Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Potassium channel, inwardly rectifying, subfamily J, member 11

The protein encoded by this gene is a potassium channel that regulates insulin secretion in pancreatic beta cells. Loss-of-funtion mutations cause autosomal recessive and less commonly dominant hyperinsulinemic hypoglycemia. Gain-of-function mutations, on the other hand, cause autosomal dominant permanent neonatal juvenile (MODY13) diabetes mellitus, a special case of which is DEND syndrome that is associated by neurological symptoms.

Protein Structure

The protein forms a heterodimer with SUR, the sulfonyl urea receptor.

Phenotype

Mutations inhibiting the beta cell result in permanent neonatal diabetes mellitus. On the other hand activating mutations lead to hyperinsulinemic hypoglycemia.

Pathology

The inwardly rectifying potassium conductance is activated by diazoxide and inhibited by sulfonyl urea, which results in decreased or increased insulin secretion. Mutations activating the channel and inhibiting its ATP inhibition result in reduced insulin secretion. The opposite is true for mutations that inhibit the channel conductance.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 25 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Hyperinsulinemic hypoglycemia 2
KCNJ11
Permanent neonatal diabetes mellitus
ABCC8
Developmental delay, epilepsy, and neonatal diabetes
KCNJ11
GCK
INS
KCNJ11
Phosphoribosylpyrophosphate synthetase superactivity
PRPS1
Wolcott-Rallison syndrome
EIF2AK3
Transient neonatal diabetes mellitus 3
KCNJ11
Developmental delay, epilepsy, and neonatal diabetes
KCNJ11
MODY13 diabetes
KCNJ11

References:

1.

Tornovsky S et. al. (2004) Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.

[^]
2.

Thomas PM et. al. (1995) Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy.

[^]
3.

Koster JC et al. (2000) Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes.

[^]
4.

Yamada K et al. (2001) Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure.

[^]
5.

Ribalet B et al. (2003) Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.

[^]
6.

Gloyn AL et al. (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

[^]
7.

Gloyn AL et al. (2004) Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel.

[^]
8.

Henwood MJ et. al. (2005) Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.

[^]
9.

Laukkanen O et. al. (2004) Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study.

[^]
10.

Massa O et al. (2005) KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.

[^]
11.

Proks P et al. (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.

[^]
12.

Gloyn AL et al. (2005) Relapsing diabetes can result from moderately activating mutations in KCNJ11.

[^]
13.

Gupta RK et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.

[^]
14.

Yorifuji T et al. (2005) The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.

[^]
15.

Hansen SK et. al. (2005) Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes.

[^]
16.

Proks P et al. (2005) A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome.

[^]
17.

Marthinet E et al. (2005) Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function.

[^]
18.

Proks P et al. (2005) Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP.

[^]
19.

Colombo C et al. (2005) Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation.

[^]
20.

Gloyn AL et al. (2006) Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism.

[^]
21.

Slingerland AS et al. (2006) Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes.

[^]
22.

Gloyn AL et al. (2006) KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.

[^]
23.

Masia R et al. (2007) An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes.

[^]
24.

et al. (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.

[^]
25.

Scott LJ et al. (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

[^]
26.

Zeggini E et al. (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.

[^]
27.

Shimomura K et al. (2007) A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.

[^]
28.

Sumnik Z et al. (2007) Sulphonylurea treatment does not improve psychomotor development in children with KCNJ11 mutations causing permanent neonatal diabetes mellitus accompanied by developmental delay and epilepsy (DEND syndrome).

[^]
29.

Mlynarski W et al. (2007) Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11.

[^]
30.

Koster JC et al. (2008) The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy.

[^]
31.

Lin YW et al. (2008) Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism.

[^]
32.

Slingerland AS et al. (2008) Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation.

[^]
33.

Pinney SE et. al. (2008) Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations.

[^]
34.

Koster JC et al. (2008) DEND mutation in Kir6.2 (KCNJ11) reveals a flexible N-terminal region critical for ATP-sensing of the KATP channel.

[^]
35.

Girard CA et al. (2009) Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes.

[^]
36.

Della Manna T et al. (2008) Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene.

[^]
37.

Taneja TK et al. (2009) Sar1-GTPase-dependent ER exit of KATP channels revealed by a mutation causing congenital hyperinsulinism.

[^]
38.

Mohamadi A et al. (2010) Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM.

[^]
39.

Clark RH et al. (2010) Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin.

[^]
40.

Inagaki N et. al. (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.

[^]
41.

Chandy KG et al. (1993) Nomenclature for mammalian potassium channel genes.

[^]
42.

Inagaki N et al. (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels.

[^]
43.

Thomas P et al. (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy.

[^]
44.

de Lonlay P et. al. (1997) Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy.

[^]
45.

Miki T et al. (1997) Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.

[^]
46.

Nestorowicz A et al. (1997) A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.

[^]
47.

Hani EH et al. (1998) Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.

[^]
Update: Sept. 26, 2018