Annotated PGx Gene 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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| Gene HGNC Name: | KCNJ11 |
|---|---|
| Gene Common Name: | potassium inwardly-rectifying channel, subfamily J, member 11 Inwardly rectifying potassium channel Kir6.2 subunit Beta-cell inward rectifier Kir6.2 BIR |
| Introductory Information: | The inwardly rectifying, ATP-sensitive potassium channel (K ATP) was first identified in cardiac muscle, but it is also expressed in pancreatic Beta-cells, central nervous system tissue, skeletal muscle, and smooth muscle. In the pancreas, the K ATPchannels close when intracellular glucose levels increase. The cessation of K+ efflux depolarizes the Beta-cell membrane, which activates voltage-gated calcium channels and facilitates insulin secretion. Sulfonylureas exert their hypoglycemic effect by inhibiting the K ATP channel. Inagaki et al. cloned the two subunits that form the K ATPchannel, Kir6.2 (the ATP-sensor and channel pore) and the sulfonylurea receptor (SUR1), and mapped both genes to a common region on chromosome 11 [PMID: 7502040]. KCNJ11 is an intronless gene that codes for the 390 amino acid Kir6.2 subunit. KCNJ11 is approximately 3.4 kilobases in size and it lies approximately 4.5 kilobases upstream from the gene encoding SUR1 (ABCC8). Twenty validated SNPs are present in KCNJ11, as reported in dbSNP, but the functional consequences of most are unknown. The most widely studied variant is a G to A substitution at nucleotide 635, which results in a change from a glutamate residue in position 23 to lysine (E23K). This substitution decreases the sensitivity of the potassium channel to ATP and thus affects insulin secretion [PMID: 15842514]. KCNJ11variation is implicated as a risk factor for type 2 diabetes based on the results of numerous clinical and population-based association studies [PMID:]. The literature for ABCC8 is not as consistent, although variants in the KCNJ11 and ABCC8 are tightly linked. [PMID: 12540637, 12540638, 15579791, 15842514, 12540637 15579791, 15111507, 15797964]. The primary target of sulfonylureas is the K ATP channel, therefore KCNJ11 variation may influence the outcome of sulfonylurea treatment in type 2 diabetes [PMID: 16595597]. Additionally, patients with rare activating variants in KCNJ11 may be able to discontinue insulin after starting oral sulfonylurea therapy. [PMID: 16885550] |
| Key PubMed IDs: | 7502040 16613899 14551916 12540637 15111507 15842514 15797964 15842514 12540638 15579791 16595597 16885550, 16782803 |
| Key Pathways: | Antiarrhythmic Drug Pathways |
| Drugs/Substrates: | Antiarrhythmics Antidiabetic agents, sulfonylurea 16595597, 15838686, 15448106, 16731836, 11318841 Diazoxide 16332676, 15807877, 12199344 16885550 |
| Phenotypes/Diseases: | Diabetes Mellitus 9032109, 12540637, 15111507, 15842514, 15797964, 15784703, 14551916, 12540638, 15579791, 11318841, 16885550, 15784703 Permanent, Neonatal Diabetes Mellitus 16329180, 16087682, 15580558 Persistent hyperinsulinemic hypoglycemia of infancy 12199344, 11395395 Cardiovascular Diseases 16782803 14871556 16455067 |
| Important Variants: | KCNJ11:E23K |