| Full gene name: | potassium inwardly-rectifying channel, subfamily J, member 11 |
|---|---|
| Entrez Gene ID: | 3767 |
| Location: | 11p15.1 |
| Synonyms: | IKATP, TNDM3, PHHI, HHF2, KIR6.2, BIR |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs5215 | 0 | within |
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor SUR. Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM), transient neonatal diabetes mellitus type 3 (TNDM3), and permanent neonatal diabetes mellitus (PNDM). Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2009]
| OMIM ID: | `OMIM ID 600937 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In a male infant with profound hypoglycemia (601820), born of consanguineous Iranian parents, Thomas et al. (1996) identified homozygosity for a 649T-C mutation in the KCNJ11 gene, resulting in a leu147-to-pro (L147P) substitution predicted to cause disruption of the M2 alpha-helical transmembrane domain of the protein. His parents were heterozygous for the mutation.
.0002 DIABETES MELLITUS, PERMANENT NEONATAL
In 4 unrelated patients with permanent neonatal DIABETES (606176), Gloyn et al. (2004) identified a heterozygous arg201-to-his (R201H) mutation in the KCNJ11 gene. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (Ribalet et al., 2003). In 1 family reported by Gloyn et al. (2004), 2 brothers and the father were affected. DIABETES in the brothers was diagnosed under the age of 3 or 4 weeks, and in the father at the age of 12 weeks. The father was age 46 years at the time of report. In another family, mother and son were affected. The diagnosis had been made at birth in the son and at age 6 weeks in the mother, who was 36 years old at the time of report. None of the patients with the R201H mutation had muscle weakness, neurologic abnormalities, or dysmorphic features. The arginine residue at position 201 of Kir6.2 lies close to the ATP-binding site and was previously implicated in ATP sensing.
By functional expression studies in Xenopus oocytes, Proks et al. (2004) found that mutations at the arg201 residue (see also R201C; 600937.0004) caused a decrease in ATP sensitivity by altering the ATP-binding site. However, the decreased sensitivity found in cells with a mutation at arg201 was not as severe as that found in cells with a mutation at val59 (see V59M, 600937.0003 and V59G, 600937.0005).
Gloyn et al. (2006) reported 2 unrelated infants with PNDM and the R201H mutation. The male infant also had dysmorphic facial features and neurologic involvement, including seizures, developmental delay, and axial hypotonia. In contrast, the other infant did not have neurologic involvement, and her mother, who also carried the mutation, had severe DIABETES mellitus without neurologic involvement. The phenotypic variability suggested that other modifying factors likely play a role.
In a 20-year-old woman with transient neonatal DIABETES mellitus (TNDM3; 610582) in whom DIABETES remitted at age 29 months and recurred at age 7 years, Colombo et al. (2005) identified heterozygosity for a de novo 602G-A (R201H) mutation in the KCNJ11 gene.
.0003 DIABETES MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
In 2 unrelated males with permanent neonatal DIABETES (606176), Gloyn et al. (2004) found heterozygosity for a val59-to-met (V59M) mutation in the KCNJ11 gene. One of the patients had muscle weakness, and mildly delayed motor and mental development.
Proks et al. (2004) noted that 2 mutations in the same residue of Kir6.2, V59M and V59G (600937.0005), are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (600937.0002) and R201C (600937.0004). They found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the ‘slide helix,’ a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel.
Massa et al. (2005) found the V59M mutation in 4 unrelated Italian patients with PNDM. Two of the patients had motor and mental developmental delay. One of the patients was diagnosed at over 6 months of age (182 days). Massa et al. (2005) suggested that the designation ‘permanent DIABETES mellitus of infancy’ (PDMI) replace ‘permanent neonatal DIABETES mellitus.’
Gloyn et al. (2006) reported a patient with the V59M mutation who had PNDM and neurologic features, including mild motor developmental delay and axial hypotonia.
.0004 DIABETES MELLITUS, PERMANENT NEONATAL
In a patient with PNDM (606176), Gloyn et al. (2004) identified a heterozygous arg201-to-cys (R201C) mutation in the Kir6.2 gene. The patient was diagnosed at 4 weeks of age and had no additional neurologic or dysmorphic features. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (Ribalet et al., 2003).
Proks et al. (2004) stated that the 2 mutations in residue arg201, R201H (600937.0002) and R201C, which lie in the ATP-binding site of Kir6.2, cause milder PNDM disease without neurologic features; however, Massa et al. (2005) identified the R201C mutation in a patient with PNDM who also had muscle weakness and delayed motor development.
