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Genotype-Phenotype Correlations in Children with Congenital Hyperinsulinism Due to Recessive Mutations of the Adenosine Triphosphate-Sensitive Potassium Channel Genes

Division of Endocrinology/Diabetes (M.J.H., A.K., C.M., C.A.S.) and General Clinical Research Center (P.B.), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104; Department of Genetics (A.G.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and Division of Endocrinology (P.S.T.), Cook Children’s Medical Center, Fort Worth, Texas 76104

Address all correspondence and requests for reprints to: Charles A. Stanley, M.D., Division of Endocrinology/Diabetes, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: stanleyc{at}email.chop.edu.

	Abstract

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Congenital hyperinsulinism (HI) is most commonly caused by recessive mutations of the pancreatic ß-cell ATP-sensitive potassium channel (K_ATP), encoded by two genes on chromosome 11p, SUR1 and Kir6.2. The two mutations that have been best studied, SUR1 g3992-9a and SUR1 delF1388, are null mutations yielding nonfunctional channels and are characterized by nonresponsiveness to diazoxide, a channel agonist, and absence of acute insulin responses (AIRs) to tolbutamide, a channel antagonist, or leucine. To examine phenotypes of other K_ATP mutations, we measured AIRs to calcium, leucine, glucose, and tolbutamide in infants with recessive SUR1 or Kir6.2 mutations expressed as diffuse HI (n = 8) or focal HI (n = 14). Of the 24 total mutations, at least seven showed evidence of residual K_ATP channel function. This included positive AIR to both tolbutamide and leucine in diffuse HI cases or positive AIR to leucine in focal HI cases. One patient with partial K_ATP function also responded to treatment with the channel agonist, diazoxide. Six of the seven patients with partial defects had amino acid substitutions or insertions; whereas, the other patient was compound heterozygous for two premature stop codons. These results indicate that some K_ATP mutations can yield partially functioning channels, including cases of hyperinsulinism that are fully responsive to diazoxide therapy.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CONGENITAL HYPERINSULINISM (HI) is the most common cause of persistent hypoglycemia in infancy and is caused by genetic defects in the pathways controlling insulin secretion by the pancreatic ß-cells (1). The most frequent form of HI is associated with recessive mutations of the ß-cell plasma membrane ATP-sensitive potassium channel (K_ATP), which is encoded by two adjacent genes on chromosome 11p15.1, SUR1 (ABCC8) and Kir6.2 (KCNJ11) (2, 3, 4, 5). Children with two mutant K_ATP alleles have diffuse HI, in which all ß-cells have dysregulation of insulin secretion. Loss of heterozygosity for the maternal chromosome 11p and expression of a paternally derived K_ATP mutation causes focal HI, in which a small discrete area of ß-cell adenomatosis is surrounded by pancreatic tissue containing normally functioning islets (6). Surgery is often necessary to control hypoglycemia in both diffuse HI and focal HI but is only curative in cases of focal HI.

The two K_ATP channel mutations that have been most extensively studied are SUR1 g3992-9a and SUR1 delF1388, which are two founder mutations that are common among Ashkenazi Jews (2). Both are assumed to be null mutations because SUR1 g3992-9a, a splice site defect, is predicted to yield no functional channels, whereas SUR1 delF1388, a single amino acid deletion, causes a failure of channel trafficking from the Golgi apparatus to the plasma membrane (7). Clinically, these two defects behave as null mutations in that affected children fail to secrete insulin in response to the channel antagonist, tolbutamide, and fail to suppress insulin secretion when treated with the channel agonist, diazoxide.

We recently reported that some infants with diffuse HI associated with recessive K_ATP channel mutations showed surprisingly positive acute insulin responses (AIRs) to tolbutamide, suggesting partial preservation of channel function (8). To examine this possibility in more detail, we analyzed the patterns of AIRs to tolbutamide and other secretagogues in these patients in relation to their associated mutations of SUR1 and Kir6.2.

