Alternative titles; symbols
HGNC Approved Gene Symbol: KCNJ11
SNOMEDCT: 609581006;
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:17,385,248-17,389,346 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | {Diabetes mellitus, type 2, susceptibility to} | 125853 | Autosomal dominant | 3 |
| Diabetes mellitus, transient neonatal 3 | 610582 | Autosomal dominant | 3 | |
| Diabetes, permanent neonatal 2, with or without neurologic features | 618856 | Autosomal dominant | 3 | |
| Hyperinsulinemic hypoglycemia, familial, 2 | 601820 | Autosomal dominant; Autosomal recessive | 3 | |
| Maturity-onset diabetes of the young, type 13 | 616329 | Autosomal dominant | 3 |
ATP-sensitive K+ (KATP) channels couple cell metabolism to membrane excitability in various cell types, including pancreatic beta cells, neurons, endocrine cells, and muscle cells. The archetypal KATP channel is an octameric complex of KCNJ11 subunits and either SUR1 (ABCC8; 600509) subunits in pancreatic beta cells and many neurons or SUR2 (ABCC9; 601439) subunits in muscle. Four KCNJ11 subunits form the channel pore, and each is associated with a SUR subunit that contributes to regulation of channel gating (summary by Girard et al., 2009).
Inagaki et al. (1995) cloned a member of the inwardly rectifying potassium channel family, which they called BIR, for 'beta-cell inward rectifier,' or Kir6.2, in the nomenclature of Chandy and Gutman (1993). The channel was expressed in large amounts in rat pancreatic islets and glucose-responsive insulin-secreting cell lines. The sequence showed a single open reading frame encoding a 390-amino acid protein with 2 putative transmembrane segments. The mouse homolog also had a single open reading frame encoding a 390-amino acid protein with 96% amino acid identity with human BIR.
Inagaki et al. (1995) determined that KCNJ11, the gene encoding human BIR, is intronless in the protein-coding region. Several other genes encoding inward rectifiers lack introns.
By fluorescence in situ hybridization, Inagaki et al. (1995) mapped the BIR gene to 11p15.1. The sequence obtained from 1 lambda clone at the 3-prime end of the SUR gene (ABCC8; 600509) matched a part of the gene encoding BIR; with a sense primer near the 3-prime end of the SUR gene and an antisense primer near the 5-prime end of the BIR gene they PCR-amplified an approximately 4.5-kb fragment. Thus, the authors determined that the 2 genes are clustered at 11p15.1, with the BIR gene immediately 3-prime of the SUR gene. The SUR gene had previously been mapped to 11p15.1 by fluorescence in situ hybridization (Thomas et al., 1995).
In pancreatic beta cells, ATP-potassium channels are crucial for the regulation of glucose-induced insulin secretion and are the target for the sulfonylureas, oral hypoglycemic agents widely used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM; 125853), and for diazoxide, a potassium channel opener. The sulfonylurea receptor (SUR) is a member of the ATP-binding cassette superfamily with multiple transmembrane-spanning domains and 2 potential nucleotide-binding folds. Inagaki et al. (1995) demonstrated that coexpression of BIR with SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to ATP and was inhibited by sulfonylureas and activated by diazoxide. The data indicated to the authors that these pancreatic beta-cell potassium channels are a complex composed of at least 2 subunits: BIR and SUR.
Inagaki et al. (1996) cloned rat SUR2 (601439) and found that coexpression of SUR2 and BIR in COS-1 cells reconstituted the properties of K(ATP) channels described in cardiac and skeletal muscle. However, they found that the SUR2/BIR channel is less sensitive than the SUR/BIR channel both to ATP and to the sulfonylurea glibenclamide, and is activated by the cardiac K(ATP) channel openers cromakalim and pinacidil but not by diazoxide. The affinity of SUR2 for sulfonylureas is 500 times lower than that of SUR.
Familial Hyperinsulinemic Hypoglycemia 2
Thomas et al. (1996) screened genomic DNA from members of 15 families with hyperinsulinemic hypoglycemia (HHF2; 601820) for mutations in the KCNJ11 gene. In a male infant with profound hypoglycemia, born of consanguineous Iranian parents, Thomas et al. (1996) identified homozygosity for a 649T-C mutation (600937.0001). His parents were heterozygous for the mutation.
