ABCMdb

ABCC8 p.Leu503Pro

Predicted by SNAP2:	A: D (71%), C: D (59%), D: D (91%), E: D (85%), F: D (63%), G: D (85%), H: D (85%), I: N (78%), K: D (85%), M: D (53%), N: D (85%), P: D (91%), Q: D (80%), R: D (85%), S: D (80%), T: D (80%), V: N (53%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Congenital hyperinsulinism associated ABCC8 mutati... Diabetes. 2007 Sep;56(9):2339-48. Epub 2007 Jun 15. Yan FF, Lin YW, MacMullen C, Ganguly A, Stanley CA, Shyng SL
Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: identification and rescue.
Diabetes. 2007 Sep;56(9):2339-48. Epub 2007 Jun 15., [PMID:17575084]

Abstract [show]
Congenital hyperinsulinism (CHI) is a disease characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K(+) (K(ATP)) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Previous studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide. The purpose of this study is to identify additional mutations that cause channel biogenesis/trafficking defects and those that are amenable to rescue by pharmacological chaperones. Fifteen previously uncharacterized CHI-associated missense SUR1 mutations were examined for their biogenesis/trafficking defects and responses to pharmacological chaperones, using a combination of immunological and functional assays. Twelve of the 15 mutations analyzed cause reduction in cell surface expression of K(ATP) channels by >50%. Sulfonylureas rescued a subset of the trafficking mutants. By contrast, diazoxide failed to rescue any of the mutants. Strikingly, the mutations rescued by sulfonylureas are all located in the first transmembrane domain of SUR1, designated as TMD0. All TMD0 mutants rescued to the cell surface by the sulfonylurea tolbutamide could be subsequently activated by metabolic inhibition on tolbutamide removal. Our study identifies a group of CHI-causing SUR1 mutations for which the resulting K(ATP) channel trafficking and expression defects may be corrected pharmacologically to restore channel function.

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47 TABLE 1 Genetic and clinical information on patients carrying the CHI mutations Mutation Disease Haplotype Diazoxide response References G7R Focal G7R No 44 N24K Diffuse N24K/R1215W No Not reported F27S Focal F27S No 39 R74W Focal R74W/R1215Q No 39,45,46 E128K Diffuse E128K No Not reported R495Q Diffuse R495Q/R1215Q No 39 E501K Focal E501K No 39 L503P Focal L503P No 44 F686S Focal F686S No 39 G716V* Diffuse G716V/G716V No 47,48 K1337N Not done g3992-9a/K1337N Yes 39 L1350Q Focal L1350Q No 44 S1387F Diffuse S1387F/NA No 9,24 L1390P NA L1390P/NA No Not reported D1472H Diffuse ⌬F1388/D1472H No 39 *Patient was from consanguineous mating and therefore was homozygous for the G716V mutation (48). Login to comment
94 The first group, including G7R, N24K, F27S, R74W, and E128K, is located in the first transmembrane domain TMD0; the second group, including R495Q, E501K, L503P, F686S, and G716V, is located in the second transmembrane domain TMD1 extending through the first nucleotide binding domain; the third group, including K1337N, L1350Q, S1387F, L1390P, and D1472H, is clustered in the second nucleotide binding domain and the COOH terminus of the protein. Login to comment
118 Results from this assay showed that F27S, R74W, E128K, R495Q, E501K, L503P, F686S, G716V, L1350Q, and D1472H mutant channels had greatly reduced surface expression (Ͻ20% of wild-type level)-whereas G7R and N24K mutant channels displayed modestly decreased surface expression level (Ͼ30% but Ͻ50% of wild-type level) and K1337N, S1378F, and L1390P exhibited normal or mildly reduced expression (Ͼ60% of wild-type level; Fig. 3A). Login to comment
48 TABLE 1 Genetic and clinical information on patients carrying the CHI mutations Mutation Disease Haplotype Diazoxide response References G7R Focal G7R No 44 N24K Diffuse N24K/R1215W No Not reported F27S Focal F27S No 39 R74W Focal R74W/R1215Q No 39,45,46 E128K Diffuse E128K No Not reported R495Q Diffuse R495Q/R1215Q No 39 E501K Focal E501K No 39 L503P Focal L503P No 44 F686S Focal F686S No 39 G716V* Diffuse G716V/G716V No 47,48 K1337N Not done g3992-9a/K1337N Yes 39 L1350Q Focal L1350Q No 44 S1387F Diffuse S1387F/NA No 9,24 L1390P NA L1390P/NA No Not reported D1472H Diffuse èc;F1388/D1472H No 39 *Patient was from consanguineous mating and therefore was homozygous for the G716V mutation (48). Login to comment
95 The first group, including G7R, N24K, F27S, R74W, and E128K, is located in the first transmembrane domain TMD0; the second group, including R495Q, E501K, L503P, F686S, and G716V, is located in the second transmembrane domain TMD1 extending through the first nucleotide binding domain; the third group, including K1337N, L1350Q, S1387F, L1390P, and D1472H, is clustered in the second nucleotide binding domain and the COOH terminus of the protein. Login to comment
119 Results from this assay showed that F27S, R74W, E128K, R495Q, E501K, L503P, F686S, G716V, L1350Q, and D1472H mutant channels had greatly reduced surface expression (b0d;20% of wild-type level)-whereas G7R and N24K mutant channels displayed modestly decreased surface expression level (b0e;30% but b0d;50% of wild-type level) and K1337N, S1378F, and L1390P exhibited normal or mildly reduced expression (b0e;60% of wild-type level; Fig. 3A). Login to comment

