Scientific background:

Summary: 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 diabetes mellitus, a special case of which is DEND syndrome that is associated by neurological symptoms.

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

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.

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

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.
	research test	Method		Gene dosage measurements
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Of the gene rearrangements, this method is useful to detect large deletions or duplications.

Literature: 

Inagaki N et al. (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.
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.
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.
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.
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.
Mlynarski W et al. (2007) Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11.
Slingerland AS et al. (2008) Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation.
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).
Shimomura K et al. (2007) A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.
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.
Gloyn AL et al. (2006) KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.
Proks P et al. (2005) A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome.
Chandy KG et al. (1993) Nomenclature for mammalian potassium channel genes.
Clark RH et al. (2010) Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin.
Colombo C et al. (2005) Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation.
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.
et al. (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
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.
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.
Gloyn AL et al. (2006) KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.
Gloyn AL et al. (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
Gloyn AL et al. (2005) Relapsing diabetes can result from moderately activating mutations in KCNJ11.
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.
Gupta RK et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.
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.
Hansen SK et al. (2005) Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes.
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.
Inagaki N et al. (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.
Inagaki N et al. (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels.
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.
Koster JC et al. (2000) Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes.
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.
Lin YW et al. (2008) Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism.
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.
Massa O et al. (2005) KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.
Miki T et al. (1997) Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.
Nestorowicz A et al. (1997) A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.
Pinney SE et al. (2008) Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations.
Proks P et al. (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.
Proks P et al. (2005) Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP.
Ribalet B et al. (2003) Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.
Scott LJ et al. (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
Shimomura K et al. (2007) A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.
Slingerland AS et al. (2006) Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes.
Taneja TK et al. (2009) Sar1-GTPase-dependent ER exit of KATP channels revealed by a mutation causing congenital hyperinsulinism.
Thomas P et al. (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy.
Thomas PM et al. (1995) Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy.
Tornovsky S et al. (2004) Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
Yamada K et al. (2001) Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure.
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.
Zeggini E et al. (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.