Using SSCP and nucleotide sequence analysis, Nestorowicz et al. (1997) screened 78 patients with hyperinsulinism for mutations in the KCNJ11 gene and identified homozygosity for a nonsense mutation (600937.0009) in 1 patient.
De Lonlay et al. (1997) showed that in cases of the focal form, but not those of the diffuse form, of hyperinsulinemic hypoglycemia there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event was consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, they provided the first molecular explanation for the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia. It is possible that in these cases of somatic loss of maternal 11p15.1, there is reduction to homozygosity for a recessive ABCC8 or KCNJ11 mutation on the paternal allele, since both ABCC8 and KCNJ11 are located in the 11p15.1 region.
Tornovsky et al. (2004) screened 15 patients with neonatal hyperinsulinemic hypoglycemia for mutations in the ABCC8 and KCNJ11 genes and identified 12 mutations in 11 patients. Homozygosity for a mutation in the promoter (600937.0010) and in exon 1 (600937.0011) of the KCNJ11 gene were identified in an Israeli Bedouin and an Arab patient, respectively.
Henwood et al. (2005) measured acute insulin responses (AIRs) to calcium, leucine, glucose, and tolbutamide in 22 infants with recessive ABCC8 or KCNJ11 mutations (see, e.g., 600937.0019), 8 of whom had diffuse hyperinsulinism and 14 of whom had focal hyperinsulinism. Of the 24 total mutations, 7 showed evidence of residual K(ATP) channel function: 2 of the patients with partial defects were homozygous and 4 heterozygous for amino acid substitutions or insertions, and 1 was a compound heterozygote for 2 premature stop codons.
Lin et al. (2008) investigated the mechanisms by which hyperinsulinism-associated mutations of arg301 (R301) in KCNJ11 (e.g., R301H; 600937.0019) lead to channel dysfunction. They found that R301 mutations in rat Kcnj11 resulted in reduced channel expression at the cell surface in transfected cells and caused rapid, spontaneous current decay, or inactivation. Mutagenesis studies indicated that R301 is near the Kcnj11 subunit-subunit interface and likely stabilizes channel activity. To evaluate the effects of channel inactivation on beta cell function, Lin et al. (2008) expressed an alternative R301 mutation, R301A, which induces channel inactivation without affecting channel surface expression, in a rat insulinoma cell line. Expression of Kcnj11 with R301A resulted in more depolarized membrane potential and elevated insulin secretion at basal glucose concentration compared with cells expressing wildtype channels. Lin et al. (2008) concluded that mutations at R301 may cause channel inactivation by disrupting subunit-subunit interactions, and that this gating defect is sufficient to cause loss of channel function and hyperinsulinism.
Pinney et al. (2008) identified 14 different dominantly inherited K(ATP) channel mutations in 16 unrelated families, 13 with mutations in the ABCC8 gene (see, e.g., 600509.0011) and 3 with mutations in the KCNJ11 gene (see, e.g., 600937.0020). Unlike recessive mutations, dominantly inherited K(ATP) mutant subunits trafficked normally to the plasma membrane when expressed in simian kidney cells; dominant mutations also resulted in different channel-gating defects, with dominant ABCC8 mutations diminishing channel responses to magnesium adenosine diphosphate or diazoxide and dominant KCNJ11 mutations impairing channel opening even in the absence of nucleotides. Pinney et al. (2008) concluded that there are distinctive features of dominant K(ATP) hyperinsulinism compared to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy.
Taneja et al. (2009) reported that the Kir6.2 channel contains a diacidic ER exit signal DXE at codons 280 to 282, which promotes concentration of the channel into COPII-enriched ER exit sites prior to ER export via a process that requires Sar1-GTPase (607690). They identified an E282K mutation (600937.0022) in a Swedish patient with HHF2 with focal adenomatous hyperplasia. The E282K mutation abrogated the ER exit signal and prevented ER export and surface expression of the channel. When coexpressed, the E282K-mutant subunit was able to associate with the wildtype Kir6.2 and form functional channels, and unlike most mutations did not cause protein misfolding. Since in focal congenital hyperinsulinism, the maternal chromosome containing the K(ATP) channel genes is lost, beta-cells of the patient lacked wildtype Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal chromosome. The resultant absence of functional KATP channels leads to insulin hypersecretion. Taneja et al. (2009) concluded that surface expression of K(ATP) channels is critically dependent on the Sar1-GTPase-dependent ER exit mechanism, and abrogation of the diacidic ER exit signal leads to congenital hyperinsulinism.