	Patients and Methods

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Patients

The 22 patients included in this study represent a subgroup of 51 infants who were referred to The Children’s Hospital of Philadelphia between 1997 and 2002 for possible surgical management of severe congenital HI (8). Most of the infants underwent AIR tests before surgery as part of a protocol to distinguish diffuse from focal disease. Disease-causing mutations of SUR1 or Kir6.2 were identified in the 22 infants reported here who also had complete AIR tests. Group data on AIRs to calcium, glucose, and tolbutamide stimulation and the results of selective pancreatic arterial calcium stimulation for individual infants were previously analyzed for differences between focal and diffuse HI (8). The present report includes the individual AIRs to the three secretagogues, as well as the AIRs to leucine in 21 of the infants in the previous report plus AIRs in one additional unoperated patient. Patients 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, and 22 in Table 1 correspond to patients 2D, 5D, 7D, 3D, 10D, 4D, 20, 26, 13, 3, 19, 9, 15, 14, 16, 22, 1, 24, and 21 reported in Stanley et al. (8). Each of the eight patients with diffuse disease had two mutations, whereas each of the 14 patients with focal lesions had a single K_ATP mutation involving the nonmaternal allele. All but three of the infants underwent pancreatectomy between 1 and 7 months of age. Of these three infants, one had surgery at age 21 months, one died of necrotizing enterocolitis before surgery, and one responded to medical management with diazoxide so that surgery was not needed to control hypoglycemia (patient 8 in Table 1). In the latter case, a diazoxide dose of 10 mg/kg·d completely normalized fasting adaptation because the infant was able to maintain plasma glucose above 70 mg/dl for 18 h and demonstrated an appropriate rise in plasma ß-hydroxybutyrate.

AIRs

AIR tests were carried out as previously described (13, 14). Briefly, patients received iv boluses of four insulin secretagogues at intervals of 60 min in the following sequence: calcium (2 mg/kg), leucine (15 mg/kg), glucose (0.5 g/kg), and tolbutamide (25 mg/kg). Blood samples for insulin and glucose were obtained at –3, –1, 0, +1, +3, and +5 min relative to the infusion of each secretagogue. AIRs were calculated as the mean increase in insulin at +1 and +3 min. Dextrose was infused throughout the study to maintain blood glucose between 60 and 80 mg/dl. Results were compared with data previously obtained in children with diffuse HI due to homozygous g3992-9a or compound heterozygous delF1388/g3992-9a mutations of SUR1, in children with the HI/hyperammonemia syndrome due to dominant gain of function mutations of glutamate dehydrogenase (GDH), and in normal adult and child controls (13, 14, 15).

Mutation screening

Peripheral blood samples from patients and their parents were used for isolation of DNA. All 39 exons of SUR1 and the single exon of Kir6.2 were amplified by PCR. Each exon was analyzed using conformation-sensitive gel electrophoresis as previously described (16). Products displaying aberrant banding patterns were sequenced to determine mutations. To exclude the possibility of common polymorphisms, mutations were confirmed by screening a panel of 100 normal alleles. In addition, conservation of amino acids was assessed across multiple species. SUR1 cDNA and protein sequences were numbered according to Nestorowicz et al. (17), with nucleotide numbering beginning with the first Met and including the alternatively spliced exon 17 sequence (National Center for Biotechnology Information accession no. L78224).

The study protocol was reviewed and approved by the Institutional Review Board of The Children’s Hospital of Philadelphia, and written informed consent was obtained from the parents of the patients.

	Results

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Table 2 shows the SUR1 and Kir6.2 mutations identified among the 22 children and listed in order of increasing nucleotide position of the SUR1 and Kir6.2 genes. Twenty-four mutations, including the two Ashkenazi Jewish founder mutations, SUR1 g3992-9a and SUR1 delF1388, were identified. There were five Kir6.2 and 11 SUR1 missense mutations, one SUR1 single amino acid deletion, one SUR1 6 amino acid insertion, three SUR1 splice site mutations, one SUR1 single nucleotide deletion, and two SUR1 nonsense mutations. Of the 24 mutations listed in Table 2, 10 have been previously identified in other patients. None of the missense mutations was found among 100 normal alleles, thereby excluding the possibility that they represented common polymorphisms. All of the mutated SUR1 amino acids were conserved across mammalian species, including guinea pig, golden hamster, European hamster, and mouse. The amino acids in two of the three Kir6.2 missense mutations were also conserved across multiple mammalian species, including pig, rat, rabbit, mouse, rhesus monkey, guinea pig, and cow. The third Kir6.2 mutation, A101D, was semiconserved as an alanine in rat, mouse, and guinea pig but as an aspartate in the pig, rhesus monkey, and cow.

