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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

Departments of Pediatrics (T.Y., K.K., M.K., T.N.) and Diabetes and Clinical Nutrition (K.N., M.H., Y.Y., N.I.), Kyoto University Hospital, Kyoto 606-8507, Japan; Oishi Clinic (M.O.), Kyoto 612-0875, Japan; Diabetes Center (Y.A.), National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan; and Department of Physiology (N.I.), Akita University School of Medicine, Akita 010-8543, Japan

Address all correspondence and requests for reprints to: Tohru Yorifuji, M.D., Ph.D., Department of Pediatrics, Kyoto University Hospital, 54 Shogoin Sakyo, Kyoto 606-8507, Japan. E-mail: yorif{at}kuhp.kyoto-u.ac.jp.

	Abstract

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Context: Known genes in maturity-onset diabetes of the young account for only a fraction of families with dominantly inherited diabetes in Japan. There should be as-yet-unidentified genes that account for the rest of the patients.

Objective: To identify and characterize the mutation responsible for a Japanese family with dominantly inherited diabetes mellitus.

Subjects: Members of a four-generation family with dominantly inherited diabetes mellitus observed in three generations. None of the patients in this family had permanent neonatal diabetes. One had transient neonatal diabetes, one had childhood diabetes, and the others had adult-onset diabetes without autoantibodies or insulin resistance.

Methods: Screening of the chromosomal location of the gene by a genome-wide linkage analysis followed by candidate gene sequencing. Confirmation of the functional significance of the identified mutation by the population survey and the physiological analysis.

Results: We identified a novel mutation (C42R) in the KCNJ11 gene coding for the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel. The 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 our patients.

Conclusions: These results broaden the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggest 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.

	Introduction

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Kir6.2, TOGETHER WITH SUR1, forms an inwardly rectifying ATP-sensitive potassium channel (K_ATP) channel, which plays a key role in ATP-dependent insulin secretion from pancreatic ß-cells (1). After entry of glucose into the ß-cells, elevated intracellular ATP levels cause closure of the K_ATP channels on the cell surface, which then depolarize the cell membrane leading to opening of the voltage-dependent calcium channels. The resultant influx of calcium leads to secretion of insulin from the ß-cells.

Inactivating mutations in the KCNJ11 gene coding for Kir6.2 have been known to cause persistent hyperinsulinemic hypoglycemia in infancy through constitutive closure of the channel (2). On the other hand, the role of the variations of KCNJ11 in the pathogenesis of diabetes mellitus has remained less definitive only with some of the polymorphisms, such as E23K, reported to be associated with the risk of developing type 2 diabetes (3, 4, 5, 6, 7, 8). Recently, however, Gloyn et al. (9) showed that activating mutations in KCNJ11 are the leading cause of permanent neonatal diabetes mellitus (PND). Other studies (10, 11) have also established the role of activating Kir6.2 mutations in the pathogenesis of PND.

Through a genome-wide linkage analysis and candidate gene sequencing conducted on a four-generation family with dominantly inherited diabetes mellitus observed in three generations, we identified a novel mutation (C42R) of the KCNJ11 gene. Unlike the cases discussed in the previous reports, the onset and severity of diabetes were variable: transient neonatal diabetes, childhood-onset diabetes, gestational diabetes, or adult-onset diabetes. Functional analysis through patch-clamp experiments revealed the biochemical basis of these milder phenotypes.

	Patients and Methods

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Patients’ profiles

Figure 1 shows the pedigree of the family. The proband (IV-2) came to our clinic at 6 wk of age because of hyperglycemia [626 mg/dl (34.8 mmol/liter)]. He was born after 41 wk of uneventful pregnancy, with a birth weight of 2866 g. The neonatal period was uneventful. On admission, laboratory data revealed elevated hemoglobin A_1c (HbA_1c) (7.7%: normal range: 4.3–5.6%) and diminished blood C-peptide (0.35 ng/ml (0.12 nmol/liter), normal range 1.0–2.5 ng/ml). Antiglutamic acid decarboxylase (GAD) or antiislet antibodies were negative. Frequent insulin injections at 2.2 U/kg·d gradually normalized his blood glucose levels, and he was discharged at 10 wk of age. After discharge, his insulin requirements gradually decreased and insulin could be stopped at 12 months of age. Currently, the patient is 1 yr 9 months old and maintains normal HbA₁c without any treatment.

View larger version (8K): [in this window] [in a new window]   FIG. 1. Pedigree of the family. Open symbols show the unaffected family members, whereas closed symbols show the affected. The morbidity status of I-1 was uncertain. Asterisks show individuals with the C42R mutation.