Bellanne-Chantelot et al. (2010) analyzed the ABCC8 and KCNJ11 genes in 109 diazoxide-unresponsive patients with congenital hyperinsulinism and identified mutations in 89 (82%) of the probands. A total of 118 mutations were found, including 106 (90%) in ABCC8 and 12 (10%) in KCNJ11; 94 of the 118 were different mutations, and 41 had previously been reported. The 37 patients diagnosed with focal disease all had heterozygous mutations, whereas 30 (47%) of 64 patients known or suspected to have diffuse disease had homozygous or compound heterozygous mutations, 22 (34%) had a heterozygous mutation, and 12 (19%) had no mutation in the ABCC8 or KCNJ11 genes.
Diabetes Mellitus Type 2 Susceptibility
Hani et al. (1998) identified an association between an E23K variant in the KCNJ11 gene (600937.0014) and type 2 diabetes mellitus (T2D; 125853) in French families.
Hansen et al. (2005) studied the effects of the E23K polymorphism and a PPARG P12A polymorphism (601487.0002) on the risk of type 2 diabetes and found that the polymorphisms may act in an additive manner to increase the risk of type 2 diabetes.
Permanent Neonatal Diabetes Mellitus 2
Because ATP-sensitive potassium channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, Gloyn et al. (2004) hypothesized that activating mutations in the KCNJ11 gene might cause neonatal diabetes. They studied 29 patients with permanent neonatal diabetes (PNDM2; 618856) characterized by ketoacidosis or marked hyperglycemia who were treated with insulin. The patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; 3 of them also had epilepsy and mild dysmorphic features (DEND). Gloyn et al. (2004) sequenced the KCNJ11 gene in all 29 patients and identified 6 novel, heterozygous missense mutations in 10. In 4 of the 10 families, the mutation was an arg201-to-his (R201H) substitution (600937.0002). In 2 patients, the diabetes was familial. In 8 patients, the diabetes arose from a spontaneous mutation (see, e.g., V59M; 600937.0003). When the most common mutation, R201H, was coexpressed with SUR in Xenopus oocytes, the ability of ATP to block mutant ATP-sensitive potassium channels was greatly reduced. Thus, whereas inactivating mutations of KCNJ11 lead to uncontrolled insulin secretion and congenital hyperinsulinism, activating mutations cause neonatal diabetes. Gloyn et al. (2004) concluded that heterozygous activating mutations of the KCNJ11 gene are a common cause (approximately 34%) of permanent neonatal diabetes. In a high proportion (80%) of subjects studied in their series, the mutation occurred de novo.
Gloyn et al. (2005) identified 3 novel heterozygous mutations (see, e.g., 600937.0017-600937.0018) in 3 of 11 probands with clinically defined TNDM who did not have chromosome 6q24 abnormalities. The mutations cosegregated with diabetes in 2 families and were not found in 100 controls. All 3 probands had insulin-treated diabetes diagnosed in the first 4 months of life and went into remission by 7 to 17 months of age. In transformed Xenopus oocytes, all 3 heterozygous mutations resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations. Gloyn et al. (2005) concluded that mutations in KCNJ11 can cause both remitting and permanent diabetes, suggesting that a fixed ion channel abnormality may result in a fluctuating glycemic phenotype.
Proks et al. (2005) studied the MgATP sensitivity of neonatal diabetes-causing KCNJ11-mutant K(ATP) channels expressed in Xenopus oocytes. In contrast to wildtype channels, Mg(2+) dramatically reduced the ATP sensitivity of heterozygous R201C (600937.0004), R201H, V59M, and V59G (600937.0005) channels. This effect was predominantly mediated via the nucleotide-binding domains of SUR1 (ABCC8; 600509) and resulted from an enhanced stimulatory action of MgATP. Proks et al. (2005) concluded that KCNJ11 mutations increase the current magnitude of heterozygous K(ATP) channels by increasing MgATP activation and by decreasing ATP inhibition. The fraction of unblocked K(ATP) current at physiologic MgATP concentrations correlated with the severity of the clinical phenotype.
