Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy

Thomas, Peedikayil E.; Ye, Yuyang; Lightner, Elmer S.

doi:10.1093/hmg/5.11.1809

Cited by 420 publications

(234 citation statements)

References 22 publications

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“…In the absence of clinical treatment, PHHI may be lethal or result in irreversible neurologic sequelae. To date, three mutations responsible for PHHI have been identified in the Kir6.2 gene (21)(22)(23) and in numerous mutations in the SUR1 gene (1, 24 -30). Some of the SUR1 mutations are nonsense or frameshift mutations that produce a truncated form of SUR1.…”

Section: Atp-sensitive Potassium (K Atpmentioning

confidence: 99%

Functional Analysis of a Mutant Sulfonylurea Receptor, SUR1-R1420C, That Is Responsible for Persistent Hyperinsulinemic Hypoglycemia of Infancy

Matsuo¹,

Trapp²,

Tanizawa³

et al. 2000

Journal of Biological Chemistry

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The ATP-sensitive potassium (K ATP ؉ ) channel is crucial for the regulation of insulin secretion from the pancreatic ␤-cell, and mutations in either the sulfonylurea receptor type 1 (SUR1) or Kir6.2 subunit of this channel can cause persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We analyzed the functional consequences of the PHHI missense mutation R1420C, which lies in the second nucleotide-binding fold ( ATP-sensitive potassium (K ATP ϩ ) channels link the metabolic state of the cell to its membrane potential in many tissues including pancreatic ␤-cells, heart, brain, and skeletal muscle (1-4). It is believed that metabolic regulation is mediated by changes in ATP and Mg 2ϩ -nucleotides (such as MgADP), which inhibit and activate the channel, respectively. In pancreatic ␤-cells, metabolically induced changes in K ATP ϩ channel activity play a key role in glucose-stimulated insulin secretion. At substimulatory glucose concentrations, K ATP ϩ channels are open, and their activity serves to maintain the resting membrane potential at a hyperpolarized level. Elevation of blood glucose concentration increases glucose uptake and metabolism by the ␤-cell producing changes in cytosolic nucleotide concentrations that result in closure of the K ATP ϩ channels. This leads to depolarization of the ␤-cell membrane potential and thus to activation of voltage-gated calcium channels and Ca 2ϩ influx. The resulting rise in the intracellular Ca 2ϩ concentration triggers insulin release.The ␤-cell K ATP ϩ channel is a hetero-octamer composed of pore-forming Kir6.2 subunits and regulatory sulfonylurea receptor (SUR1) subunits that coassemble with 4:4 stoichiometry (5-8). Kir6.2 is a member of the inwardly rectifying potassium channel family (9, 10), whereas SUR1 belongs to the ATPbinding cassette transporter superfamily (11). Like other members of this family, SUR1 has two intracellular nucleotidebinding folds (NBFs), 1 each containing a Walker A and a Walker B motif that is involved in Mg 2ϩ -nucleotide binding and hydrolysis. Nucleotides interact with both Kir6.2 and SUR1 subunits; ATP inhibits the channel by binding to , whereas Mg 2ϩ -nucleotides stimulate channel activity by binding to the NBFs of SUR1 (1,(15)(16)(17)(18)(19)(20).Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is an autosomal recessive disorder characterized by inappropriate insulin secretion despite severe hypoglycemia. In the absence of clinical treatment, PHHI may be lethal or result in irreversible neurologic sequelae. To date, three mutations responsible for PHHI have been identified in the Kir6.2 gene (21-23) and in numerous mutations in the SUR1 gene (1, 24 -30). Some of the SUR1 mutations are nonsense or frameshift mutations that produce a truncated form of SUR1. Others are missense mutations, many of which are found within the NBFs of SUR1 and impair K ATP ϩ channel activity by affecting Mg 2ϩ -nucleotide interactions with SUR1 (1, 29). As a consequence, the K ATP ϩ channel remains closed even in the absence of glucose, which...