[hide] ABCC8 and KCNJ11 molecular spectrum of 109 patient... J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3. Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y, Nihoul-Fekete C, de Lonlay P
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.
J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3., [PMID:20685672]

Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic beta-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.

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104 1 DPET htzP Flanagan et al, 200817 ABCC8 Exon 8 c.1177-?_1332+?del p.Thr393_Gln444del52 1 DH c-htz This report ABCC8 Exon 8 c.1331A/G p.Gln444Arg 1 FH Damaj et al, 200845 ABCC8 Exon 10 c.1508T/C p.Leu503Pro 1 FH Flanagan et al, 200817 ABCC8 Exon 10 c.1531C/A p.Leu511Met 2 DH htz, htznovo This report ABCC8 Intron 10 c.1630+1G/T p.? Login to comment
107 1 DH c-htz This report ABCC8 Exon 16 c.2124_2127delGACT p.Thr709X 1 FH This report ABCC8 Exon 16 c.2147G/A p.Gly716Asp 1 DPET htzm This report ABCC8 Exon 16 c.2153delG p.Gly718fs 1 DH htzP This report ABCC8 Exon 20 c.2425C/T p.Gln809X 1 DH c-htz Damaj et al, 200845 ABCC8 Exon 20 c.2473G/A p.Glu825Lys 1 DPET htzP This report ABCC8 Exon 22 c.2560-?_2697+?del p.Asp854_Trp899del46 1 DH c-htz This report ABCC8 Exon 22 c.2581G/C p.Asp861His 1 DPVS c-htz This report ABCC8 Exon 22 c.2669A/C p.Lys890Thr 1 DH htzP Flanagan et al, 200817 ABCC8 Exon 22 c.2672T/C p.Leu891Pro 1 DH htznovo This report ABCC8 Exon 23 c.2702T/C p.Ile901Thr 2 DH, DPET c-htz This report ABCC8 Exon 23 c.2784G/A p.Trp928X 1 FH This report ABCC8 Exon 23 c.2803C/T p.Gln935X 1 DPET c-htz This report ABCC8 Exon 24 c.2860C/T p.Gln954X 1 FH Flanagan et al, 200817 ABCC8 Intron 24 c.2924-9G/A p.? Login to comment

[hide] The spectrum of ABCC8 mutations in Norwegian patie... Clin Genet. 2009 May;75(5):440-8. Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Sovik O, Njolstad PR, Molven A
The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy.
Clin Genet. 2009 May;75(5):440-8., [PMID:19475716]

Abstract [show]
Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11, respectively. Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI). Twenty-six Norwegian probands with CHI were analyzed for alterations in ABCC8 and KCNJ11. Fifteen probands (58%) had mutations in the ABCC8 gene. Nine patients were homozygous or compound heterozygous for the mutations, indicating diffuse pancreatic disease. In five patients, heterozygous and paternally inherited mutations were found, suggesting focal disease. One patient had a de novo mutation likely to cause a milder, dominant form of CHI. Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C>G, I462V, Q917X and T1531A) were identified. The mutations IVS10+1G>T, R1493W and V21D occurred in five, three and two families, respectively. KCNJ11 mutations were not found in any patients. Based on our mutation screening, we estimate the minimum birth prevalence of ABCC8-CHI in Norway to 1:70,000 during the past decade. Our results considerably extend the knowledge of the molecular genetics behind CHI in Scandinavia.