Gloyn et al. (2004) described a family in which 2 affected paternal half-sibs were heterozygous for the R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father’s leukocyte DNA detected no trace of mutant DNA. These results were consistent with the father being mosaic for the mutation, which was restricted to his germline. Gloyn et al. (2004) concluded that the high percentage of permanent neonatal DIABETES cases due to de novo KCNJ11 mutations (Gloyn et al., 2004) suggests that germline mosaicism may be common.
.0005 DIABETES MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
In a male patient with permanent neonatal DIABETES (606176), Gloyn et al. (2004) found heterozygosity for a val59-to-gly (V59G) mutation in the KCNJ11 gene. In addition to neonatal DIABETES, the patient had muscle weakness, marked motor and mental developmental delay, myoclonic seizures with abnormal EEG, and dysmorphic features, including a downturned mouth, bilateral ptosis, and contractures primarily in the legs at birth.
Proks et al. (2004) noted that 2 mutations in the same residue of Kir6.2, V59M (600937.0003) and V59G, are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (600937.0002) and R201C (600937.0004). Proks et al. (2004) found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the ‘slide helix,’ a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel.
.0006 DIABETES MELLITUS, PERMANENT NEONATAL
In an Italian patient with PNDM, Massa et al. (2005) identified a 149G-C transversion in the KCNJ11 gene, resulting in an arg50-to-pro (R50P) substitution. The patient had no neurologic abnormalities.
.0007 DIABETES MELLITUS, PERMANENT NEONATAL
In an Italian patient with PNDM (606176), Massa et al. (2005) identified a 175G-A transition in the KCNJ11 gene, resulting in a lys170-to-arg (K170R) substitution. The patient had no neurologic abnormalities.
.0008 DIABETES MELLITUS, PERMANENT NEONATAL
In an Italian patient with PNDM (606176), Massa et al. (2005) identified a 510G-C transversion in the KCNJ11 gene, resulting in a lys170-to-asn (K170N) substitution. The patient was diagnosed at age 63 days and had delayed mental development; however, this patient also had a brain infarction.
.0009 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In a Palestinian Arab boy with hyperINSULINemic hypoglycemia (601820), born of first-cousin parents, Nestorowicz et al. (1997) identified homozygosity for a 39C-A transversion in the KCNJ11 gene, resulting in a tyr12-to-ter (Y12X) substitution. The mutation is predicted to produce a truncated Kir6.2 polypeptide lacking the putative K+ ion-selective pore region as well as those domains proposed to confer the gating and inward rectification properties of the molecule. In vitro studies in transfected COS-1 cells confirmed the deleterious effect of the mutation on channel activity. The authors noted that this patient was clinically indistinguishable from patients with severe hyperINSULINism caused by mutations in SUR1 (ABCC8; 600509; see HHF1, 600509).
.0010 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In an Israeli Bedouin infant with hyperINSULINemic hypoglycemia (601820), Tornovsky et al. (2004) identified homozygosity for an 88G-T transversion 5-prime of the transcription start site in the promoter region of the KCNJ11 gene. Functional studies using a luciferase reporter vector revealed a 44% decrease in reporter gene expression for the mutant variant compared to wildtype.
.0011 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In an Arab infant in whom a prenatal diagnosis of hyperINSULINism was made due to a family history of hyperINSULINemic hypoglycemia (601820), Tornovsky et al. (2004) identified homozygosity for a C-T transition at codon 254 in exon 1 of the KCNJ11 gene, resulting in a pro254-to-leu (P254L) substitution. Photolabeling studies after transient transfection into COSm6 cells revealed impaired trafficking of the mutant channel.
.0012 DIABETES MELLITUS, TRANSIENT NEONATAL, 3
In affected members of a 4-generation Japanese family with dominantly inherited DIABETES mellitus observed in 3 generations, Yorifuji et al. (2005) detected a T-to-C transition at nucleotide 124 of the KCNJ11 gene that gave rise to a cys42-to-arg amino acid substitution (C24R). The proband had transient neonatal DIABETES (TNDM3; 610582), and his paternal grandfather had childhood DIABETES. The others had adult-onset DIABETES without autoantibodies or INSULIN resistance. Patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of the patients. The authors concluded that these results broadened the spectrum of DIABETES phenotypes caused by mutations of KCNJ11 and suggested that mutations in this gene should be taken into consideration for not only permanent neonatal DIABETES but also other forms of DIABETES with milder phenotypes and later onset.