The proband’s paternal grandfather (II-3) was first diagnosed with diabetes at 3 yr of age. Data on the autoantibodies at diagnosis are not available. He had been on insulin (dose unknown) since diagnosis until 21 yr of age, when sulfonylurea therapy was introduced. At 23 yr of age, insulin was stopped, and he was entirely on sulfonylurea. Currently he is 58 yr of age. He is still taking sulfonylurea (chlorpropamide 500 mg/d). His diabetes is well controlled (HbA_1c ranging between 5.0 and 5.8%), and he does not have any diabetic complications. He has never been obese, which suggests that the etiology of his diabetes was not insulin resistance. Actually, his current homeostasis model assessment index is low, at 0.58.

The proband’s paternal aunt (III-1) had been well until 26 yr of age, when she was diagnosed with gestational diabetes. Her yearly urinalyses during school age were negative for glucosuria. Although she initially required insulin injections, the episode was transient, and her blood glucose returned to normal (HbA_1c 4%) after delivery. At the age of 28 yr, she was found to have elevated postprandial blood glucose [228 mg/dl (12.7 mmol/liter)] again and was diagnosed with diabetes. At diagnosis, she was not obese (height 160 cm, weight 44 kg). Blood HbA_1c was elevated, at 9.6%, and insulin secretion was diminished, at 3.3 µU/ml (19.8 pmol/liter), when fasting blood glucose was 200 mg/dl (11.0 mmol/liter). Anti-GAD autoantibody was negative. Insulin injections (16 U/d) were initiated. However, after 4 months, insulin therapy could be stopped, and she remains in fair control of her diabetes (HbA_1c 5.1–6.4%) with oral sulfonylurea alone (glimepiride, 1 mg/d).

The proband’s mother, paternal grandmother (II-5), and great grandmother (I-2) have never been diabetic. The morbidity status of his paternal great grandfather (I-1) is uncertain, although he is currently not overtly diabetic. Although the proband’s cousin (IV-1) is still at younger age, her HbA_1c and postprandial plasma glucose measurements gave normal results.

DNA isolation

After obtaining written informed consent, genomic DNA was isolated from peripheral blood leukocytes by using the QIAmp DNA maxikit (QIAGEN, Hilden, Germany). The study protocol was approved by the institutional review board.

Genome-wide linkage analysis

Polymorphic markers covering the whole genome at approximately 10-cM intervals were typed with the Linkage Mapping Set (version 2.5; Applied Biosystems, Foster City, CA) in accordance with the manufacturer’s recommendations. Multipoint linkage analysis was performed with the Genehunter 2 program (12) under an assumption of dominant inheritance and full penetrance. Although the morbidity status of I-1 was uncertain because I-2 was clearly unaffected, the initial analysis was performed assuming that he was affected.

Sequencing analysis

The whole coding region of the KCNJ11 gene was amplified as two overlapping fragments using primer pairs 5'-CGAGAGGACT CTGCAGTGAG-3' (Kir1)/5'-GCTTGCTGAAGATGAGGGTC-3' (Kir2) and 5'-CATCGTGCAGAACATCGTG-3' (Kir3)/5'-TAACACCCTGGATGAGCAG-3' (Kir4) in 25-µl reactions containing 1 x GC buffer I, 200 µM each of the deoxynucleotide triphosphates, 30 ng of template DNA, and 0.5 U of LA-Taq DNA polymerase (Takara, Shiga, Japan). The initial denaturation at 94 C for 2 min was followed by 30 cycles of denaturation at 94 C for 30 sec, annealing at 60 C for 30 sec, and extension at 72 C for 60 sec. The amplified products were purified with the Wizard PCR Preps DNA purification system (Promega, Madison, WI) and directly sequenced with the BigDye Terminator cycle sequencing kit (version 3.1; Applied Biosystems). Similarly, the whole coding region of the NEUROG3 gene and the SUR1 (ABCC8) gene was directly sequenced (the sequences of the primers are available from the authors).

Population survey

A reverse mismatched primer, 5'-GATGTTCTTGTGGGCCACGCTGC-3', which would generate a novel PstI site in the wild-type allele, and a forward primer, 5'-CGCTTTGTGTCCAAGAAAG-3', were used to amplify a 48-bp fragment spanning the cysteine at position 42 in 5-µl reactions containing 20 ng of genomic DNA, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl₂, 0.01% (wt/vol) gelatin, 12.5 pmol of each primer, and 0.1 U AmpliTaq Gold DNA polymerase (Applied Biosystems). The initial denaturation at 94 C for 10 min was followed by 35 cycles of denaturation at 94 C for 30 sec, annealing at 45 C for 15 sec, and extension at 72 C for 30 sec. Two microliters of the PCR products were then digested with PstI in 5-µl reactions and analyzed by PAGE and staining with ethidium-bromide.

