Background The ATP-sensitive potassium (KATP) channel, composedof the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifyingpotassium channel subunit Kir6.2, is a key regulator of insulinrelease. It is inhibited by the binding of adenine nucleotidesto subunit Kir6.2, which closes the channel, and activated bynucleotide binding or hydrolysis on SUR1, which opens the channel.The balance of these opposing actions determines the low open-channelprobability, PO, which controls the excitability of pancreaticbeta cells. We hypothesized that activating mutations in ABCC8,which encodes SUR1, cause neonatal diabetes.
Methods We screened the 39 exons of ABCC8 in 34 patients withpermanent or transient neonatal diabetes of unknown origin.We assayed the electrophysiologic activity of mutant and wild-typeKATP channels.
Results We identified seven missense mutations in nine patients.Four mutations were familial and showed vertical transmissionwith neonatal and adult-onset diabetes; the remaining mutationswere not transmitted and not found in more than 300 patientswithout diabetes or with early-onset diabetes of similar geneticbackground. Mutant channels in intact cells and in physiologicconcentrations of magnesium ATP had a markedly higher PO thandid wild-type channels. These overactive channels remained sensitiveto sulfonylurea, and treatment with sulfonylureas resulted ineuglycemia.
Conclusions Dominant mutations in ABCC8 accounted for 12 percentof cases of neonatal diabetes in the study group. Diabetes resultsfrom a newly discovered mechanism whereby the basal magnesium-nucleotide–dependentstimulatory action of SUR1 on the Kir pore is elevated and blockadeby sulfonylureas is preserved.
Neonatal diabetes is a form of diabetes mellitus defined bythe onset of mild-to-severe hyperglycemia within the first monthsof life. Permanent neonatal diabetes requires lifelong therapy;transient neonatal diabetes remits early, with a possible relapseduring adolescence. More than half of cases of transient neonataldiabetes are associated with abnormalities of an imprinted regionon chromosome 6q24.1,2 Some cases of permanent neonatal diabetesand rare cases of transient neonatal diabetes are caused bymutations in the KCNJ11 gene encoding the inwardly rectifyingpotassium-channel subunit (Kir6.2) of the ATP-sensitive potassium(KATP) channel expressed at the surface of the pancreatic betacell.3,4 A few cases of permanent neonatal diabetes are attributedto mutations in the genes that encode glucokinase,5 insulinpromoter factor 1,6 pancreas transcription factor 1,7FOXP3,8,9or the eukaryotic translation initiation factor 2-alpha kinase3.10
KATP channels of the pancreatic beta cell regulate insulin release.A small number of overactive mutant channels can hyperpolarizethe beta cell, reduce calcium influx through voltage-gated calciumchannels, and decrease insulin secretion. The beta-cell KATPchannel is a hetero-octamer11,12,13 assembled from Kir6.214and the high-affinity beta-cell sulfonylurea receptor (SUR1,encoded by ABCC8).15 KATP channels link nutrient metabolismwith membrane electrical activity by sensing adenine nucleotides.Nucleotide binding to the tetrameric Kir6.2 pore reduces themean open-channel probability (PO),16,17 whereas magnesium-nucleotidebinding or hydrolysis (or both) on SUR1 counterbalances thisinhibition to increase the PO.18,19,20 Mutations affecting eithersubunit could alter this balance. Consistent with this mechanismare the findings that mutant Kir6.2 with reduced sensitivityto inhibitory ATP causes neonatal diabetes in mice21 and humans,3,22whereas mutations in ABCC8 that compromise the stimulatory effectof magnesium-nucleotide binding cause persistent hyperinsulinemichypoglycemia.23,24 Since there are numerous cases of neonataldiabetes of unknown cause, we screened patients with neonataldiabetes for mutations in ABCC8.