.0013 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In a patient with severe congenital hyperINSULINism (601820), Marthinet et al. (2005) identified a homozygous A-to-G transition at nucleotide 776 of the KCNJ11 gene that resulted in a his-259-to-arg substitution (H259R). The patient presented with macrosomia at birth and severe hyperINSULINemic hypoglycemia. Despite medical treatment, the newborn continued to suffer from severe hypoglycemic episodes, and at 4 months of age subtotal pancreatectomy was performed. Coexpression of KCNJ11 H259R with ABCC8 (600509) in HEK293T cells completely abolished K(ATP) currents in electrophysiologic recordings. Double immunofluorescence staining revealed that mutant KCNJ11 was partly retained in the endoplasmic reticulum (ER) causing decreased surface expression as observed with total internal reflection fluorescence. Mutation of an ER-retention signal partially rescued the trafficking defect without restoring whole-cell currents.
.0014 DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO
Hani et al. (1998) identified a glu23-to-lys (E23K) amino acid substitution in the KCNJ11 gene by molecular screening using SSCP and direct sequencing in 72 French Caucasian type II diabetic families. They genotyped this variant in French cohorts of 191 unrelated type II diabetic probands and 119 normoglycemic control subjects and performed association studies. Homozygosity for lys23 (KK) was more frequent in type II diabetic than in control subjects (27 vs 14%; p = 0.015). Analyses in a recessive model (KK vs EK/EE) showed a stronger association of the K allele with DIABETES. In a metaanalysis of their data for the E23K variant and data obtained from 3 other Caucasian groups, Hani et al. (1998) found the E23K variant to be significantly associated with type II DIABETES.
Hansen et al. (2005) investigated the separate and combined effects of the PPARG pro12-to-ala (P12A; 601487.0002) and the KCNJ11 E23K polymorphisms on risk of type II DIABETES. The combined analysis involved 1,164 type II diabetic patients and 4,733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of KCNJ11 E23K associated with type II DIABETES (odds ratio, 1.19; P = 0.0002), whereas PPARG P12A showed no significant association with type 2 DIABETES. The combined analysis indicated that the 2 polymorphisms acted in an additive manner to increase the risk of type II DIABETES, and the authors found no evidence for a synergistic interaction between them. Together, the 2 polymorphisms conferred a population-attributable risk for type II DIABETES of 28%. The authors concluded that their results showed no evidence of a synergistic interaction between the KCNJ11 E23K and PPARG P12A polymorphisms, but indicated that they may act in an additive manner to increase the risk of type II DIABETES.
Laukkanen et al. (2004) found an additive effect of a high risk ABCC8 (600509) haplotype, composed of a silent polymorphism (AGG-AGA; arg1273 to arg) and 3 promoter polymorphisms, and the 23K allele of the KCNJ11 gene.
In genomewide association studies of type 2 DIABETES involving genotype data from a variety of international consortia, the DIABETES Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed association of the E23K polymorphism (rs5219) with DIABETES susceptibility. Although this association was not strongly observed in any single scan, all-data metaanalyses resulted in genomewide significant association (OR = 1.14, P = 6.7 x 10(-11)).
Association with Impaired Exercise Stress Response
Reyes et al. (2009) found that the E23K polymorphism was overrepresented in 115 individuals with dilated cardiomyopathy (see 115200) and congestive heart failure (CHF) compared to 2,031 community-based controls (p less than 0.001). In addition, the KK genotype, which was present in 18% of the CHF patients, was associated with abnormal cardiopulmonary exercise stress testing: despite similar baseline heart rates among genotype subgroups, individuals with the KK genotype had a significantly reduced heart rate increase at matched workload, at 75% of maximum oxygen consumption, and at peak VO(2), compared to those with the EE or EK genotypes. Noting that the glu23 residue is located within the functionally relevant intracellular slide helix region, Reyes et al. (2009) suggested that E23K might represent a biomarker for impaired stress performance.
.0015 DIABETES MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
In an infant with a severe form of permanent neonatal DIABETES mellitus with neurologic features (606176), Gloyn et al. (2006) identified a heterozygous G-to-T transversion in the KCNJ11 gene, resulting in a cys166-to-phe (C166F) substitution. The infant had feeding problem from birth and was diagnosed with DIABETES mellitus at age 3 months. She also had seizures with hypsarrhythmia, progressive neurologic deterioration, diffuse hypotonia, and dysmorphic facial features. She died from aspiration pneumonia at age 6 months. Gloyn et al. (2006) noted that the C166F mutation is predicted to result in a channel with a marked increase in open probability and reduced sensitivity to ATP, which would severely alter the function of the channel in brain, muscle, and nerves, in addition to pancreatic beta cells.