Table 1 shows the individual haplotypes and AIR patterns for patients with diffuse HI ranked in order of increasing response to tolbutamide. As shown, normal controls do not respond to calcium or leucine stimulation, but they do respond to glucose and tolbutamide, the latter indicating intact K_ATP channel function (13, 14, 15). The disease control group with SUR1 null mutations responds to calcium (AIR > 5 µU/ml), fails to respond to leucine or tolbutamide (AIR < 5 µU/ml), and shows blunted responses to glucose (13, 14, 15). The GDH mutation control group has abnormal positive AIRs to leucine (15). Diffuse patients 1 and 2 showed no response to tolbutamide, suggesting that all four of their defects (D1472H, G134A, P266L, and delF1388) were null mutations yielding nonfunctional K_ATP channels. Diffuse patients 5 through 8 had positive AIRs to tolbutamide, suggesting that their mutations yielded channels that retained partial function. Note that the partial function in patient 5 occurred despite the presence of two nonsense mutations predicted to cause premature termination of the SUR1 protein. Patients 6, 7, and 8 also had positive AIRs to leucine, whereas patients 1 and 2 did not, suggesting that the partial channel defects produced hypersensitivity to leucine stimulation. These three patients also appeared to have larger responses to glucose stimulation, which is consistent with greater residual channel function. Patients 3 and 4 had intermediate AIR patterns, possibly consistent with some residual K_ATP activity. Patient 8, who was compound heterozygous for the g3992-9a null mutation and a K1337N missense mutation, was responsive to diazoxide, as well as to tolbutamide and leucine, indicating that the K1337N mutation produced a channel with considerable residual responsiveness to both channel agonists and antagonists.

The AIR pattern for one additional patient with diffuse HI was not included in Table 1 or this analysis because of unusually high basal levels of insulin that made interpretation of the AIR pattern impossible. This patient, with a known trafficking mutation and a splice site mutation of SUR1 (L1544P/t1176 + 2c), had a baseline insulin level of 85 µU/ml, which is approximately 10 times higher than values usually encountered in children with HI (18). Absolute AIR values in this patient (calcium, 27 µU/ml; leucine, 44 µU/ml; glucose, 65 µU/ml; and tolbutamide, –6.5 µU/ml) suggested responsiveness to leucine but not to tolbutamide. However, when calculated as the percent change, the AIR leucine was not impressive (64% compared with an average value of 450% in patients with GDH HI, n = 8).

Table 1 also lists individual haplotypes and AIR results for the 14 children with focal HI in order of increasing insulin response to leucine. For this group, only the AIR to leucine is informative because responses to tolbutamide and glucose reflect activity of both the focal lesion and the normally functioning K_ATP channels in the unaffected normal tissue. The patients in the upper half of the list showed little or no response to leucine. However, the patients at the bottom of the list (particularly patients 21, 22, and possibly 20) show clearly positive responses to leucine. Based on the observations above in diffuse patients, patients 9–11 appear to have complete absence of channel activity, whereas patients 21–22 have some residual channel function. Patients 21 and 22 with partial channel function had missense mutations, one in Kir6.2 and one in SUR1. One of these mutations, SUR1 R1215W, was also present in a second focal patient (17) who did not respond to leucine. However, all of the AIRs in this second patient were low, suggesting that the tests may have been invalid due to overall suppression of insulin release by intercurrent stress or other factors. Several other patients (4, 11, and 12) showed similar patterns of generalized suppression of insulin responses. Patient 19 with focal HI showed an unexpectedly negative AIR to tolbutamide, which, as reported previously, was judged to be of doubtful validity and likely reflected failure of drug administration (8).

Based on the data in Table 1, thresholds for AIR values that seemed to indicate partial channel function were selected (AIR tolbutamide > 10–20 µU/ml and AIR leucine > 15 µU/ml). Using these criteria, Table 3 categorizes the mutations found in the 22 infants with focal or diffuse HI according to the degree of residual K_ATP channel function. Although some combinations of alleles could not be distinguished and some could not be unambiguously classified, the proportions of null and partial mutations appear to be similar.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

As shown in Fig. 1, leucine triggers insulin release by allosteric activation of GDH to increase glutamate oxidation in the tricarboxylic acid cycle and subsequent insulin release. Children with null mutations of the K_ATP channel (SUR1 g3992-9a and SUR1 delF1388) have little or no response to leucine because their K_ATP channels are nonfunctional (15). Similarly, isolated islets from SUR1 knockout mice are unresponsive to stimulation with either leucine or glucose (19). The present observation that patients with partial K_ATP channel defects have exaggerated insulin responses to leucine suggests that the channels in these patients have heightened sensitivity to increases in the ATP to ADP ratio. Consistent with this interpretation, sensitivity to glucose stimulation appeared to be increased in those cases of diffuse disease associated with partial K_ATP mutations (Table 1). In addition, we recently found leucine sensitivity in a family with a partial K_ATP channel defect due to a dominantly expressed mutation of SUR1 (20).