Methods
Between 1995 and 2005, we studied 73 patients from the FrenchNetwork for the Study of Neonatal Diabetes Mellitus: 44 hadreceived a diagnosis of transient neonatal diabetes, whereas29 had received a diagnosis of permanent neonatal diabetes,3 of whom had associated pancreatic aplasia or hypoplasia.2We screened the patients for abnormalities in chromosome 6q24and mutations in the KCNJ11 gene; glucokinase sequencing wasrestricted to patients with permanent neonatal diabetes. Alterationsin chromosome 6q were found in 25 patients with transient neonataldiabetes (34 percent of the total study group), and mutationsin the KCNJ11 gene were found in 13 patients (18 percent ofthe total study group; 12 with permanent neonatal diabetes and1 with transient neonatal diabetes). A glucokinase mutationwas identified in one patient.2,4 We screened the 34 remainingpatients (16 with permanent neonatal diabetes and 18 with transientneonatal diabetes) for mutations in the ABCC8 gene using sequenceanalysis, as described in the Supplementary Appendix (availablewith the full text of this article at www.nejm.org). We genotypedthe parents of each proband with mutated ABCC8, and we confirmedfamily relationships by genotyping the DNA of probands and theirparents with six microsatellite markers. Other members of Family16 and Family 17, both of which had a history of transient neonataldiabetes, were genotyped to determine whether the mutant allelessegregated with diabetes. The study was approved by the localethics committees, and all participating patients gave writteninformed consent. Parental consent was given on behalf of patientsyounger than 18 years of age; the study was explained to childrencapable of giving assent, and they provided oral assent.
Clinical Studies
Probands with mutations of the ABCC8 gene had a thorough clinicalexamination, and their medical records were reviewed. The twopatients with permanent neonatal diabetes underwent a glucagonstimulation test (1 mg was given intravenously, with C-peptidemeasured 5 and 0 minutes before glucagon administration and5, 10, and 15 minutes afterward) and glyburide (also known asglibenclamide) stimulation test (0.2 mg per kilogram of bodyweight). Treatment with sulfonylureas was indicated on the basisof the mutant SUR1-channel response to tolbutamide. The patientswith permanent neonatal diabetes and the father of the probandin Family 13 with transient neonatal diabetes received oralglyburide, starting at a dose of 0.2 mg per kilogram per dayand gradually increasing the dose during a one-week period.Glucose levels were monitored and insulin was discontinued whensatisfactory metabolic control was achieved. Therapy for memberswith recurrent diabetes in Family 28 and Family 19 was similarlyswitched to glipizide and glyburide, respectively.
We compared the clinical features of the patients with transientneonatal diabetes carrying mutations of ABCC8 and KCNJ114 inour case series and 25 persons with transient neonatal diabeteslinked to anomalies of chromosome 6 (see the Supplementary Appendix).2The Wilcoxon rank-sum test was used to evaluate differencesin quantitative variables, and the chi-square and Fisher's exacttests were used for qualitative data. All tests were two-sided.Differences with a P value of less than 0.05 were consideredto indicate statistical significance.
Molecular Biology and Electrophysiological Analysis
The observed mutations were introduced separately into hamsterABCC8 complementary DNA (cDNA)15 with the use of standard methodsas described in the Supplementary Appendix. Wild-type or mutantSUR1 cDNA, or both, were coexpressed with human Kir6.2 and greenfluorescent protein (to mark transfection) in COSm6 cells.25Patch–clamp recordings and analyses of the KATP-channelcurrent were carried out as described previously.18,25 To comparethe responses of the different channels to physiologic nucleotideconditions, the channels in the same patch were recorded inintact cells and inside-out mode immediately after patch isolationand the values were normalized relative to their maximum ligand-independentresponse and expressed as the fraction of maximal activity (seethe Supplementary Appendix).
