Important Variant Information for KCNJ11
Submitted by: Daniel Gonzalez, Michael Pacanowski, and Julie A. Johnson (PEAR)
Reviewed by: Under Review
Submitted date: October 11, 2006
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There is One Important Variant for KCNJ11.
KCNJ11:E23K
| Gene HGNC Name: | KCNJ11 |
|---|---|
| Variant Summary: | Two subunits form the ATP-sensitive potassium channel - the sulfonylurea receptor (SUR1) and the Kir6.2 subunit (Kir6.2). KCNJ11 encodes the Kir6.2 subunit. The nonsynonymous E23K variant in the NH2-terminal of Kir6.2 may alter pancreatic Beta-cell sensitivity to adenosine tri-phosphate (ATP) [PMID: 11872696]. ATP, a byproduct of glucose metabolism, activates the pancreatic potassium channel causing it to depolarize the cell and ultimately release insulin. The E23K variant may alter the charge of the ATP-binding region, decreasing the sensitivity of the channel to ATP, thereby increasing the open probability [PMID: 15565284, 12198096, 12475776]. The E23K variant is common, with minor allele frequencies reported in dbSNP and in the literature as follows: African American 8%, Caucasian 34-48%, Chinese 24%, and Japanese 30%. Several large association studies, including a meta-analysis, provide strong evidence that the E23K variant is associated with type 2 diabetes [PMID: 12540638, 12540637, 15111507, 12605956, 15855351, 15842514,15579791]. Recent investigations demonstrated that the E23K variant impairs insulin secretion, whereas another describes a functional effect through abnormal glucagon secretion.[PMID: 12540638, 15111507, 12351459, 12196481]. Sulfonylureas target the pancreatic ATP-sensitive potassium channel, specifically the sulfonylurea receptor subunit. Consequently, the E23K variant could affect the response to sulfonylureas. In UKPDS, the change in glucose following sulfonylurea therapy and failure of sulfonylurea therapy did not differ by E23K genotype (or ABCC8 polymorphisms) [PMID: 11318841]. However, another study demonstrated that secondary sulfonylurea failure was more likely in those who carried the K allele.[PMID: 16595597] In vitro, the variant did not affect tolbutamide responsiveness.[PMID: 8897013]. Linkage with ABCC8 variants could be responsible for the pharmacogenetic association, as one study suggested that exonic and intronic variants in ABCC8 decreased tolbutamide response.[PMID: 9568693]. |
| Key PubMed IDs: | 15565284, 12540638, 12198096, 12540637, 15111507, 12605956, 15855351, 15842514, 15579791, 11318841, 8897013, 9568693, 11872696, 12351459, 12196481, 9032109 |
| Genomic Variant & GenBank ID: | 16196813 T>C on NT_009237 |
| mRNA Variant & GenBank ID: | 635 A>G on NM_000525(note: this mRNA sequence encodes KCNJ11:E23K, so the A at position 635 represents the variant, and the G represents reference KCNJ11) |
| Protein Variant & GenBank ID: | Lys23Glu on NP_000516 (note: this protein sequence is for KCNJ11:E23K, so the change from the variant to the reference KCNJ11 becomes Lys23Glu) |
| dbSNP rs#: | rs5219 |
| dSNP ss#: | ss6665 |
| GoldenPath Position: | chr11:17366148;(hg18) |
| Drugs/Substrates: | Antiarrhythmics Antidiabetic agents, sulfonylurea 16595597, 15838686, 15448106, 16731836, 11318841 Diazoxide 16332676, 15807877, 12199344 |
| Phenotypes/Diseases: | Diabetes Mellitus, Non-Insulin-Dependent 9032109, 12540637, 15111507, 15842514, 15797964, 15784703, 14551916, 12540638, 15579791, 11318841 Permanent, Neonatal Diabetes Mellitus 16329180, 16087682, 15580558 Persistent hyperinsulinemic hypoglycemia of infancy 12199344, 11395395 |