 was detected in the brains of patients with schizophrenia.<ref name=":6" />


== Possible link to autism ==
== Possible link to autism ==


Mutations and copy number variations in SLC39A12 have been reported for autism, although it is unclear whether genetic variability contributes towards autism risk. In one study assessing copy number variations in Han Chinese subjects with autism, one person had a heterozygous deletion in SLC39A12. In another study, a premature stop codon was detected in one copy of SLC39A12 for one autistic subject.
Mutations and copy number variations in SLC39A12 have been reported for autism, although it is unclear whether genetic variability contributes towards autism risk. In one study assessing copy number variations in Han Chinese subjects with autism, one person had a heterozygous deletion in SLC39A12.<ref>{{Cite journal|last=Gazzellone|first=Matthew J.|last2=Zhou|first2=Xue|last3=Lionel|first3=Anath C.|last4=Uddin|first4=Mohammed|last5=Thiruvahindrapuram|first5=Bhooma|last6=Liang|first6=Shuang|last7=Sun|first7=Caihong|last8=Wang|first8=Jia|last9=Zou|first9=Mingyang|last10=Tammimies|first10=Kristiina|last11=Walker|first11=Susan|date=2014|title=Copy number variation in Han Chinese individuals with autism spectrum disorder|url=https://pubmed.ncbi.nlm.nih.gov/25170348|journal=Journal of Neurodevelopmental Disorders|volume=6|issue=1|pages=34|doi=10.1186/1866-1955-6-34|issn=1866-1947|pmc=4147384|pmid=25170348}}</ref> In another study, a premature stop codon was detected in one copy of SLC39A12 for one autistic subject.<ref>{{Cite journal|last=Krumm|first=Niklas|last2=Turner|first2=Tychele N.|last3=Baker|first3=Carl|last4=Vives|first4=Laura|last5=Mohajeri|first5=Kiana|last6=Witherspoon|first6=Kali|last7=Raja|first7=Archana|last8=Coe|first8=Bradley P.|last9=Stessman|first9=Holly A.|last10=He|first10=Zong-Xiao|last11=Leal|first11=Suzanne M.|date=2015-06|title=Excess of rare, inherited truncating mutations in autism|url=https://pubmed.ncbi.nlm.nih.gov/25961944|journal=Nature Genetics|volume=47|issue=6|pages=582–588|doi=10.1038/ng.3303|issn=1546-1718|pmc=4449286|pmid=25961944}}</ref>