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109 Clinical characteristics of Norwegian CHI patients carrying mutations in ABCC8 Proband Sex Birth weight (g)/gestation length (weeks)a Treatment Mutationsd Medicalb Surgeryc Maternal chromosome Paternal chromosome Hypo-N3 F 6190/38 Deceased Yes (S) R1493W R1493W Hypo-N6 M 5340/38 Somatostatin, diet (FM, PEG) No V21D V21D Hypo-N8 F 5740/37 Insulin Yes (S) G1400R R1493W Hypo-N9 F 5130/40 Diet (FM) Yes (S) - IVS1011G.T Hypo-N11 M 4000/38 None No - G1478Re Hypo-N14 M 5000/40 Somatostatin, diet (FM, PEG) No - IVS1011G.T Hypo-N16 F 3780/38 Diet (FM) No - C267X Hypo-N19 F 5240/40 Somatostatin, diet (FM, PEG) No IVS1011G.T T1531Af Hypo-N22 M 4500/39 Diazoxide Yes (S) IVS6-3C.G, I462V Q917X Hypo-N23 F 4860/38 Insulin Yes (S) P1413Lg IVS1011G.Tg Hypo-N25 M 3910/34 Insulin Yes (S) V21Dg E490Xg Hypo-N26 M 3790/35 Diet (FM, PEG) Yes (H) V187D R248X Hypo-N29 F 3350/37 None Yes (P) - IVS1011G.T Hypo-N30 F 3800/37 Diazoxide No W231R L503P Hypo-N31 M 4340/40 None Yes (P) - R1493W a All cases had birth weights 12 standard deviation scores except for Hypo-N29 whose score was 11. b Current therapy is given. Login to comment
122 We classified the mutations as either MnMn Hypo-N3 R1493W MMMM Mn Mn Hypo-N6 V21D MM MnMn Hypo-N8 G1400R / R1493W MM nnMn Hypo-N9 IVS10 Mn Hypo-N11 G1478R Mn nnMn Hypo-N16 C267X Mn Mn Hypo-N19 IVS10 / T1531A MM Mn nn Hypo-N29 IVS10 Mn Mn Hypo-N30 W231R / L503P MM MM x Hypo-N23 IVS10 / P1413L MM x Hypo-N14 IVS10 Mn Hypo-N22 IVS6 (I462V) / Q917X MM Hypo-N25 V21D / E490X MM xx Hypo-N26 V187D / R248 X MM x Hypo-N31 R1493W nnMnMnMn nnnnMn MnMn MM MnMn Mn nnnn Fig. 1. Login to comment
133 ABCC8 mutations found in Norwegian CHI patientsa Nucleotide change Location Amino acid change Mutation type PSIC score PD Number of families Reference c.62 T.A Exon 1 V21D Mis 1.96 PoD 2 (24) c.560 T.A Exon 4 V187D Mis 2.01 PrD 1 (2) c.691 T.C Exon 5 W231R Mis 4.03 PrD 1 NR c.742 C.T Exon 5 R248X Non - - 1 (34, 42) c.801 C.A Exon 5 C267X Non - - 1 NR IVS6-3C.G Intron 6 - AS - - 1 NR c.1384 A.G Exon 9 I462V Mis 0.62 PrB 1 NR c.1468 G.T Exon 10 E490X Non - - 1 (43) c.1508 T.C Exon 10 L503P Mis 2.36 PrD 1 (24) IVS1011G.T Intron 10 - AS - - 5 (44) c.2749 C.T Exon 23 Q917X Non - - 1 NR c.4198 G.A Exon 35 G1400R Mis 2.37 PrD 1 (42) c.4238 C.T Exon 35 P1413L Mis 2.76 PrD 1 (25) c.4432 G.A Exon 37 G1478R Mis 2.37 PrD 1 (14, 31) c.4477 C.T Exon 37 R1493W Mis 2.79 PrD 3 (26) c.4591 A.G Exon 38 T1531A Mis 1.93 PoD 1 NR AS, aberrant splicing; Mis, missense; NR, not previously reported; Non, nonsense; PD, pathogenic description; PoD, possibly damaging; PrB, predicted to be benign; PrD, probably damaging; PSIC, position-specific independent counts. Login to comment
168 A largenumber (.150)ofABCC8 alterations have been reported to cause CHI (19) including 10 of the mutations observed in this study (V21D, V187D, R248X, E490X, L503P, IVS1011G.T, G1400R, P1413L, G1478R, and R1493W). Login to comment