A homology model26 of the human SUR1 core was used to map themutant residues.27
Results
ABCC8 Mutations in Patients with Permanent or Transient Neonatal Diabetes
We identified seven heterozygous ABCC8 mutations in 9 of 34patients with neonatal diabetes: L213R and I1424V in 2 withpermanent neonatal diabetes and C435R, L582V, H1023Y, R1182Q,and R1379C in patients with transient neonatal diabetes. Theaffected amino acids are conserved in the rat, mouse, chicken,and Japanese Takifugu fish; this suggests that they are criticalfor channel function. We did not observe these mutations onsequencing the relevant exons of 180 patients with diabetesand 140 unrelated white persons of French origin without diabetes.Furthermore, we detected no additional nonsynonymous changesin the ABCC8 exons that were unaffected by mutations in a subgroupof 110 patients with diabetes, including 24 probands with maturity-onsetdiabetes of the young (MODY) from families without known MODY-associatedmutations.
The partial pedigrees of families carrying mutations of ABCC8are shown in Figure 1. The L213R, H1023Y, and I1424V were noninheritedmutations, as were the L582V and R1379C mutations in one familyeach. The L582V and R1397C mutations were also inherited inone family each, as were the C435R and R1182Q mutations. Inthese four families, the father of each proband was heterozygousfor the mutation and the mutant alleles cosegregated with diabetes.The father of the proband with a C435R mutation in Family 13was given a diagnosis of diabetes mellitus at 13 years of age;after he was found to have the C435R mutation, he discontinuedinsulin (after 24 years of treatment) after a successful responseto glyburide (10 mg per day). An oral glucose-tolerance testshowed that the father of the proband with an R1182Q mutationin Family 34 had diabetes; he is currently being treated withdiet alone. In Family 16 with a history of transient neonataldiabetes, family members II-3 and II-4 were given a diagnosisof diabetes after 30 years of age on the basis of the resultsof an oral glucose-tolerance test and are currently being treatedwith diet alone. Diabetes developed in the father of the proband(with an R1379C mutation) in Family 17 when he was 32 yearsold, and he is receiving glyburide. The R1379C allele was alsoidentified in the proband's paternal grandmother who had hadgestational diabetes and is currently being treated with dietand in a paternal great-aunt who was given a diagnosis of diabetesat 44 years of age and is currently being treated with sulfonylureas.
Figure 1. Diabetes and ABCC8 Mutations in Nine Families with Neonatal Diabetes.
Panel A shows the pedigrees of seven families with ABCC8 mutations. Panel B shows the extended pedigrees of two additional families. In each panel, the mutation identified in each family is given in parentheses, and the ABCC8 alleles are indicated: N denotes wild-type, M mutant, and NA not available for testing. Squares represent male family members, circles female family members, symbols with a slash deceased family members, gray symbols family members with neonatal diabetes, black symbols family members with type 2 diabetes occurring later in life, and hatched symbols family members with remitting diabetes. In Family 19 and Family 28, both of which had a history of transient neonatal diabetes, the age (in years) at relapse of transient neonatal diabetes is indicated within the gray symbols. In Family 17 with a history of transient neonatal diabetes (Panel B), Patient III-3 was given a diagnosis of gestational diabetes (indicated by cross hatching). In Families 13, 16, and 17, the proband with transient neonatal diabetes is indicated by an asterisk.
We found mutations of ABCC8 in 9 of the 34 patients with neonataldiabetes in our case series in whom no genetic defect had previouslybeen identified. These 9 patients account for 12 percent ofthe 73 patients with neonatal diabetes included in the study.Of the 29 patients with permanent neonatal diabetes in the study,12 had KCNJ11 mutations (41 percent), 2 had ABCC8 mutations(7 percent), and 15 had no apparent mutations (52 percent).Fifty-seven percent of the 44 cases of transient neonatal diabeteswere attributable to anomalies of chromosome 6q, 2 percent tomutations of KCNJ11, and 15 percent to mutations of ABCC8. Thecause of 11 cases of transient neonatal diabetes remains tobe determined.