== Possible associations with cancer ==
== Possible associations with cancer ==


Altered expression and mutations in ZIP12 have been detected in various cancers. In 145 patients with esophageal adenocarcinoma, whole exome sequencing found that 12 patients had ZIP12 missense mutations in tumors negative for microsatellite instability. Coding mutations in ZIP12 were also detected in a separate study on esophageal adenocarcinoma. Differences in ZIP12 expression has been reported in different cancers. ZIP12 mRNA was elevated in non-small cell lung cancer biopsied tissues from at least half of tested patients. ZIP12 protein abundance was lower in the breast cancer lines T47D and MDA-MB-231 when compared to non-malignant mammary cell line MCF10A.
Altered expression and mutations in ZIP12 have been detected in various cancers. In 145 patients with esophageal adenocarcinoma, whole exome sequencing found that 12 patients had ZIP12 missense mutations in tumors negative for microsatellite instability.<ref>{{Cite journal|last=Dulak|first=Austin M.|last2=Stojanov|first2=Petar|last3=Peng|first3=Shouyong|last4=Lawrence|first4=Michael S.|last5=Fox|first5=Cameron|last6=Stewart|first6=Chip|last7=Bandla|first7=Santhoshi|last8=Imamura|first8=Yu|last9=Schumacher|first9=Steven E.|last10=Shefler|first10=Erica|last11=McKenna|first11=Aaron|date=2013-05|title=Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity|url=https://pubmed.ncbi.nlm.nih.gov/23525077|journal=Nature Genetics|volume=45|issue=5|pages=478–486|doi=10.1038/ng.2591|issn=1546-1718|pmc=3678719|pmid=23525077}}</ref> Coding mutations in ZIP12 were also detected in a separate study on esophageal adenocarcinoma.<ref>{{Cite journal|last=Murugaesu|first=Nirupa|last2=Wilson|first2=Gareth A.|last3=Birkbak|first3=Nicolai J.|last4=Watkins|first4=Thomas|last5=McGranahan|first5=Nicholas|last6=Kumar|first6=Sacheen|last7=Abbassi-Ghadi|first7=Nima|last8=Salm|first8=Max|last9=Mitter|first9=Richard|last10=Horswell|first10=Stuart|last11=Rowan|first11=Andrew|date=2015-08|title=Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy|url=https://pubmed.ncbi.nlm.nih.gov/26003801|journal=Cancer Discovery|volume=5|issue=8|pages=821–831|doi=10.1158/2159-8290.CD-15-0412|issn=2159-8290|pmc=4529488|pmid=26003801}}</ref> Differences in ZIP12 expression has been reported in different cancers. ZIP12 mRNA was elevated in non-small cell lung cancer biopsied tissues from at least half of tested patients.<ref>{{Cite journal|last=Huang|first=Cuiping|last2=Cui|first2=Xiaobo|last3=Sun|first3=Xiaotian|last4=Yang|first4=Jingxuan|last5=Li|first5=Min|date=2016-10-11|title=Zinc transporters are differentially expressed in human non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/27611948|journal=Oncotarget|volume=7|issue=41|pages=66935–66943|doi=10.18632/oncotarget.11884|issn=1949-2553|pmc=5341848|pmid=27611948}}</ref> ZIP12 protein abundance was lower in the breast cancer lines T47D and MDA-MB-231 when compared to non-malignant mammary cell line MCF10A.<ref>{{Cite journal|last=Chandler|first=Paige|last2=Kochupurakkal|first2=Bose S.|last3=Alam|first3=Samina|last4=Richardson|first4=Andrea L.|last5=Soybel|first5=David I.|last6=Kelleher|first6=Shannon L.|date=2016-01-05|title=Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer|url=https://pubmed.ncbi.nlm.nih.gov/26728511|journal=Molecular Cancer|volume=15|pages=2|doi=10.1186/s12943-015-0486-y|issn=1476-4598|pmc=4700748|pmid=26728511}}</ref>


== References ==
== References ==

Revision as of 14:33, 29 April 2021

SLC39A12
Identifiers
AliasesSLC39A12, LZT-Hs8, ZIP-12, bA570F3.1, solute carrier family 39 member 12, ZIP12
External IDsOMIM: 608734; MGI: 2139274; HomoloGene: 17654; GeneCards: SLC39A12; OMA:SLC39A12 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

221074

277468

Ensembl

n/a

ENSMUSG00000036949

UniProt

Q504Y0

Q5FWH7

RefSeq (mRNA)

NM_152725
NM_001145195
NM_001282733
NM_001282734

NM_001012305

RefSeq (protein)

NP_001138667
NP_001269662
NP_001269663
NP_689938

NP_001012305

Location (UCSC)n/aChr 2: 14.39 – 14.5 Mb
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Solute carrier family 39 member 12 is a protein that in humans is encoded by the SLC39A12 gene. [4]

Function

Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. SLC39A12 belongs to a subfamily of proteins that show structural characteristics of zinc transporters.[5]

Basic properties

Zinc transporter ZIP12 is a protein that is encoded by the solute carrier 39 member 12 (SLC39A12) gene.[5][6] ZIP12 is part of a family of Zrt-like, IRT-like proteins (ZIPs) that transport metals. ZIP12 is most closely related to a similar transporter, ZIP4, which is mutated in the genetic disorder acrodermatitis enteropathica.[7][8] Human ZIP12 shares 31 percent of its amino acids with human ZIP4 between their conserved regions.[9] There are two main splice variants of ZIP12 in humans, which are 691 and 654 amino acids long.[9] The difference in the lengths of these 2 variants of ZIP12 are due to the inclusion or exclusion of an in-frame exon.[9]