[hide] Molecular and immunohistochemical analyses of the ... Mod Pathol. 2006 Jan;19(1):122-9. Suchi M, MacMullen CM, Thornton PS, Adzick NS, Ganguly A, Ruchelli ED, Stanley CA
Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism.
Mod Pathol. 2006 Jan;19(1):122-9., [PMID:16357843]

Abstract [show]
Congenital hyperinsulinism is a rare pancreatic endocrine cell disorder that has been categorized histologically into diffuse and focal forms. In focal hyperinsulinism, the pancreas contains a focus of endocrine cell adenomatous hyperplasia, and the patients have been reported to possess paternally inherited mutations of the ABCC8 and KCNJ11 genes, which encode subunits of an ATP-sensitive potassium channel (K(ATP)). In addition, the hyperplastic endocrine cells show loss of maternal 11p15, where imprinted genes such as p57(kip2) reside. In order to evaluate whether all cases of focal hyperinsulinism are caused by this mechanism, 56 pancreatectomy specimens with focal hyperinsulinism were tested for the loss of maternal allele by two methods: immunohistochemistry for p57(kip2) (n=56) and microsatellite marker analysis (n=27). Additionally, 49 patients were analyzed for K(ATP) mutations. Out of 56 focal lesions, 48 demonstrated clear loss of p57(kip2) expression by immunohistochemistry. The other eight lesions similarly showed no nuclear labeling, but the available tissue was not ideal for definitive interpretation. Five of these eight patients had paternal K(ATP) mutations, of which four demonstrated loss of maternal 11p15 within the lesion by microsatellite marker analysis. All of the other three without a paternal K(ATP) mutation showed loss of maternal 11p15. K(ATP) mutation analysis identified 32/49 cases with paternal mutations. There were seven patients with nonmaternal mutations whose paternal DNA material was not available, and one patient with a mutation that was not present in either parent's DNA. These eight patients showed either loss of p57(kip2) expression or loss of maternal 11p15 region by microsatellite marker analysis, as did the remaining nine patients with no identifiable K(ATP) coding region mutations. The combined results from the immunohistochemical and molecular methods indicate that maternal 11p15 loss together with paternal K(ATP) mutation is the predominant causative mechanism of focal hyperinsulinism.

