Zinc transporter 8

Zinc transporter 8 (ZNT8) is a protein that in humans is encoded by the SLC30A8 gene.^[5] ZNT8 is a zinc transporter related to insulin secretion in humans. In particular, ZNT8 is critical for the accumulation of zinc into beta cell secretory granules and the maintenance of stored insulin as tightly packaged hexamers. Certain alleles of the SLC30A8 gene may increase the risk for developing type 2 diabetes, but a loss-of-function mutation appears to greatly reduce the risk of diabetes.^[6]

SLC30A8
Identifiers
Aliases	SLC30A8, ZNT8, ZnT-8, solute carrier family 30 member 8
External IDs	OMIM: 611145; MGI: 2442682; HomoloGene: 13795; GeneCards: SLC30A8; OMA:SLC30A8 - orthologs
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8q24.11 Start 116,950,273 bp[1] End 117,176,714 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 C Start 52,158,949 bp[2] End 52,199,194 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans pancreatic epithelial cell testicle body of pancreas tibialis anterior muscle mucosa of ileum gonad right testis left testis deltoid muscle Top expressed in islet of Langerhans embryo right kidney foregut stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity cation transmembrane transporter activity zinc ion binding protein binding zinc ion transmembrane transporter activity Cellular component integral component of membrane Golgi apparatus secretory granule membrane membrane plasma membrane transport vesicle membrane secretory granule cytoplasmic vesicle Biological process response to interleukin-1 response to interferon-gamma glucose homeostasis regulation of vesicle-mediated transport zinc ion transport response to zinc ion cation transport insulin secretion ion transport response to glucose cation transmembrane transport sequestering of zinc ion cellular zinc ion homeostasis regulation of sequestering of zinc ion positive regulation of insulin secretion zinc ion transmembrane transport transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 169026 239436 Ensembl ENSG00000164756 ENSMUSG00000022315 UniProt Q8IWU4 Q8BGG0 RefSeq (mRNA) NM_001172811 NM_001172813 NM_001172814 NM_001172815 NM_173851 NM_172816 RefSeq (protein) NP_001166282 NP_001166284 NP_001166285 NP_001166286 NP_776250 NP_766404 Location (UCSC) Chr 8: 116.95 – 117.18 Mb Chr 15: 52.16 – 52.2 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical significance

Association with type 2 diabetes (T2D)

Twelve rare variants in SLC30A8 have been identified through the sequencing or genotyping of approximately 150,000 individuals from 5 different ancestry groups. SLC30A8 contains a common variant (p.Trp325Arg), which is associated with T2D risk and levels of glucose and proinsulin.^[7][8][9] Individuals carrying protein-truncating variants collectively had 65% reduced risk of T2D. Additionally, non-diabetic individuals from Iceland harboring a frameshift variant p. Lys34Serfs*50 demonstrated reduced glucose levels.^[6] Earlier functional studies of SLC30A8 suggested that reduced zinc transport increased T2D risk.^[10][11] Conversely, loss-of-function mutations in humans indicate that SLC30A8 haploinsufficiency protects against T2D. Therefore, ZnT8 inhibition can serve as a therapeutic strategy in preventing T2D.^[6]

See also

• Solute carrier family

References

1. GRCh38: Ensembl release 89: ENSG00000164756 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022315 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: SLC30A8 solute carrier family 30 (zinc transporter), member 8".
6. Flannick, Jason; et al. (2014). "Loss-of-function mutations in SLC30A8 protect against type 2 diabetes". Nature Genetics. 46 (4): 357–363. doi:10.1038/ng.2915. PMC 4051628. PMID 24584071.
7. Dupis, J.; et al. (Feb 2010). "New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk". Nature Genetics. 42 (2): 105–16. doi:10.1038/ng.520. PMC 3018764. PMID 20081858.
8. Strawbridge, R.J.; et al. (October 2011). "Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes". Diabetes. 60 (10): 2624–34. doi:10.2337/db11-0415. PMC 3178302. PMID 21873549.
9. Morris, A.P.; et al. (Sep 2012). "Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes". Nature Genetics. 44 (9): 981–90. doi:10.1038/ng.2383. PMC 3442244. PMID 22885922.
10. Nicolson, T.J.; et al. (Sep 2009). "Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes–associated variants". Diabetes. 58 (9): 2070–83. doi:10.2337/db09-0551. PMC 2731533. PMID 19542200.
11. Rutter, G.A.; et al. (2010). "Think zinc: new roles for zinc in the control of insulin secretion". Islets. 2 (1): 49–50. doi:10.4161/isl.2.1.10259. PMID 21099294.

Further reading

• Chimienti F, Favier A, Seve M (2006). "ZnT-8, a pancreatic beta-cell-specific zinc transporter". Biometals. 18 (4): 313–7. doi:10.1007/s10534-005-3687-9. PMID 16158222. S2CID 25680038.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Seve M, Chimienti F, Devergnas S, Favier A (2004). "In silico identification and expression of SLC30 family genes: an expressed sequence tag data mining strategy for the characterization of zinc transporters' tissue expression". BMC Genomics. 5 (1): 32. doi:10.1186/1471-2164-5-32. PMC 428573. PMID 15154973.
• Chimienti F, Devergnas S, Favier A, Seve M (2004). "Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules". Diabetes. 53 (9): 2330–7. doi:10.2337/diabetes.53.9.2330. PMID 15331542.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
• Sladek R, Rocheleau G, Rung J, et al. (2007). "A genome-wide association study identifies novel risk loci for type 2 diabetes". Nature. 445 (7130): 881–5. Bibcode:2007Natur.445..881S. doi:10.1038/nature05616. PMID 17293876. S2CID 4302932.
• Wenzlau JM, Juhl K, Yu L, et al. (2007). "The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes". Proc. Natl. Acad. Sci. U.S.A. 104 (43): 17040–5. Bibcode:2007PNAS..10417040W. doi:10.1073/pnas.0705894104. PMC 2040407. PMID 17942684.

External links

• Type 2 diabetes genes mapped out, BBC News article