The ZIP12 protein contains many elements that are conserved across other ZIP transporters in vertebrates (including mammals and humans).[9] ZIP12 has eight transmembrane domains and contains histidine residues within transmembrane regions four and five that are believed to be necessary for zinc transport across cellular membranes.[5][6][9] ZIP12 is present at the plasma membrane and can transport zinc ions from the outside of the cell to the inside.[10][11]

The SLC39A12 gene is conserved across vertebrates, including humans, non-human primates like rhesus monkeys, cats, dogs, rodents including rats and mice, birds such as chickens, and frogs such as Xenopus laevis and Xenopus tropicalis.[9] The SLC39A12 gene is present in some fish such as Japanese medaka, Nile tilapia, and European seabass, but the SLC39A12 gene is not present in zebrafish.[9] ZIP12 has been shown to transport zinc, and there is currently no evidence that ZIP12 can transport metals other than zinc. ZIP12 is expressed in many tissues and is particularly high in the brain and eye.[9][10] In mice, ZIP12 mRNA is not detected in pancreas.[10]

Role in neurite extension and mitochondria in mouse neural cells

In mouse Neuro-2a neuroblastoma cells and primary mouse neurons, ZIP12 is necessary for neurite extension.[10] Neurites are projections from the cell body of a neural cell during differentiation, and neurites can refer to either axons or dendrites. To study how ZIP12 is important for a neural cell to extend neurites out from the cell body, researchers used short hairpin RNA (shRNA) to induce RNA interference to degrade ZIP12 mRNA and reduce ZIP12 protein.[10] In Neuro-2a cells and primary mouse neurons transfected with shRNA specifically targeting ZIP12, the neural cells have shorter neurites.[10] Increasing intracellular zinc with a zinc ionophore that can cross the cellular membrane while bypassing ZIP12 can restore neurite extension in cells with targeted ZIP12 depletion.[10]

In a subsequent study, Neuro-2a cells with targeted ZIP12 mutations using CRISPR-mediated genome editing also have shorter neurites during differentiation and impaired mitochondrial function.[12] In addition, ZIP12-deleted cells have reduced cellular respiration,[12] which is a measure of mitochondrial function. Neurite extension of Neuro-2a is more affected by rotenone and sodium azide,[12] which are inhibitors of the electron transport chain of the mitochondria, in cells without ZIP12. ZIP12-deleted cells also have increased superoxide generation and higher oxidative damage[12], which are consistent with mitochondrial dysfunction. Exposing ZIP12-deleted cells to antioxidants such as alpha-tocopherol (vitamin E), MitoQ, or MitoTEMPO can restore neurite length, which indicates that the oxidative damage present in cells without ZIP12 leads to stunted neurites.[12]

Role in early nervous system development of Xenopus tropicalis

ZIP12 is present in the forebrain, midbrain, and eye of Xenopus tropicalis in nervous system development.[10] ZIP12 is also present at the anterior neuropore during neural tube closure.[10] ZIP12 mRNA is concentrated in the neural tube, and ZIP12 expression is higher in the neural tube compared to the rest of the embryo. To study how ZIP12 is necessary for Xenopus tropicalis embryo development, the researchers injected embryos with antisense morpholino oligonucletoides that deplete the embryos of ZIP12.[10] In embryos injected with morpholinos targeting the translation start site of ZIP12, the embryos have incomplete closure of the neural tube at the anterior neuropore, followed by embryonic death.[10] Embryos injected with morpholinos that alter ZIP12 splicing and impair its function have slower neural tube closure, often lack eyes (called anopia), and undergo embryonic death shortly after neural tube closure.[10]

Impact on human brain MRI patterns

Genome-wide association and exome sequencing studies from subjects in the UK Biobank show that polymorphisms and mutations in ZIP12 are associated with altered susceptibility weighted magnetic resonance imaging (MRI) intensity and T1 FAST MRI in the human brain.[13][14] Polymorphisms (rs10430577, rs10430578) near SLC39A12 are the lead single nucleotide polymorphisms (SNPs) most associated with altered swMRI intensity in the caudate, putamen, and pallidum and T1 FAST MRI in the putamen.[13] Susceptibility weighted magnetic resonance imaging is sensitive to metal content in the tissues analyzed. Associated missense ZIP12 mutations (rs10764176, rs72778328) have reduced zinc transport activity when measured in Chinese hamster ovary (CHO) cells.[12] However, the impact of the changes in the human brain caused by ZIP12 polymorphisms and mutations is currently unknown.