Plasmids

The mammalian expression plasmids containing the whole coding region of the human Kir6.2 and SUR1 have been described previously (1, 13). To generate the expression plasmid containing C42R, the whole coding region of the KCNJ11 gene was amplified from IV-2’s DNA by using the primers Kir1 and Kir4 under the same conditions as for the sequencing. Then the amplification products were doubly digested with KpnI/XhoI and ligated to the Kir6.2 expression plasmid, generating pKir6.2C42R. The presence of C42R and the absence of other mutations were confirmed by sequencing the whole insert.

Cell culture and DNA transfection

COS-1 cells were plated on 35-mm dishes containing cover slips. The cells were then transiently transfected with wild-type or mutated human Kir6.2 cDNA (1.5 µg/dish) plus human SUR1 (1.5 µg/dish) using Lipofectamine 2000 (Invitrogen, Carlsbad, CA). pEGFP-N1 (Clontech, Palo Alto, CA) coding for the green fluorescent protein was cotransfected as a reporter gene.

Patch-clamp experiments

Recordings were made 24–72 h after transfection. The ATP sensitivity of the wild-type and mutant channels were determined basically as described previously (1, 13) with a patch-clamp amplifier, Axopatch 200B (Axon Instruments, Foster City, CA). Sulfonylurea sensitivity was assessed as the ratio between the amplitudes of the K_ATP channel currents before and after tolbutamide application. To determine the open probability, the channel density at the cell surface, and the detectable rate of the K_ATP channels, single-channel recordings were performed by using an ATP-free bath solution (1, 13). The detectable rate of the channels was determined by the ratio between the patches expressing K_ATP channels and the total number of examined patches. The number of channels in a patch was estimated by dividing the maximum current amplitude by the K_ATP channel unitary current. Single-channel currents were analyzed by a combination of pCLAMP (version 9.0, Axon Instruments) and in-house software. Mann-Whitney U tests (detectable rate of the channels) or unpaired Student’s t tests (others) were used to test for statistical significances, and the results were expressed as mean ± SE.

	Results

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By the genome-wide linkage analysis, nine chromosomal regions of interest with LOD scores higher than 1.2 were identified (chromosomes 2p, 3p, 9p, 10q, 11p, 14q, 18q, 19p, 22q). These regions were then compared with a list of the known chromosomal locations of 32 candidate genes involved in pancreatogenesis or insulin secretion (list not shown). All known genes in maturity-onset diabetes of the young (MODY) were readily excluded and three final candidate genes, KCNJ11, ABCC8, and NUUROG3, were further analyzed for sequence alterations, leading to the identification of a novel mutation, C42R (124T>C) in the KCNJ11 gene. No other mutations were identified in the other two genes. Sequencing analysis of all family members for C42R showed that the initial assumption that I-1 was affected was incorrect, and that the mutation arose de novo in II-3. The presence of diabetes was in complete concordance with the presence of the C42R mutation (Fig. 1). PSI-BLAST analysis (National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov) showed that the cysteine at position 42 was evolutionally well conserved and identical in the human, mouse, rat, chicken, and even Drosophila melanogaster, suggesting the functional importance of this amino acid residue. In addition, by the population survey, the C42R mutation was absent in 100 normal volunteers without diabetes, further suggesting that the mutation is not a simple polymorphism.

The electrophysiological studies have shown reduced ATP sensitivity of the mutant channel (Fig. 2). A response to tolbutamide was detected in the mutant channel, but the sensitivity was significantly reduced (Fig. 3). Spontaneous open probability (Po) was also increased in the mutant channel (Table 1), suggesting a shift toward the open state even in the absence of ATP. On the other hand, the functional expression at the cell surface, as measured by the channel density (the rate of detectable channels and the number of channels in a patch), was markedly reduced in cells expressing mutant K_ATP channels (Table 1). Although assessed in the homozygous state, these results suggest that the increase of Po and the reduction of ATP sensitivity account for the decrease in insulin secretion but that this is partially compensated by the reduction of functional K_ATP channel expression at the cell surface.

View larger version (19K): [in this window] [in a new window]   FIG. 2. ATP sensitivity of wild-type and mutant KATP channels. The dose-dependent effects of ATP concentration on the activities of the wild-type (Kir6.2/SUR1) and mutant (Kir6.2 C42R/SUR1) KATP channels are shown. Five experiments were conducted for each type of channel. IC50 shows the concentration of ATP at which the inhibition is half of the maximal.