Diabetes
Table 1 summarizes the clinical characteristics of probandswith mutant SUR1. Diabetes mellitus was diagnosed in patientsat a median of 32 days of age (range, 3 to 125) with hyperglycemialeading to polyuria and polydipsia in five patients and ketoacidosisin two patients. Probands in Family 17 and Family 34 had lowbirth weights and hyperglycemia. There were no detectable anti-isletantibodies, and ultrasonography revealed no pancreatic abnormalities.Initial insulin treatment was required for 1, 2.5, 3, 4, 4,8.5, and 10 months in probands with transient neonatal diabetesin Families 16, 34, 17, 19, 13, 36, and 28, respectively. Thelast documented dose of insulin varied from 0.12 to 1.2 U perkilogram per day, with a mean of 0.67 U per kilogram per day.After identification of the mutations in the patients with permanentneonatal diabetes, glyburide therapy was initiated and foundto be successful and insulin was discontinued after 2 days inthe proband from Family 12 and after 15 days in the probandfrom Family 16. The current doses of glyburide are 0.59 and0.22 mg per kilogram per day, respectively.
Table 1. Clinical Characteristics of Probands with Neonatal Diabetes with Mutant SUR1.
Two of the patients with transient neonatal diabetes requiredinsulin again later in life. Hyperglycemia recurred in the probandfrom Family 28 at 16 years of age; this patient was treatedwith insulin and then was given glipizide (0.16 mg per kilogramper day). The proband from Family 19 required insulin at 11years of age, and when he was 16 years of age, his treatmentwas switched to glyburide (0.28 mg per kilogram per day). Thesedoses are at the high end of, or exceed, doses of glipizideand glyburide currently recommended by the Food and Drug Administrationfor treating type 2 diabetes in adults.
Neurologic Features
The proband with permanent neonatal diabetes from Family 12presented with developmental delay, but in contrast to somepersons carrying a mutation of KCNJ11, did not have seizuresor muscle weakness. His parents reported that he had motor anddevelopmental delays, which were subsequently documented toinclude dyspraxia. The proband with transient neonatal diabetesfrom Family 17 presented with minor dystonia. The proband withtransient neonatal diabetes from Family 16 showed slow ideation,and the proband with transient neonatal diabetes from Family13 had minor visual and spatial dyspraxia. None of the probandshad the facial features associated with some mutations of KCNJ11.3None of the other index patients had abnormal cognitive functionor development.
Metabolic Tests
The baseline fasting levels of C-peptide in the proband withpermanent neonatal diabetes from Family 12 and Family 16 werelow (0.24 and 0.63 nM, respectively) but increased by 358 percentto 1.1 nM and by 222 percent to 1.4 nM, respectively, two hoursafter treatment with oral glyburide. Consistent with the presenceof beta-cell dysfunction, stimulation by glucagon was impaired,with increments of 79 percent (0.19 nM) and 106 percent (0.67nM), respectively, over baseline levels. (A normal responseis an increment of at least 150 percent.)
Clinical Features of Neonatal Diabetes According to Genetic Cause
The birth weights of 25 patients with transient neonatal diabeteslinked to anomalies of chromosome 6 were low, with the birthweight of 20 of 25 in the lowest 3 percent of the population,as compared with 3 of 7 patients with transient neonatal diabetescaused by mutant SUR1 (P=0.01) (Table 1, and the Supplementary Appendix).Macroglossia was present in 4 of the 25 probands with transientneonatal diabetes related to an anomaly in chromosome 6q24 region,but not in the patients with transient neonatal diabetes associatedwith a SUR1 mutation. Diabetes was diagnosed earlier in patientsin the former group than in the latter group (mean of 4.0 vs.29.9 days, P<0.05), which probably reflects, at least inpart, the lower birth weights of the patients in the formergroup (20 vs. 2 with low birth weights, P=0.02), since patientswith a low birth weight are more likely to have systematic glucosemonitoring. Other clinical features, including developmentaldelay and the frequency and time of recurrence of diabetes,did not differ significantly between the groups. Anomalies ofchromosome 6 were not associated with permanent neonatal diabetes.