Role in hypoxia-induced pulmonary hypertension

Hypoxia induces the expression of ZIP12 in the endothelium of mammalian pulmonary vessels. The induction of ZIP12 results in the proliferation and thickening of pulmonary vascular smooth muscle cells, which leads to pulmonary hypertension. Zhao et al.[15] identified ZIP12 as the responsible gene through a congenic breeding program between Fisher 344 (F344) rats, which are resistant to hypoxia-induced pulmonary hypertension, and susceptible Wistar Kyoto (WKY) rats. Resistant F344 rats crossed with non-resistant WKY rats produce subcongenic strains, and quantitative trait loci (QTL) analysis was used to determine which genes co-segregate with the hypoxic response by the pulmonary vessels and sensitivity to pulmonary hypertension[15]. A ZIP12 frameshift mutation in F344 rats truncates the protein and reduces cellular zinc uptake by pulmonary endothelial smooth muscle cells.[15] Additional support for ZIP12 as the responsible gene was shown when a similar resistance to hypoxia-induced pulmonary hypertension was observed in rats with targeted deletion of the SLC39A12 (ZIP12) gene by zinc finger nucleases.[15] In addition to rats, cattle and humans also show increased ZIP12 protein when housed in hypoxic environments, which implies that response of increased ZIP12 protein to hypoxia is found across different mammals.[15] A hypoxia response element (HRE) is present within a SLC39A12 intron, which can increase ZIP12 expression under hypoxic conditions.[15] In a separate study using human vascular endothelial and smooth muscle cells, ZIP12 expression increased after intracellular zinc chelation.[16]

Association with schizophrenia

Associations between ZIP12 and schizophrenia have been reported. A non-coding polymorphism in ZIP12 has been described as being more prevalent in patients with schizophrenia,[17] although this finding has not yet been replicated in other studies. In another study using genome-wide microarrays and post-mortem brain tissue, researchers found higher abundance of ZIP12 mRNA in frontal lobe, superior frontal gyrus, and inferior frontal gyrus of brains from schizophrenic subjects.[11] Higher expression of both splice variants of ZIP12 was detected in the brains of patients with schizophrenia.[11]

Possible link to autism

Mutations and copy number variations in SLC39A12 have been reported for autism, although it is unclear whether genetic variability contributes towards autism risk. In one study assessing copy number variations in Han Chinese subjects with autism, one person had a heterozygous deletion in SLC39A12.[18] In another study, a premature stop codon was detected in one copy of SLC39A12 for one autistic subject.[19]

Possible associations with cancer

Altered expression and mutations in ZIP12 have been detected in various cancers. In 145 patients with esophageal adenocarcinoma, whole exome sequencing found that 12 patients had ZIP12 missense mutations in tumors negative for microsatellite instability.[20] Coding mutations in ZIP12 were also detected in a separate study on esophageal adenocarcinoma.[21] Differences in ZIP12 expression has been reported in different cancers. ZIP12 mRNA was elevated in non-small cell lung cancer biopsied tissues from at least half of tested patients.[22] ZIP12 protein abundance was lower in the breast cancer lines T47D and MDA-MB-231 when compared to non-malignant mammary cell line MCF10A.[23]

