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Gene Review

ABCC8  -  ATP-binding cassette, sub-family C...

Homo sapiens

Synonyms: ABC36, ATP-binding cassette sub-family C member 8, HHF1, HI, HRINS, ...
 Suchi,  MacMullen,  Thornton,  Ganguly,  Stanley,  Ruchelli,  Babenko,  Bryan,  Hussain,  Cosgrove,  Shepherd,  Luharia,  Smith,  Kassem,  Gregory,  Sivaprasadarao,  Christesen,  Jacobsen,  Brusgaard,  Glaser,  Maher,  Lindley,  Hindmarsh,  Dattani,  Dunne,  Cheung,  Gregg,  Gogolin-Ewens,  Bandong,  Stanley,  Baker,  Higgins,  Nowak,  Shows,  Ewens,  Nelson,  Spielman,  Sempoux,  Guiot,  Dahan,  Moulin,  Stevens,  Lambot,  de Lonlay,  Fournet,  Junien,  Jaubert,  Nihoul-Fekete,  Saudubray,  Rahier,  Elbein,  Sun,  Scroggin,  Teng,  Hasstedt,  An,  Rice,  Rankinen,  Leon,  Skinner,  Wilmore,  Bouchard,  Rao,  Hirano,  Nakamura,  Kubokawa,  Katz,  Ferry,  Stanley,  Collett-Solberg,  Baker,  Cohen,  Darendeliler,  Fournet,  Baş,  Junien,  Gross,  Bundak,  Saka,  Günöz,  van Dam,  Hoebee,  Seidell,  Schaap,  de Bruin,  Feskens,  Suchi,  MacMullen,  Thornton,  Adzick,  Ganguly,  Ruchelli,  Stanley,  Bitner-Glindzicz,  Lindley,  Rutland,  Blaydon,  Smith,  Milla,  Hussain,  Furth-Lavi,  Cosgrove,  Shepherd,  Barnes,  O'Brien,  Farndon,  Sowden,  Liu,  Scanlan,  Malcolm,  Dunne,  Aynsley-Green,  Glaser,  Otonkoski,  Näntö-Salonen,  Seppänen,  Veijola,  Huopio,  Hussain,  Tapanainen,  Eskola,  Parkkola,  Ekström,  Guiot,  Rahier,  Laakso,  Rintala,  Nuutila,  Minn,  Tanizawa,  Matsuda,  Matsuo,  Ohta,  Ochi,  Adachi,  Koga,  Mizuno,  Kajita,  Tanaka,  Tachibana,  Inoue,  Furukawa,  Amachi,  Ueda,  Oka,  
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Disease relevance of ABCC8

  • Paternal mutation of ATP-sensitive K(+) (K(ATP)) channel genes and loss of heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8, IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic hypoglycemia of infancy (FoPHHI) [1].
  • Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11 [2].
  • Insulinomas, composed of beta-cell nests or cords, have similar proinsulin mRNA compared with adjacent islets, highly variable proinsulin production, lower insulin stock (P < or = 0.02), and higher ABCC8 peptide labeling (P<0.05) [1].
  • Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity [3].
  • Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K(+)(ATP) channel, the sulfonylurea receptor (ABCC8 or SUR1) [2].

High impact information on ABCC8


Chemical compound and disease context of ABCC8

  • Leucine-sensitive hypoglycemia in this family was found to result from a dominantly expressed SUR1 mutation [8].
  • A subfamily, referred as ABCC, includes the famous/infamous cystic fibrosis transmembrane regulator (CFTR), the sulfonylurea receptors (SUR 1 and 2), and the multidrug resistance-associated proteins (MRPs) [9].
  • Mutations in SUR have been identified in individuals affected with familial persistent hyper-insulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder of glucose metabolism which is linked to chromosome 11p15.1 and characterized by unregulated secretion of insulin and profound hypoglycemia [10].
  • Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1 [11].
  • The clinical use of diazoxide has been hampered by its lack of potency and selectivity giving rise to side effects, such as oedema and hirsutism and new selective openers of Kir6.2/SUR1 channels have been pursued [12].

Biological context of ABCC8

  • Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated [13].
  • The results explain and predict pathologies associated with alteration of the 5' ends of clustered ABCC8 (9)/KCNJ11 (8) genes [14].
  • We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11 [3].
  • Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened [3].
  • PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation [15].