As compared with 9 patients with neonatal diabetes caused bymutant SUR1, 13 patients with neonatal diabetes caused by mutantKir6.2 had a similar frequency of low birth weight, similardistribution of age at diagnosis, and similar glucose levelsat presentation. Ketoacidosis was more frequently associatedwith diabetes caused by mutant Kir6.2 than with diabetes causedby mutant SUR1 (9 of 13 patients vs. 2 of 9), but this differencewas not significant (P=0.09), possibly because of the smallnumber of patients in each group. The prevalence of developmentaldelay was not significantly different (3 of 13 patients vs.1 of 9) and epilepsy was diagnosed in 1 of 13 patients withneonatal diabetes caused by mutant Kir6.2, but in none of thepatients with neonatal diabetes caused by mutant SUR1. Dyspraxiawas observed in two patients with neonatal diabetes caused bymutant Kir6.2 and in one patient with neonatal diabetes causedby mutant SUR1. In our case series, mutations of KCNJ11 weremainly associated with permanent neonatal diabetes (12 of 13),whereas most mutations of ABCC8 (7 of 9) were linked to transientneonatal diabetes.
Effect of ABCC8 Mutations on KATP Channel Activity
The amino acids of SUR1 affected by mutation are at positionsconsistent with the mutations that affect protein function (seethe Supplementary Appendix). To determine whether mutationsin the ABCC8 gene changed the PO through a change in the intrinsiceffect of SUR1 on channel activity or by amplifying the stimulatoryeffect of magnesium ATP, we compared the activities of mutantand wild-type channels in intact mammalian cells and under controllednucleotide conditions. Measurements were made on the same patchin the intact cells and in the excised, inside-out configurationat a quasi-physiologic concentration of ATP in the presenceand absence of physiologic concentrations of magnesium (freemagnesium concentration, 0.7 mM) (examples of currents are providedin Figure S2 of the Supplementary Appendix). Figure 2 showsthat the normalized activities of mutant channels (containingthe I1424V or H1023Y variant) in intact cells and in 1 mM magnesiumATP are nearly four and seven times as great, respectively,as those of wild-type channels under similar nucleotide conditions.A similar concentration of submembrane nucleotides (1 mM) insimian kidney cells has been gauged by others.28 In the absenceof magnesium, and in the presence of 1 mM ATP, the PO of themutant and wild-type channels did not differ significantly.
Figure 2. Activities of Mutant and Wild-Type KATP Channels in Intact Cells and in Physiologic Concentrations of ATP in the Presence or Absence of Magnesium.
The mean (±SE) proportion of maximal channel activity for each type of channel is shown. The results were from 10 cells in five independent transfections of Kir6.2 plus the mutant or wild-type SUR1, or both, as indicated on the left. (See the Methods section, and Fig. S2 of the Supplementary Appendix, for details of the electrophysiologic analysis.) The P values between rows of bars are for the comparison between different types of channels, and the P values to the right of the bars are for the comparison of channels in the presence and absence of magnesium.
To test the effect of heterozygosity, we mixed both wild-typeand mutant SUR1 with Kir6.2 and found that the average meanactivities (in intact cells and in the presence of 1 mM magnesiumATP) were significantly greater than those of wild-type channels(P<0.001), although somewhat lower than those of "homozygous"mutant channels. In addition, the channels associated with neonataldiabetes were more active than wild-type channels at other concentrationsof magnesium ATP 0.1 mM (see Figure S3 of the Supplementary Appendix).These findings suggest that the heterozygous mutations of ABCC8overactivate beta-cell KATP channels by overstimulating thepore. To exclude the possibility that overactivity of the mutantI1424V and H1023Y channels is caused by either a gain in theintrinsic, ligand-independent, activity or by attenuation ofthe inhibitory action of ATP on Kir6.2, we measured the meanligand-independent PO values and steady-state ATP-inhibitorycurves (i.e., without magnesium) (Figure 3). The maximal PO(PO MAX) values and the ATP-inhibitory curves for both mutantchannels overlapped those of wild-type channels. We concludethat mutant I1424V and H1023Y channels overactivate beta-cellKATP channels under physiologic magnesium-nucleotide conditionsby increasing the magnesium-nucleotide–dependent stimulatoryaction of SUR1 on the pore.