References

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036949 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Entrez Gene: Solute carrier family 39 member 12". Retrieved 2017-06-15.
  5. ^ a b c Taylor KM, Nicholson RI (April 2003). "The LZT proteins; the LIV-1 subfamily of zinc transporters". Biochimica et Biophysica Acta. 1611 (1–2): 16–30. doi:10.1016/s0005-2736(03)00048-8. PMID 12659941.
  6. ^ a b Eide DJ (February 2004). "The SLC39 family of metal ion transporters". Pflugers Archiv. 447 (5): 796–800. doi:10.1007/s00424-003-1074-3. PMID 12748861.
  7. ^ Küry, Sébastien; Dréno, Brigitte; Bézieau, Stéphane; Giraudet, Stéphanie; Kharfi, Monia; Kamoun, Ridha; Moisan, Jean-Paul (2002-07). "Identification of SLC39A4, a gene involved in acrodermatitis enteropathica". Nature Genetics. 31 (3): 239–240. doi:10.1038/ng913. ISSN 1061-4036. PMID 12068297. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Wang, Kun; Zhou, Bing; Kuo, Yien-Ming; Zemansky, Jason; Gitschier, Jane (2002-07). "A novel member of a zinc transporter family is defective in acrodermatitis enteropathica". American Journal of Human Genetics. 71 (1): 66–73. doi:10.1086/341125. ISSN 0002-9297. PMC 419995. PMID 12032886. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  9. ^ a b c d e f g h Chowanadisai, Winyoo (2014). "Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development". PloS One. 9 (11): e111535. doi:10.1371/journal.pone.0111535. ISSN 1932-6203. PMC 4222902. PMID 25375179.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ a b c d e f g h i j k l Chowanadisai, Winyoo; Graham, David M.; Keen, Carl L.; Rucker, Robert B.; Messerli, Mark A. (2013-06-11). "Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12)". Proceedings of the National Academy of Sciences of the United States of America. 110 (24): 9903–9908. doi:10.1073/pnas.1222142110. ISSN 1091-6490. PMC 3683776. PMID 23716681.
  11. ^ a b c Scarr, Elizabeth; Udawela, Madhara; Greenough, Mark A.; Neo, Jaclyn; Suk Seo, Myoung; Money, Tammie T.; Upadhyay, Aradhana; Bush, Ashley I.; Everall, Ian P.; Thomas, Elizabeth A.; Dean, Brian (2016). "Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia". NPJ schizophrenia. 2: 16002. doi:10.1038/npjschz.2016.2. ISSN 2334-265X. PMC 4898896. PMID 27336053.
  12. ^ a b c d e f Strong, Morgan D.; Hart, Matthew D.; Tang, Tony Z.; Ojo, Babajide A.; Wu, Lei; Nacke, Mariah R.; Agidew, Workneh T.; Hwang, Hong J.; Hoyt, Peter R.; Bettaieb, Ahmed; Clarke, Stephen L. (2020-09). "Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function". FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 34 (9): 10702–12725. doi:10.1096/fj.202000772R. ISSN 1530-6860. PMID 32716562. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  13. ^ a b Elliott, Lloyd T.; Sharp, Kevin; Alfaro-Almagro, Fidel; Shi, Sinan; Miller, Karla L.; Douaud, Gwenaëlle; Marchini, Jonathan; Smith, Stephen M. (2018-10). "Genome-wide association studies of brain imaging phenotypes in UK Biobank". Nature. 562 (7726): 210–216. doi:10.1038/s41586-018-0571-7. ISSN 1476-4687. PMC 6786974. PMID 30305740. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Cirulli, Elizabeth T.; White, Simon; Read, Robert W.; Elhanan, Gai; Metcalf, William J.; Tanudjaja, Francisco; Fath, Donna M.; Sandoval, Efren; Isaksson, Magnus; Schlauch, Karen A.; Grzymski, Joseph J. (2020-01-28). "Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts". Nature Communications. 11 (1): 542. doi:10.1038/s41467-020-14288-y. ISSN 2041-1723. PMC 6987107. PMID 31992710.
