Activating Mutations in Kir6.2 and Neonatal Diabetes

Hattersley, Andrew T.; Ashcroft, Frances M.

doi:10.2337/diabetes.54.9.2503

Cited by 394 publications

(418 citation statements)

References 71 publications

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“…This adds to accumulating evidence that KCNJ11 mutations that cause neonatal diabetes do so by affecting K ATP channel ATP sensitivity, either directly or indirectly [8,9,13,14,[26][27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…In some patients, the diabetes is transient, although it may frequently relapse, whereas in other cases it is permanent and requires insulin treatment for life. The commonest cause of permanent neonatal diabetes (PNDM) are heterozygous activating mutations in the KCNJ11, the gene encoding Kir6.2, which constitutes the pore-forming subunit of the K ATP channel in the pancreatic beta cell [7][8][9]. KCNJ11 mutations account for around 50% of cases of PNDM [7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…KCNJ11 mutations account for around 50% of cases of PNDM [7][8][9][10][11][12][13]. Some of these mutations lead to a more severe syndrome in which developmental delay and epilepsy accompany neonatal diabetes, a condition known as DEND syndrome [9]. Mutations in KCNJ11 can also result in transient neonatal diabetes mellitus (TNDM) [14], although in most patients TNDM is caused by an abnormality of the imprinted region on chromosome 6q24 [15].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in K ATP channel subunits that reduce channel function lead to congenital hyperinsulinism, whereas those that enhance channel function cause diabetes [8,9]. To date, mutations in Kir6.2 associated with TNDM and PNDM have been shown to enhance K ATP channel activity by decreasing ATP inhibition at Kir6.2 [7-9, 13, 14, 26-31].…”

Section: Introductionmentioning

confidence: 99%

“…These drugs stimulate insulin secretion by binding to SUR1, and closing K ATP channels directly, thus bypassing beta cell metabolism. They have proved effective in treating neonatal diabetes that results from gain-of-function mutations in Kir6.2 [9,10,33].…”

Section: Introductionmentioning

confidence: 99%

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Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

Girard

Shimomura

Proks

et al. 2006

Pflugers Arch - Eur J Physiol

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ATP-sensitive potassium (K ATP ) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. K ATP channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the K ATP channel to inhibition by MgATP, and enhanced whole-cell K ATP currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the K ATP current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs.

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