View larger version (16K): [in this window] [in a new window]   FIG. 1. Pathways of ß-cell insulin secretion. Glucose stimulates insulin release by metabolism to increase the ATP to ADP ratio, leading to inhibition of the plasma membrane KATP channel, depolarization of the plasma membrane, activation of voltage-gated calcium channels, and influx of calcium to activate insulin release from storage granules. Leucine stimulates insulin secretion by activating glutamate oxidation via GDH. Tolbutamide stimulates insulin release by inhibiting KATP channels, whereas diazoxide inhibits release by activating KATP channels. In patients with recessive KATP mutations, the plasma membrane is continuously depolarized, and infusion of calcium can acutely stimulate insulin release.

There are a few reports consistent with partially functional channels in other infants with HI due to recessive K_ATP mutations. Huopio et al. (22) reported AIRs to tolbutamide in three patients with diffuse HI due to recessive K_ATP mutations. Whereas one patient who was homozygous for the common Finnish SUR1 V187D mutation had a negative AIR to tolbutamide (0.14 µU/ml), a second patient with the same mutations had a modest response (11.7 µU/ml); the third patient with compound heterozygosity for Kir6.2 (c 1–54 t)/K67N mutations had an AIR to tolbutamide of 68 µU/ml, implying considerable residual channel function. In a recent report by Giurgea et al. (23) positive AIRs to tolbutamide of 30 and 82 µU/ml were noted in two of seven infants with diazoxide-unresponsive diffuse HI.

Heterogeneity of residual K_ATP channel function in children with HI is also suggested by the electrophysiological studies of islets isolated during pancreatectomy reported by Cosgrove et al. (24). Although mutation analysis was not done in these cases, the fact that all of the infants failed to respond to diazoxide makes it highly likely that they had recessive K_ATP channel mutations. Of four patients with diffuse HI, Cosgrove et al. found a total absence of channel function in two patients, suggesting that these patients had null mutations. However, in the other two patients, the studies showed residual channel activity that responded appropriately to inhibition by channel antagonists. Both of the latter patients also responded to channel agonists in vitro by demonstrating normal channel opening, indicating that even patients who fail to respond clinically to diazoxide might respond to medical therapy with more potent analogs of the drug.

The positive AIR to tolbutamide in patient 5 (Table 1), who was compound heterozygous for two nonsense mutations, was surprising because these mutations would be predicted to yield truncated nonfunctioning proteins. A possible explanation may be that one or both of these mutations induces exon skipping during transcription, yielding a channel protein missing some internal amino acids but with a normal C terminus capable of trafficking to the plasma membrane as part of a partly functional channel (25, 26).

In conclusion, the present results indicate that recessive mutations of the K_ATP channel genes can be associated with a range of residual channel function in children with either diffuse or focal HI. The clinical phenotype of insulin secretion in the null mutations includes nonresponsiveness to either channel agonists or antagonists and to stimulation with leucine. In contrast, in patients with partial mutations, some insulin responsiveness to channel inhibition by tolbutamide is retained. In one patient in the present study with an SUR1 mutation, the channel agonist, diazoxide, was able to suppress insulin secretion very effectively, and partial K_ATP mutations should be considered in other patients with diazoxide-responsive HI. Partial K_ATP mutations are also characterized by exaggerated insulin responses to leucine stimulation. The relationship between this form of leucine sensitivity and sensitivity to protein-induced hypoglycemia requires further exploration.

	Acknowledgments

 
We thank the nursing and laboratory staff of The Children’s Hospital General Clinical Research Center for their expert assistance with these studies.

	Footnotes

 
First Published Online November 23, 2004

Abbreviations: AIR, Acute insulin response; GDH, glutamate dehydrogenase; HI, hyperinsulinism; K_ATP, ATP-sensitive potassium channel.

This work was supported in part by National Institutes of Health Grants MO1 RR-00240, T32 DK63688, and RO1 DK56268.

Received August 11, 2004.