.0016 DIABETES MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
In an Italian boy with a severe form of permanent neonatal DIABETES with neurologic features (606176), Shimomura et al. (2007) identified a heterozygous de novo 499A-C transversion in the KCNJ11 gene, resulting in an ile167-to-leu (I167L) substitution at the cytoplasmic end of the second transmembrane domain near the internal gate of the channel. In vitro functional expression studies showed that the mutant I167L channel had severely impaired sensitivity to ATP and markedly increased open channel probability. Sulfonylurea treatment resulted in partial blockade of current in the mutant channels, and the patient showed a good response to sulfonylurea treatment, with both improved glycemic control and neurologic improvement.
.0017 DIABETES MELLITUS, TRANSIENT NEONATAL, 3
In a sister and brother with TNDM3 (610582), Gloyn et al. (2005) identified a heterozygous G-to-A transition in the KCNJ11 gene, resulting in a gly53-to-ser (G53S) substitution. The mutation was not identified in 100 control individuals. Both children had INSULIN-treated DIABETES diagnosed in the first 3 weeks of life and went into remission by age 20 months. The affected mother was positive for the mutation but had a milder phenotype, having been diagnosed at age 4 years and requiring only a low dose of INSULIN for glycemic control. In transformed Xenopus oocytes, the G53S mutation resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations.
.0018 DIABETES MELLITUS, TRANSIENT NEONATAL, 3
In a male proband with TNDM3 (610582), Gloyn et al. (2005) identified a heterozygous G-to-C transversion in the KCNJ11 gene, resulting in a gly53-to-arg (G53R) substitution. The mutation was not identified in 100 control individuals. The proband had INSULIN-treated DIABETES diagnosed at age 16 weeks and went into remission by 17 months with relapse at age 28 months. The affected mother was positive for the mutation and was diagnosed with DIABETES at 11 weeks with no periods of remission. Both mother and son had learning difficulties. In transformed Xenopus oocytes, the G53R mutation resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations.
.0019 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In an infant with focal hyperINSULINism (HHF2; 601820), Henwood et al. (2005) identified heterozygosity for a paternally derived 902G-A transition in the KCNJ11 gene, resulting in an arg301-to-his (R301H) substitution. KCNJ11 with this mutation retained partial channel function.
.0020 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In a female proband with hyperINSULINemic hypoglycemia (HHF2; 601820), Pinney et al. (2008) identified heterozygosity for a gly156-to-arg (G156R) substitution in the KCNJ11 gene. The mutation was also identified in her 34-year-old father, who had symptoms consistent with hypoglycemia.
.0021 DIABETES MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
Koster et al. (2008) reported a 27-year-old patient with intermediate developmental delay, epilepsy, and neonatal DIABETES (606176) in whom sequencing revealed a heterozygous gly53-to-asp (G53D) mutation in the KCNJ11 gene. Treatment was progressively transferred from INSULIN to the inhibitory sulfonylureas (SUs) gliclazide and finally to glibenclamide. The patient demonstrated improved glycemic control and motor coordination with SU treatment, with glibenclamide more effective than gliclazide. Reconstituted G53D channels exhibited reduced ATP sensitivity, which was predicted to suppress electrical activity in vivo. G53D channels coexpressed with the pancreatic and neuronal isoform of the sulfonylurea receptor SUR1 (600509) exhibited high-affinity block by gliclazide but were insensitive to block when coexpressed with the skeletal muscle isoform SUR2A (601439). Koster et al. (2008) concluded that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle ATP-sensitive potassium channel.
.0022 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2
In a Swedish patient with HHF2 (601820) with focal adenomatous hyperplasia, Taneja et al. (2009) identified an 844G-A transition in the KCNJ11 gene, resulting in a glu282-to-lys (E282K) substitution within a diacidic endoplasmic reticulum (ER) exit signal DXE at codons 280 to 282. The paternal E282K mutation abrogated the exit signal and prevented the ER export and surface expression of the channel. Since in focal hyperINSULINemic hypoglycemia, the maternal chromosome containing the K(ATP) channel genes are lost, beta-cells of the patient would lack wildtype Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal chromosome.
.0023 DIABETES MELLITUS, PERMANENT NEONATAL, WITH NEUROLOGIC FEATURES
In a patient with neonatal DIABETES, developmental delay, and epilepsy (606176), Mannikko et al. (2010) identified heterozygosity for 2 novel mutations on the same haplotype (cis), phe60 to tyr (F60Y) and val64 to leu (V64L), in the slide helix of Kir6.2 (KCNJ11). Functional analysis revealed that the F60Y mutation increased the intrinsic channel open probability, thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell potassium-ATP currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same, but not a different, subunit. The authors concluded that F60Y is the pathogenic mutation and that interactions between slide helix residues may influence KATP channel gating.
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