Transient Neonatal Diabetes Mellitus 3
Yorifuji et al. (2005) found a missense mutation in the KCNJ11 gene (600937.0012) in a 4-generation family with dominantly inherited diabetes mellitus observed in 3 generations (see 610582). The onset and severity of the diabetes were variable: transient neonatal diabetes (TNDM3), childhood-onset diabetes, gestational diabetes, or adult-onset diabetes.
In a 20-year-old woman who had transient neonatal diabetes mellitus that recurred at age 7 years, Colombo et al. (2005) identified heterozygosity for a de novo R201H mutation in the KCNJ11 gene.
Maturity-Onset Diabetes of the Young 13
Yorifuji et al. (2005) and Bonnefond et al. (2012) reported families in which affected members had autosomal dominant early-onset type 2 diabetes that was responsive to sulfonylureas. The disease usually manifested before age 25 years and occurred in nonobese individuals, suggesting a diagnosis of maturity-onset diabetes of the young (MODY13; 616329).
Association with Impaired Exercise Stress Response
Reyes et al. (2009) found that the E23K polymorphism (600937.0014) was overrepresented in individuals with dilated cardiomyopathy (see 115200) and congestive heart failure (CHF) compared to controls, and that the KK genotype was associated with abnormal cardiopulmonary exercise stress testing. Reyes et al. (2009) suggested that E23K might represent a biomarker for impaired stress performance.
To determine why some mutations in the KCNJ11 gene cause PNDM in isolation whereas others cause PNDM associated with marked developmental delay, muscle weakness, and epilepsy, Proks et al. (2004) expressed wildtype or mutant Kir6.2/sulfonylurea receptor-1 channels in Xenopus oocytes. All of the mutations investigated (R201C, Q52R, and V59G) increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but in the simulated heterozygous state, the mutation causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). These findings suggested that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extra pancreatic cell function. Proks et al. (2004) also found that mutations causing PNDM alone impaired ATP sensitivity directly (at the binding site), whereas those associated with severe disease acted indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflected the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. The results showed that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating and suggesting that the efficacy of sulfonylurea therapy in PNDM may vary with genotype.
Massa et al. (2005) screened the KCNJ11 gene in 18 Italian patients with what they termed 'permanent diabetes mellitus of infancy' (PDMI), including 12 patients with onset within 3 months after birth and 6 with onset between 3 months to 1 year of age. Five different heterozygous mutations were identified in 8 patients with diabetes diagnosed between day 3 and day 182. Two of these mutations were novel. Four of the 8 patients also had motor and/or developmental delay. Massa et al. (2005) concluded that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay.
The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutations in the genes encoding the 2 essential subunits of the channel, KCNJ11 and ABCC8, can result in either hypoglycemia or hyperglycemia. Gloyn et al. (2006) reviewed the loss-of-function mutations in KCNJ11 and ABCC8, which can cause oversecretion of insulin and result in hyperinsulinemia of infancy. They reviewed the management of patients in whom mutations in these genes are found.
From a study of 49 patients with activating Kir6.2 mutations, Slingerland and Hattersley (2006) concluded that these mutations cause a severe reduction in fetal insulin secretion and hence fetal growth but that this is independent of mutation severity. Postnatal catch-up required insulin treatment but was complete, except in those with epilepsy.
Miki et al. (1997) generated transgenic mice expressing a dominant-negative mutation within the conserved gly-tyr-gly motif of the putative K(+)-permeable domain of Kcnj11. The gene was inserted downstream of the human insulin promoter region for selective expression in pancreatic beta cells. Transgenic mice developed hypoglycemia with hyperinsulinemia as neonates and hyperglycemia with hypoinsulinemia and decreased beta cell numbers as adults. Kcnj11 function was impaired in the beta cells of transgenic mice with hyperglycemia, and both resting membrane potential and basal calcium concentrations were significantly elevated in transgenic mice. Miki et al. (1997) also observed a high frequency of apoptotic beta cells prior to the development of hyperglycemia, suggesting a role for Kcnj11 in cell survival as well as in regulating insulin secretion.