  15. ^ a b c d e f Zhao, Lan; Oliver, Eduardo; Maratou, Klio; Atanur, Santosh S.; Dubois, Olivier D.; Cotroneo, Emanuele; Chen, Chien-Nien; Wang, Lei; Arce, Cristina; Chabosseau, Pauline L.; Ponsa-Cobas, Joan (2015-08-20). "The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia". Nature. 524 (7565): 356–360. doi:10.1038/nature14620. ISSN 1476-4687. PMC 6091855. PMID 26258299.
  16. ^ Abdo, Adrian I.; Tran, Hai Bac; Hodge, Sandra; Beltrame, John F.; Zalewski, Peter D. (2021-06). "Zinc Homeostasis Alters Zinc Transporter Protein Expression in Vascular Endothelial and Smooth Muscle Cells". Biological Trace Element Research. 199 (6): 2158–2171. doi:10.1007/s12011-020-02328-z. ISSN 1559-0720. PMID 32776265. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Bly, Mike (2006-01-31). "Examination of the zinc transporter gene, SLC39A12". Schizophrenia Research. 81 (2–3): 321–322. doi:10.1016/j.schres.2005.07.039. ISSN 0920-9964. PMID 16311021.
  18. ^ Gazzellone, Matthew J.; Zhou, Xue; Lionel, Anath C.; Uddin, Mohammed; Thiruvahindrapuram, Bhooma; Liang, Shuang; Sun, Caihong; Wang, Jia; Zou, Mingyang; Tammimies, Kristiina; Walker, Susan (2014). "Copy number variation in Han Chinese individuals with autism spectrum disorder". Journal of Neurodevelopmental Disorders. 6 (1): 34. doi:10.1186/1866-1955-6-34. ISSN 1866-1947. PMC 4147384. PMID 25170348.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Krumm, Niklas; Turner, Tychele N.; Baker, Carl; Vives, Laura; Mohajeri, Kiana; Witherspoon, Kali; Raja, Archana; Coe, Bradley P.; Stessman, Holly A.; He, Zong-Xiao; Leal, Suzanne M. (2015-06). "Excess of rare, inherited truncating mutations in autism". Nature Genetics. 47 (6): 582–588. doi:10.1038/ng.3303. ISSN 1546-1718. PMC 4449286. PMID 25961944. {{cite journal}}: Check date values in: |date= (help)
  20. ^ Dulak, Austin M.; Stojanov, Petar; Peng, Shouyong; Lawrence, Michael S.; Fox, Cameron; Stewart, Chip; Bandla, Santhoshi; Imamura, Yu; Schumacher, Steven E.; Shefler, Erica; McKenna, Aaron (2013-05). "Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity". Nature Genetics. 45 (5): 478–486. doi:10.1038/ng.2591. ISSN 1546-1718. PMC 3678719. PMID 23525077. {{cite journal}}: Check date values in: |date= (help)
  21. ^ Murugaesu, Nirupa; Wilson, Gareth A.; Birkbak, Nicolai J.; Watkins, Thomas; McGranahan, Nicholas; Kumar, Sacheen; Abbassi-Ghadi, Nima; Salm, Max; Mitter, Richard; Horswell, Stuart; Rowan, Andrew (2015-08). "Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy". Cancer Discovery. 5 (8): 821–831. doi:10.1158/2159-8290.CD-15-0412. ISSN 2159-8290. PMC 4529488. PMID 26003801. {{cite journal}}: Check date values in: |date= (help)
  22. ^ Huang, Cuiping; Cui, Xiaobo; Sun, Xiaotian; Yang, Jingxuan; Li, Min (2016-10-11). "Zinc transporters are differentially expressed in human non-small cell lung cancer". Oncotarget. 7 (41): 66935–66943. doi:10.18632/oncotarget.11884. ISSN 1949-2553. PMC 5341848. PMID 27611948.
  23. ^ Chandler, Paige; Kochupurakkal, Bose S.; Alam, Samina; Richardson, Andrea L.; Soybel, David I.; Kelleher, Shannon L. (2016-01-05). "Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer". Molecular Cancer. 15: 2. doi:10.1186/s12943-015-0486-y. ISSN 1476-4598. PMC 4700748. PMID 26728511.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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