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93 KATP mutationsa Nuclear labeling of p57kip2 Microsatellite marker analysis at 11p15 Remarks on histology Lesion Islets in normal area 1 g3992-9a/ + ND 2 R1494Q/ + ND 3 V21D/ + ND 4 g3992-9a/ + ND 5 3576 del g/ Small lesion + ND 6 R74W/ Small normal area and weak Loss of maternal allele 7 C717X/ + Loss of maternal allele 8 1874 del c/ + ND 9 Q954X/ + ND 10 g3992-9g/ + Loss of maternal allele 11 E501K/ + Loss of maternal allele 12 R136Lb / Weak Loss of maternal allele 13 c2924-9a/ + Loss of maternal allele Focal lesion occupies large area of pancreas 14 g3992-9a/ + ND 15 3084 del g/ + ND 16 R302Hb / + Loss of maternal allele 17 g3992-9a/ + ND 18 536-539 del atgg/ + ND 19 R1215W/ + Loss of maternal allele 20 R999X/ + ND 21 L1350Q/ + ND 22 G1401R/ Weak Loss of maternal allele 23 g2041-21a/ + Loss of maternal allele 24 G7R/ Weak Loss of maternal allele 25 g3992-9a/ + Loss of maternal allele Rare nonadjacent large islet cell nuclei 26 g3992-9a/ + ND 27 Q954X/ + ND 28 delF1388/ + ND 29 Q472X/ + ND 30 G40Db / + Loss of maternal allele 31 S116Pb / + ND 32 g3992-9a/ + ND 33 g2116+1t, nonmaternal + ND 34 A101Db , nonmaternal Small normal area Loss of maternal allele Focal lesion occupies large area of pancreas 35 F27S, nonmaternal Weak Loss of maternal allele 36 G1379R, nonmaternal + ND 37 1631 del t, nonmaternal + ND 38 R1215W, nonmaternal + Loss of maternal allele 39 L503P, nonmaternal + Loss of maternal allele 40 F686S, de novo + Loss of maternal allele 41 1332+4 del c, maternalc + Loss of maternal allele 42 / + Loss of maternal allele 43 / + ND 44 / Small lesion + Loss of maternal allele 45 / + Loss of maternal allele 46 / + Loss of maternal allele 47 / + ND 48 / + Loss of maternal allele 49 / + ND 50 ND + ND 51 ND + ND 52 ND + Loss of maternal allele Rare nonadjacent large islet cell nuclei 53 ND + Loss of maternal allele Focal lesion occupies large area of pancreas All 10 pancreatic specimens studied from patients with diffuse hyperinsulinism did not show loss of p57kip2 labeling of the islet cell nuclei (data not shown). Login to comment

[hide] Pharmacological rescue of trafficking-impaired ATP... Front Physiol. 2013 Dec 24;4:386. doi: 10.3389/fphys.2013.00386. Martin GM, Chen PC, Devaraneni P, Shyng SL
Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels.
Front Physiol. 2013 Dec 24;4:386. doi: 10.3389/fphys.2013.00386., [PMID:24399968]

Abstract [show]
ATP-sensitive potassium (KATP) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic beta-cells, KATP channels play a key role in glucose-stimulated insulin secretion, and gain or loss of channel function results in neonatal diabetes or congenital hyperinsulinism, respectively. The beta-cell KATP channel is formed by co-assembly of four Kir6.2 inwardly rectifying potassium channel subunits encoded by KCNJ11 and four sulfonylurea receptor 1 subunits encoded by ABCC8. Many mutations in ABCC8 or KCNJ11 cause loss of channel function, thus, congenital hyperinsulinism by hampering channel biogenesis and hence trafficking to the cell surface. The trafficking defects caused by a subset of these mutations can be corrected by sulfonylureas, KATP channel antagonists that have long been used to treat type 2 diabetes. More recently, carbamazepine, an anticonvulsant that is thought to target primarily voltage-gated sodium channels has been shown to correct KATP channel trafficking defects. This article reviews studies to date aimed at understanding the mechanisms by which mutations impair channel biogenesis and trafficking and the mechanisms by which pharmacological ligands overcome channel trafficking defects. Insight into channel structure-function relationships and therapeutic implications from these studies are discussed.

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218 Mutation Domain Rescue Rescue Gating References by SU by CBZ property SUR1 G7R TMD0 Yes Yes Normal Yan et al., 2007 N24K TMD0 Yes Yes Normal Yan et al., 2007 F27S TMD0 Yes Yes Normal Yan et al., 2007 R74W TMD0 Yes Yes ATP-insensitive Yan et al., 2007 A116P TMD0 Yes Yes Normal Yan et al., 2004 E128K TMD0 Yes Yes ATP-insensitive Yan et al., 2007 V187D TMD0 Yes Yes Normal Yan et al., 2004 R495Q TMD1 Yes Yes Unknown Yan et al., 2007 E501K TMD1 Yes Yes Unknown Yan et al., 2007 L503P TMD1 No No Unknown Yan et al., 2007 F686S NBD1 No No Unknown Yan et al., 2007 G716V NBD1 No No Unknown Yan et al., 2007 E1324K TMD2 N.D.3 N.D. Login to comment