View larger version (15K): [in this window] [in a new window]   FIG. 3. Sulfonylurea sensitivity of the wild-type (Kir6.2/SUR1) and mutant (Kir6.2 C42R/SUR1) KATP channels. Residual KATP channel activities were determined by the ratio between the amplitudes of KATP channel currents before and after 100 mM tolbutamide application. Asterisk, P < 0.01.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Taking into account the characteristics of diabetes in this family, i.e. diminished insulin secretion without autoantibodies or insulin resistance, we identified a novel mutation (C42R) in the KCNJ11 gene.

The results of the patch-clamp experiments showed that the degree of ATP insensitivity and the increase in Po was comparable with the mutations reported in patients with milder permanent neonatal diabetes (14) but that these diabetogenic effects were partially compensated by the decreased expression of the mutant Kir6.2 at the cell surface. This reduction in expression probably accounts for the reason that our patients showed relatively milder phenotypes and later onset rather than PND. The molecular mechanism leading to the reduction in expression is currently unknown. One possibility is that the C42R mutation affected coassembly of the mutant Kir6.2 with the SUR1 subunits because it has been shown that the coassembly is important for the effective sorting of the channel to the cell surface (14).

Other than the mutations in the KCNJ11 gene that cause the extremely rare PND cases, more common single-nucleotide polymorphisms (SNPs) in the same gene, such as E23K, have been shown to confer a predisposition to type 2 diabetes, with an odds ratio of 1.18–1.49 (4, 8). Although much milder, the biochemical basis of this type of diabetes is basically the same as for PND: reduced ATP-sensitivity and increased open probabilities (6, 9, 15). Taken together with our results, these results reveal the phenotypic spectrum of diabetes caused by the mutated KCNJ11, the mildest end being common SNPs such as E23K, which is a risk factor for type 2 diabetes (its effect is evident only in large-scale association studies), and the most severe end being the extremely rare PND mutations with very high penetrance. The in-between mutations, such as C42R, cause milder diabetes but with much higher penetrance than the common SNPs. The exact prevalence of these moderate mutations in KCNJ11 is currently under investigation. We have already searched for the KCNJ11 mutations in five additional Japanese families with similar clinical characteristics. At present, none had mutations in KCNJ11, probably suggesting that this gene is not the major unidentified MODY gene in the Japanese population.

Clinically it is important to identify patients with mutations in KCNJ11 because it has been shown that oral sulfonylurea might be effective for treating even severely affected patients (9, 16). Two of our patients (II-3, III-1) could be successfully treated with oral sulfonylurea alone. Although tolbutamide sensitivity of the C42R mutation was reduced as assayed in the homozygous state, the reduction in sensitivity could be much milder when assayed in the heterozygous state, i.e. cotransfection of the wild-type and mutant Kir6.2. This phenomenon has previously been reported for the R210H mutation (9) and could be an explanation for this apparent discrepancy between the sensitivity data and the clinical responses.

The severity of diabetes caused by mutations in the KCNJ11 gene probably reflects the variable effects of each mutation on the Kir6.2 molecules, which includes ATP sensitivity, spontaneous Po, sulfonylurea sensitivity, or cell surface expression. In addition, the presented cases demonstrate that, with the same mutation, the clinical presentation could be variable. Moreover, even in the same patient, the disease severity fluctuates from time to time. This suggests that other factors, both genetic and environmental, affect the clinical presentation of the patients with milder KCNJ11 mutations. Although the efficacy of sulfonylurea therapy appears promising, it could also be affected by the above factors. Accumulation of more cases is necessary to achieve the optimal management of these patients.

	Acknowledgments

 
We thank Dr. S. Seino (Kobe University, Graduate School of Medicine) for providing us with human SUR1.

	Footnotes

 
First Published Online March 22, 2005

Abbreviations: GAD, Glutamic acid decarboxylase; HbA_1c, hemoglobin A_1c; K_ATP, ATP-sensitive potassium channel; MODY, maturity-onset diabetes of the young; PND, permanent neonatal diabetes mellitus; Po, open probability; SNP, single-nucleotide polymorphism.

Received January 18, 2005.

Accepted March 14, 2005.

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/3174    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yorifuji, T. Articles by Nakahata, T. Search for Related Content PubMed PubMed Citation Articles by Yorifuji, T. Articles by Nakahata, T. Related Collections Diabetes and Insulin Metabolism Pediatric Endocrinology