Figure 3. Effect of SUR1 Mutations on the Ligand-Independent Activity of KATP Channels and Their Magnesium-Independent Inhibition by ATP.
Panel A shows the mean (±SE) PO MAX for each type of channel. Panel B shows the concentration of ATP (on a logarithmic scale) required to produce half-maximal inhibition (IC50(ATP)) for each type of channel. The I bars represent the best fits of a pseudo-Hill equation to the steady-state ATP dose responses. The IC50(ATP) and Hill coefficient values (h) were not significantly different. Representative examples of the response of each channel current to ATP at levels close to the IC50(ATP) are provided in Figure S4 of the Supplementary Appendix.
Inhibition of Mutant Channels by Sulfonylureas
A key issue in the treatment of neonatal diabetes is whethermutant channels are inhibited by sulfonylureas; if they are,they could be used in place of insulin.29 We used tolbutamide(which binds SUR1 specifically and is more rapidly reversiblethan glyburide and glipizide) to assess the sensitivity of themutant recombinant channels (Figure 4A and 4B). A concentrationof 200 µM tolbutamide, which saturates the high-affinitybinding site of wild-type SUR1,25 inhibited wild-type and mutantchannels (containing the I1424V or H1023Y variant) to a similardegree in the absence of magnesium nucleotides (Figure 4A).This inhibition indicated that tolbutamide binding to SUR1 andits functional coupling to the Kir6.2 pore were not alteredby the I1424V or H1023Y mutations.
Figure 4. Effect of SUR1 Mutations on Response to Tolbutamide (Tlb).
The mean (±SE) activity of each type of channel is shown in response to 200 µM tolbutamide in magnesium-free conditions (Panel A) and to 50 µM tolbutamide in the presence of 0.5 mM magnesium ATP and 0.5 mM magnesium ADP (Panel B). The data were derived from six experiments for each condition and type of channel. Representative current records are provided in Figure S5 of the Supplementary Appendix. Panel C shows how ATP inhibits beta-cell KATP channels through its interaction with Kir6.2 in a control subject. When glucose levels are low, this inhibitory action is balanced by the stimulatory action of magnesium nucleotides on SUR1 (indicated by the large green arrow), which increases channel activity. Membrane depolarization activates voltage-dependent calcium channels, and calcium influx stimulates insulin secretion. An increase in glucose metabolism increases the ratio of ATP to ADP and thereby reduces the stimulatory action of SUR1 (Panel D). In a patient with neonatal diabetes, the enhanced stimulatory action of the mutant receptor is sufficient to keep KATP channels open even at an elevated ratio of ATP to ADP, thus attenuating insulin release and producing hyperglycemia (Panels E and F). The data presented in Panels A and B, however, suggest that a sulfonylurea (tolbutamide) counters the stimulatory effect of the mutation to stimulate insulin release. This result is confirmed by the response of patients with permanent neonatal diabetes and transient neonatal diabetes to glyburide and glipizide.
To determine whether the increased stimulatory activity of themutant receptor compromised the ability of a pharmacologic concentrationof sulfo-nylureas to abolish the stimulatory action of magnesiumnucleotides,25,30 we assessed the effect of 50 µM tolbutamideunder magnesium-nucleotide conditions that maintain substantialsteady-state KATP currents in inside-out patches, where accuratedetection of zero current level is possible (Figure 4B). Weobserved the normal, enhanced inhibition of both permanent neonataldiabetes and mutant channels of transient neonatal diabetesin the presence of magnesium nucleotides. On the basis of theseresults, treatment with sulfonylureas, glyburide, and glipizide,respectively, was initiated in patients with permanent neonataldiabetes and transient neonatal diabetes and has proved effective.