Koster et al. (2000) generated transgenic mice expressing pancreatic beta-cell K(ATP) channels with reduced ATP sensitivity. They used transgenes with truncation of the N-terminal 30 amino acids of the Kir6.2 subunit, and a double mutant with the 30-amino acid truncation and a lys185-to-gln mutation. These transgenes were fused at the C terminus with the green fluorescent protein to allow for detection under ultraviolet illumination. Transgenic animals developed severe hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days, and typically died within 5 days. Nevertheless, islet morphology, insulin localization, and alpha- and beta-cell distributions were normal (before day 3), pointing to reduced insulin secretion as causal. The data indicated that normal K(ATP) channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion.
In mice with a conditional deletion of Hnf4a (600281) in pancreatic beta cells, Gupta et al. (2005) observed hyperinsulinemia in fasted and fed animals but also impaired glucose tolerance. Islet perfusion and calcium-imaging studies showed abnormal beta cell responses to stimulation by glucose and sulfonylureas, explainable in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. Cotransfection assays revealed that the Kir6.2 gene is a transcriptional target of HNF4A. Gupta et al. (2005) concluded that HNF4A is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.
ATP-sensitive potassium channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in the control of seizures. Yamada et al. (2001) studied mutant mice lacking the Kir6.2 subunit of ATP-sensitive potassium channels and found that they were susceptible to generalized seizures after brief hypoxia. In normal mice, the substantia nigra pars reticulata neuron activity was inactivated during hypoxia by the opening of the postsynaptic ATP-sensitive potassium channels, whereas in knockout mice, the activity of these neurons was enhanced. ATP-sensitive potassium channels exert a depressant effect on substantia nigra pars reticulata neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures.
Girard et al. (2009) created a mouse strain conditionally expressing the human Kir6.2 V59M mutation (600937.0003) specifically in pancreatic beta cells. Kir6.2(V59M) mRNA was expressed at a level comparable to that of endogenous wildtype Kir6.2 mRNA. Mutant mice (beta-V59M mice) developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Isolated beta-V59M islets displayed a reduced percentage of beta cells, abnormal morphology, abnormal calcium oscillations, lower insulin content, and decreased expression of Kir6.2, Sur1, and insulin mRNA. Beta-V59M islets secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose than wildtype islets, which was due to reduced sensitivity of Kir6.2(V69M) channels to ATP or glucose. Current and secretion events downstream of channel closure remained intact.
By using mice carrying the human V59M mutation in Kir6.2 (600937.0003) targeted to either muscle or nerve, Clark et al. (2010) showed that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. Clark et al. (2010) also identified locomotor hyperactivity as a feature of K(ATP) channel overactivity. Clark et al. (2010) concluded that their finding suggested that drugs targeted against neuronal, rather than muscle, K(ATP) channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability.
In a male infant with profound hypoglycemia (HHF2; 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.
Permanent Neonatal Diabetes Mellitus 2
In 4 unrelated patients with permanent neonatal diabetes (PNDM2; 618856), 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 (family NECKER4) also had dysmorphic facial features and neurologic involvement, including seizures, developmental delay, and axial hypotonia. On the basis of clinical and neuroimaging findings, the neurological involvement was thought to represent acute cerebral edema, which is a known complication of severe ketoacidosis in young children. The facial dysmorphism was considered to be unlike the classical features reported in other cases of syndromic PNDM. In contrast, the other infant (family NECKER6) did not have neurologic involvement, and her mother, who also carried the mutation, had severe diabetes mellitus without neurologic involvement.
Transient Neonatal Diabetes Mellitus 3
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.
In 2 unrelated males (ISPAD54 and ISPAD55) with permanent neonatal diabetes (PNDM2; 618856), Gloyn et al. (2004) found heterozygosity for a val59-to-met (V59M) mutation in the KCNJ11 gene. One of the patients (ISPAD55) had muscle weakness and 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 (ANGERS1) with the V59M mutation who had PNDM and neurologic features, including mild motor developmental delay and axial hypotonia.
In a patient with permanent neonatal diabetes mellitus (PNDM2; 618856), 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.