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Section: Atp-sensitive Potassium (K Atpmentioning

confidence: 99%

Functional Analysis of a Mutant Sulfonylurea Receptor, SUR1-R1420C, That Is Responsible for Persistent Hyperinsulinemic Hypoglycemia of Infancy

Matsuo¹,

Trapp²,

Tanizawa³

et al. 2000

Journal of Biological Chemistry

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“…Loss of function of the pancreatic islet K ATP channel, because of mutation of either the SUR1 or Kir6.2 subunit (11)(12)(13)(14), has been demonstrated to lead to persistent hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder characterized by unregulated insulin secretion and severe hypoglycemia (15). Disease phenotypes have not yet been assigned to the other K ATP channels.…”

Section: Atp-sensitive Potassium (K Atp )mentioning

confidence: 99%

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

Nasonkin¹,

Alikaşifoğlu²,

Ambrose³

et al. 1999

Journal of Biological Chemistry

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Sulfonylurea receptors (SURx) are required subunits of the ATP-sensitive potassium channel. SURx alone is electrophysiologically inert. However, when SURx is combined with an inward rectifier Kir6.2 subunit, ATPsensitive potassium channel activity is generated. We report the identification, characterization, and localization of Dsur, a novel Drosophila gene that is highly related to the vertebrate SUR family. The Dsur coding sequence contains structural features characteristic of the ABC transporter family and, in addition, harbors 1.7 kilobases of a distinctive sequence that does not share homology with any known gene. When Dsur alone is expressed in Xenopus oocytes glibenclamide-sensitive potassium channel activity occurs. During Drosophila embryogenesis, the Dsur gene is specifically expressed in the developing tracheal system and dorsal vessel. Studies of the Drosophila genome support that only a single Dsur gene is present. Our data reveal conservation of glibenclamide-sensitive potassium channels in Drosophila and suggest that Dsur may play an important role during Drosophila embryogenesis. The lack of gene duplication in the Drosophila system provides a unique opportunity for functional studies of SUR using a genetic approach.

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“…Rare mutations in KCNJ11 14 can lead to neonatal diabetes and hyperinsulinaemia of infancy (depending on the direction of their effect on channel function). 15 Previous comprehensive tagging studies have demonstrated that common variation within the single exon of KCNJ11, in particular the E23K variant (which is in almost complete LD (40.9) with the A1369S variant within the neighbouring ABCC8 but with no other nonsynonymous variants in KCNJ11), is heavily implicated in susceptibility to multifactorial T2D. 16 Furthermore, E23K is the polymorphism within KCNJ11 most likely to be aetiological for T2D, on both statistical and functional grounds.…”

Section: Introductionmentioning

confidence: 99%

Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels

et al. 2007

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Polycystic ovary syndrome (PCOS) is strongly associated with hyperinsulinaemia and type II diabetes (T2D). Sequence variation within KCNJ11 (encoding Kir6.2, the beta-cell inwardly rectifying potassium channel) is implicated in the pathogenesis of neonatal diabetes, hyperinsulinaemia of infancy and multifactorial T2D. Comprehensive tagging studies have demonstrated that the KCNJ11 E23K variant (or ABCC8 A1369S in LD40.9) is responsible for the known association between KCNJ11 and T2D. Given the phenotypic overlap between PCOS and T2D, we investigated whether E23K is involved in susceptibility to PCOS and related traits. Case -control analyses for the KCNJ11 E23K variant were performed in (a) 374 PCOS cases and 2574 controls of UK British/Irish origin, and (b) 550 women with PCOS symptoms and 1114 controls from a Finnish birth cohort. The relationship between E23K genotype and androgen levels (a key intermediate phenotype relevant to PCOS) in 1380 samples was studied. The UK case-control analysis revealed no association between E23K genotypes and PCOS status (P ¼ 0.49; Cochran -Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (P ¼ 0.19). Similarly, the Finnish case-control analysis showed no association between E23K genotypes and PCOS status (P ¼ 0.75; Cochran -Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (Finnish controls, P ¼ 0.25; Finnish cases, P ¼ 0.08). In conclusion, these data (involving 44600 subjects) provide no evidence that common variants of the KCNJ11 E23K polymorphism have a major influence on PCOS susceptibility, though modest effect sizes (ORo1.25) cannot be excluded.

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Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy

Cited by 420 publications

References 22 publications

Functional Analysis of a Mutant Sulfonylurea Receptor, SUR1-R1420C, That Is Responsible for Persistent Hyperinsulinemic Hypoglycemia of Infancy

Functional Analysis of a Mutant Sulfonylurea Receptor, SUR1-R1420C, That Is Responsible for Persistent Hyperinsulinemic Hypoglycemia of Infancy

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels

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