Accepted November 10, 2004.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Stanley CA 1997 Hyperinsulinism in infants and children. Pediatr Clin North Am 44:363–374[CrossRef][Medline]
2. Nestorowicz A, Wilson BA, Schoor KP, Inoue H, Glaser B, Landau H, Stanley CA, Thornton PS, Clement IV JP, Bryan J, Aguilar-Bryan L, Permutt MA 1996 Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 5:1813–1822[Abstract/Free Full Text]
3. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B, Landau H, Stanley CA, Thornton PS, Seino S, Permutt MA 1997 A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 46:1743–1748[Abstract]
4. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J 1995 Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268:426–429[Abstract/Free Full Text]
5. Thomas P, Ye YY, Lightner E 1996 Mutations of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 5:1809–1812[Abstract/Free Full Text]
6. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fekete C, Saundubray JM, Junie C 1998 Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 102:1286–1291[Medline]
7. Cartier EA, Conti LR, Vandenberg CA, Shyng SL 2001 Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci USA 98:2882–2887[Abstract/Free Full Text]
8. Stanley CA, Thornton PS, Ganguly A, MacMullen C, Underwood P, Bhatia P, Steinkrauss L, Wanner L, Kaye R, Ruchelli E, Suchi M, Adzick NS 2004 Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab 89:288–296[Abstract/Free Full Text]
9. Finegold DN, Stanley CA, Baker L 1980 Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 96:257–259[CrossRef][Medline]
10. Stanley CA, Baker L 1976 Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics 57:702–711[Abstract/Free Full Text]
11. Rahier J, Guiot Y, Sempoux C 2000 Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 82:F108–F112
12. Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED 2003 Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol 6:322–333[CrossRef][Medline]
13. Ferry Jr RJ, Kelly A, Grimberg A, Koo-McCoy S, Shapiro MJ, Fellows KE, Glaser B, Aguilar-Bryan L, Stafford DE, Stanley CA 2000 Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism. J Pediatr 137:239–246[CrossRef][Medline]
14. Grimberg A, Ferry RJ, Kelly A, Koo-McCoy S, Polonsky K, Glaser B, Permutt A, Aguilar-Bryan L, Stafford D, Thornton PS, Baker L, Stanley CA 2001 Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 50:322–328[Abstract/Free Full Text]
15. Kelly A, Ng D, Ferry Jr RJ, Grimberg A, Koo-McCoy S, Thornton PS, Stanley CA 2001 Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome. J Clin Endocrinol Metab 86:3724–3728[Abstract/Free Full Text]
16. MacMullen C, Fang J, Hsu BYL, DeLonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA 2001 Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory GTP binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab 86:1782–1787[Abstract/Free Full Text]
17. Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG Stanley CA, Thornton PS, Permutt MA 1998 Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet 7:1119–1128[Abstract/Free Full Text]
18. Taschenberger G, Mougey A, Shen S, Lester LB, LaFranchi S, Shyng SL 2002 Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels. J Biol Chem 277:17139–17146[Abstract/Free Full Text]
19. Li C, Buettger C, Kwagh J, Matter A, Daikhin Y, Nissim IB, Collins HW, Yudkoff, M, Stanley CA, Matschinsky FM 2004 A signaling role of glutamine in insulin secretion. J Biol Chem 279:13393–13401[Abstract/Free Full Text]
20. Magge SN, Shyng SL, MacMullen C, Steinkrauss L, Ganguly A, Katz LE, Stanley CA 2004 Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the ß-cell sulfonylurea receptor. J Clin Endocrinol Metab 89:4450–4456[Abstract/Free Full Text]
21. Fajans SS, Floyd Jr JC, Knopf RF, Conn FW 1967 Effect of amino acids and proteins on insulin secretion in man. Recent Prog Horm Res 23:617–662
22. Huopio H, Jaaskelainen J, Komulainen J, Miettinen R, Karkkainen P, Laakso M, Tapanainen P, Voutilainen R, Otonkoski T 2002 Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism. J Clin Endocrinol Metab 87:4502–4507[Abstract/Free Full Text]
23. Giurgea I, Laborde K, Touati G, Bellanne-Chantelot C, Nassogne MC, Sempoux C, Jaubert F, Khoa N, Chigot V, Rahier J, Brunelle F, Nihoul-Fekete C, Dunne MJ, Stanley C, Saudubray JM, Robert JJ, de Lonlay P 2004 Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism. J Clin Endocrinol Metab 89:925–929[Abstract/Free Full Text]
24. Cosgrove KE, Antoine MH, Lee AT, Bellanne-Chantelot C, Nassogne MC, Sempoux C, Jaubert F, Khoa N, Chigot V, Rahier J, Brunelle F, Nihoul-Fekete C, Dunne MJ, Stanley C, Saudubray JM, Robert JJ, de Lonlay P 2002 BPDZ 154 activates adenosine 5'-triphosphate-sensitive potassium channels: in vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism. J Clin Endocrinol Metab 87:4860–4868[Abstract/Free Full Text]
25. Liu HX, Cartegni L, Zhang MQ, Krainer AR 2001 A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet 27:55–58[Medline]
26. Sharma N, Crane A, Clement IV JP, Gonzalez G, Babenko AP, Bryan J, Aguilar-Bryan L 1999 The C terminus of SUR1 is required for trafficking of KATP channels. J Biol Chem 274:20628–20632[Abstract/Free Full Text]

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