Discussion
Our results indicate that heterozygous activating mutationsin ABCC8, encoding the SUR1 regulatory subunit of the ATP-sensitivepotassium channels found in beta cells, cause both permanentand transient neonatal diabetes. Although the molecular mechanismsof the ABCC8 and KCNJ11 mutations are distinct, the cellularmechanism reducing insulin release is common to both (Figure 4C, 4D, 4E, and 4F).Our results are consistent with a report that neonatal diabetesdevelops in transgenic mice expressing a mutant Kir6.2 subunitwith reduced sensitivity to inhibitory ATP and that some casesof permanent neonatal diabetes and transient neonatal diabetesare caused by mutations in KCNJ11. These studies underscorethe key role of KATP channels in coupling beta-cell membranepotential (and thus the requirement for calcium to release insulin-containinggranules) with nutrient metabolism. The common pathway accountsfor the direct overlap of the clinical features related to abnormalinsulin release secondary to mutations in ABCC8 and KCNJ11.As compared with patients with neonatal diabetes related toa SUR1 mutation, patients with neonatal diabetes related toa Kir6.2 mutation revealed no significant differences in theprevalence of low birth weight, age at diagnosis, or severityof hyperglycemia or accompanying ketoacidosis. Mutations ofKCNJ11 are typically associated with permanent neonatal diabetes,whereas most mutations of ABCC8 are associated with transientneonatal diabetes, perhaps reflecting a less severe form ofdiabetes.
Previous reports3,4 have highlighted a heterogeneity of symptomsassociated with neonatal diabetes caused by mutant Kir6.2, whichmay reflect the sharing of the Kir6.2 pore by both SUR1–Kir6.2neuroendocrine channels and sarcolemmal SUR2A–Kir6.2 channels.The neurologic features of several persons with neonatal diabetesrelated to a mutant SUR1 channel imply that SUR1-containingKATP channels can control the membrane potential of neuronalcells, such as inhibitory motor neurons.
Our data show that the net inhibitory action of ATP on two typesof neonatal diabetes caused by a mutant SUR1 channel was unchanged(as compared with wild-type SUR1) and that the increased activityof the channels, under physiologic conditions, was caused byan increase in the magnesium-dependent stimulatory action ofSUR1 on the pore. The position of the mutations that we havedescribed, together with further investigations, should provideinsight into the stimulatory mechanism. This finding is at variancewith that of a recent study31 showing an alteration in the inhibitoryaction of ATP on a mutant SUR1 channel.
Experiments designed to approximate the heterozygous conditionby expression of 1:1 mixtures of mutant with wild-type subunitsresulted in average mean activities, under physiologic magnesium-nucleotideconditions, intermediate to those of wild-type and mutant channels.The maximal activity of mixed KATP channels declines exponentiallyas the number of wild-type subunits (with the less stable activeconformation)18 increases in the complex. Therefore, the overactivatingeffect of a mutation is expected to drop off rapidly with theinclusion of wild-type subunits. The results imply that a smallsubpopulation of pure mutant channels can make a considerablecontribution to the hyperpolarization of beta cells and perhapsof some neurons with electrically tight membranes whose potentialis dominated by a small number of channels.
In clinical practice, there is no way to distinguish patientswith ABCC8 or KCNJ11 mutations from those with abnormalitiesin chromosome 6q24. Gene sequencing is required, and a usefulstrategy is to screen chromosome 6 and the short, one-exon KCNJ11gene first, unless the patients present with hyperglycemia afteran overnight fast, in which case GCK is analyzed. If no mutationsare identified, ABCC8 is analyzed. Genetic testing clearly hasprofound implications for counseling and therapy for patientswith neonatal diabetes. In the absence of the discovery of mutationsin ABCC8 that compromise inhibition by sulfonylureas, oral sulfonylureatherapy should be effective for most patients with neonataldiabetes caused by mutant SUR1. The efficacy of such therapywas also demonstrated for patients with Kir6.2 mutations ina study by Pearson et al.,32 which appears elsewhere in thisissue of the Journal.