In a male patient with permanent neonatal diabetes and neurologic features (ISPAD25) (PNDMNF; see 618856), 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.
In an Italian patient with permanent neonatal diabetes mellitus (PNDM2; 618856), 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.
In an Italian patient with permanent neonatal diabetes mellitus (PNDM2; 618856), 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.
In an Italian patient with permanent neonatal diabetes mellitus (PNDM2; 618856), 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.
In a Palestinian Arab boy with hyperinsulinemic hypoglycemia (HHF2; 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).
In an Israeli Bedouin infant with hyperinsulinemic hypoglycemia (HHF2; 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.
In an Arab infant in whom a prenatal diagnosis of hyperinsulinism was made due to a family history of hyperinsulinemic hypoglycemia (HHF2; 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.
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 early adult-onset diabetes without autoantibodies or insulin resistance (MODY13; 616329). No affected individual was obese. 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.
In a patient with severe congenital hyperinsulinism (HHF2; 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.
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 families with type 2 diabetes (125853). They genotyped this variant in French cohorts of 191 unrelated type 2 diabetic probands and 119 normoglycemic control subjects and performed association studies. Homozygosity for lys23 (KK) was more frequent in type 2 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 2 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 2 diabetes. The combined analysis involved 1,164 type 2 diabetic patients and 4,733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of KCNJ11 E23K associated with type 2 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 2 diabetes, and the authors found no evidence for a synergistic interaction between them. Together, the 2 polymorphisms conferred a population-attributable risk for type 2 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 2 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.
In an infant (NECKER29) with a severe form of permanent neonatal diabetes mellitus with neurologic features (PNDM2; 618856), 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) considered this patient to be a case of DEND (developmental delay, epilepsy, and neonatal diabetes). 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.
In an Italian boy with a severe form of permanent neonatal diabetes with neurologic features (PNDM2; 618856), 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. Shimomura et al. (2007) considered this patient to be a case of DEND (developmental delay, epilepsy, and neonatal diabetes).
In a sister and brother with transient neonatal diabetes (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.
In a male proband with transient neonatal diabetes (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.
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.
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.
Koster et al. (2008) reported a 27-year-old female patient with intermediate developmental delay and neonatal diabetes (PNDM2; 618856) 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. Koster et al. (2008) noted that the G53D mutation had been reported by Flanagan et al. (2006) in a patient with 'intermediate DEND,' which included seizures in infancy and abnormal electroencephalogram.
In a Swedish patient with hyperinsulinemic hypoglycemia (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.
In a patient with neonatal diabetes, developmental delay, and epilepsy (PNDM2; 618856), 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.
Bonnefond et al. (2012) analyzed a 4-generation French family with maturity-onset diabetes of the young-13 (MODY13; 616329), including 12 affected individuals; 2 additional individuals had impaired fasting glucose and impaired glucose tolerances, respectively. Twenty-two relatives were unaffected. Whole-exome sequencing was performed on 4 individuals: a patient with diabetes diagnosed at age 17 years, his father who developed diabetes at age 20, an unaffected mother, and a diabetic man diagnosed at age 13. The only mutation that segregated with all family members was a c.679G-A transition (c.679G-A, NM_000525.3) resulting in a glu227-to-lys (E227K) substitution in the KCNJ11 gene. Linkage analysis using a dominant parametric model showed a lod score of 3.68 at KCNJ11 lys227. Lod scores were even higher using nonparametric linkage. This mutation was not found in the dbSNP (build 130) database, in 406 French controls, or in any of 22 French probands with MODY.
In a patient (patient 11-III-a) with hyperinsulinemic hypoglycemia (HHF2; 601820) who presented on the first day of life, Boodhansingh et al. (2019) identified a paternally inherited heterozygous 3-bp deletion (c.892_894del) in the KCNJ11 gene, resulting in the deletion of threonine-298 (thr298del). The mutation was identified by direct gene sequencing and was absent in the gnomAD database. The father did not report symptoms of hypoglycemia, but phenotype testing (fasting test, oral protein tolerance test, oral glucose tolerance test) showed evidence for abnormal regulation of glucose. The rubidium ion efflux assay of Kir6.2 with deletion of thr298 expressed in COSm6 cells demonstrated impaired ATP-dependent potassium channel efflux.
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