The diagnosis of diabetes in fathers with ABCC8 mutations isconsistent with adult-onset type 2 diabetes mellitus or a mildform of transient neonatal diabetes. Systematic blood screeningin French newborns makes the latter unlikely, and we proposethat mutations of the ABCC8 gene may give rise to a monogenicform of type 2 diabetes with variable expression and age atonset. The potential contribution of overactive ABCC8 mutationsto familial early-onset type 2 diabetes remains to be evaluated,but our findings emphasize how molecular understanding of arare pediatric form of diabetes may illuminate the more commonform of the disease.
Supported by the French nonprofit associations Aide aux JeunesDiabétiques and Association Française des Diabétiques,by the Juvenile Diabetes Research Foundation (1-2005-950, toDr. Bryan), and by grants from the National Institutes of Health(DK44311 and DK52771, to Dr. Bryan).
No potential conflict of interest relevant to this article wasreported.
We are indebted to Aurélie Dechaume, Pasteur Institute,Lille, France, and Christine Bellané-Chantelot, HôpitalSaint Antoine, Paris, for their help with sequence analysis;to Pascale De Lonlay for helpful discussions and to KathleenLaborde for C-peptide determinations, both at the HôpitalNecker Enfants Malades, Paris; to Guiling Zhao, Baylor Collegeof Medicine, Houston, for construction of the mutant plasmidsand for cell transfections; to Saïda Lahmidi, Pasteur Institute,for technical assistance; to Sabrina Pereira, HôpitalRobert Debre, Paris, for the handling of the DNA bank; to thenursing staff and I. Flechtner in the pediatric endocrine wardat the Necker Enfants Malades Hospital, for care of the patients;to the physicians of the SURNDM study group: C. Metz, Brest;C. Stuckens, Lille; P. Ganga-Zandzou, H. Ythier, Roubaix; D.Kaufman, Caen; H. Bruel, Le Havre; and A. Grimaldi, Paris —all in France; and to D. Paul, Lakeland AFB, Tex., and R. Nimriand M. Phillip, Tel Aviv, Israel, who are currently followingsome of the patients.
Source Information
From the Departments of Molecular and Cellular Biology (A.P.B., J.B.) and Medicine (L.A.-B.), Baylor College of Medicine, Houston; the Faculty of Medicine, René Descartes University, INSERM Unité 0363, Hôpital Necker Enfants Malades, Paris (M.P., K.B., R.S.); the Departments of Genetic Biochemistry (H.C.) and Pediatric Endocrinology (P.C.), Hôpital Robert Debré, Paris; Centre National de la Recherche Scientifique Unité 8090, the Pasteur Institute, Lille, France (M.V., P.F.); and the Department of Genomic Medicine, Imperial College London, Hammersmith Hospital, London (P.F.). Drs. Babenko and Polak contributed equally to this article.
Address reprint requests to Dr. Polak at the Faculty of Medicine, René Descartes, Pediatric Endocrinology, INSERM Unité 0363, Hôpital Necker Enfants Malades, Paris, France, or at michel.polak{at}nck.aphp.fr.
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,7 FOXP3,8,9 or the eukaryotic translation initiation factor 2-alpha kinase 3.10 
0.1 mM (see Figure S3 of the Supplementary Appendix). These findings suggest that the heterozygous mutations of ABCC8 overactivate beta-cell KATP channels by overstimulating the pore. To exclude the possibility that overactivity of the mutant I1424V and H1023Y channels is caused by either a gain in the intrinsic, ligand-independent, activity or by attenuation of the inhibitory action of ATP on Kir6.2, we measured the mean ligand-independent PO values and steady-state ATP-inhibitory curves (i.e., without magnesium) (Figure 3). The maximal PO (PO MAX) values and the ATP-inhibitory curves for both mutant channels overlapped those of wild-type channels. We conclude that mutant I1424V and H1023Y channels overactivate beta-cell KATP channels under physiologic magnesium-nucleotide conditions by increasing the magnesium-nucleotide–dependent stimulatory action of SUR1 on the pore. 
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