Anatomical context of ABCC8

  • This may explain the observation from several groups of an association of the ABCC8 variants in diabetes and is consistent with other studies showing a role of ABCC8 variants in pancreatic beta-cell function [16].
  • 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)) [17].
  • We also obtained leukocyte genomic DNA from 29 cases and screened the exons of ABCC8 and KCNJ11 genes for the presence of mutations [18].
  • The single-channel conductance of the homomeric KIR6.2 channels is equivalent to SUR/KIR6.2 channels, but they differ in all other respects, including bursting behavior, pharmacological properties, sensitivity to ATP and ADP, and trafficking to the plasma membrane [19].
  • We mutated the PKA consensus sequences of the human SUR1 and Kir6.2 subunits and tested their phosphorylation capacities in Xenopus oocyte homogenates and in intact cells [15].

Associations of ABCC8 with chemical compounds

  • We evaluated the utility of fluorine-18 l-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) positron emission tomography (PET) to identify focal pancreatic lesions in 14 CHI patients, 11 of which carried mutations in the ABCC8 gene (age 1-42 months) [20].
  • However, combined genotypes of ABCC8 exon 16 and 18 variants again significantly predicted both indexes of glucose and tolbutamide-stimulated insulin secretion [16].
  • RESULTS: An intronic variant of the ABCC8 gene just upstream of exon 16 was a significant determinant of both DI and an analogous index based on acute insulin response to tolbutamide [16].
  • Drugs which act on K+ATP channels, such as diazoxide, seem to need intact ABCC8 to be able to show their effects [21].
  • PHHI mutations have been informative on the function of SUR1 and regulation of KATP channels by adenine nucleotides [19].

Physical interactions of ABCC8

  • Only SUR1 and SUR1Delta17 showed high-affinity binding of glibenclamide (K(d) approximately 2 nM in the presence of 1 mM ATP) and formed functional K(ATP) channels upon coexpression with Kir6.2 [22].
  • This discovery may help design specific agents to selectively modulate the function of Kir6.1/SUR1 channel complex and facilitate the understanding of the structure-function relationship of specific subtype of K(ATP) channels [23].

Regulatory relationships of ABCC8

  • (86)Rb(+) efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function [8].
  • Interestingly in this study, the linkage evidence on 11 p at the SUR locus was somewhat enhanced (lod score went up from 1.7 to 2.0) in a prehypertensive (BP >or= 135/80 mm Hg) subset of 40 White families suggesting a pleiotropic gene for BP and RHR with interactions [24].
  • These results suggest that besides the common natures of the BK channel family such as regulation by cytoplasmic Ca(2+) and membrane potential, the BK channel in RPTECs is directly inhibited by intracellular ATP independent of phosphorylation processes and sulfonylurea receptor [25].

Other interactions of ABCC8


Analytical, diagnostic and therapeutic context of ABCC8

  • Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed [13].
  • RESEARCH DESIGN AND METHODS: We typed 124 nondiabetic members of 26 familial type 2 diabetic kindreds who had undergone tolbutamide-modified intravenous glucose tolerance tests for two variants of the ABCC8 (sulfonylurea) gene, two variants of the GCK gene, and one common amino acid variant in the TCF1 (HNF1alpha) gene [16].
  • Studies of the ABCC8 variants that were published first or had smaller sample sizes (for the exon 18 variant) showed stronger associations, which may indicate publication bias [30].
  • Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein [31].
  • Confocal microscopy using enhanced green fluorescent protein-tagged SUR or Kir6.x did not provide any evidence for involvement of these splice forms in the mitochondrial K(ATP) channel [22].


  1. The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. Sempoux, C., Guiot, Y., Dahan, K., Moulin, P., Stevens, M., Lambot, V., de Lonlay, P., Fournet, J.C., Junien, C., Jaubert, F., Nihoul-Fekete, C., Saudubray, J.M., Rahier, J. Diabetes (2003) [Pubmed]
  2. Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Fournet, J.C., Mayaud, C., de Lonlay, P., Gross-Morand, M.S., Verkarre, V., Castanet, M., Devillers, M., Rahier, J., Brunelle, F., Robert, J.J., Nihoul-Fékété, C., Saudubray, J.M., Junien, C. Am. J. Pathol. (2001) [Pubmed]
  3. Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. Tornovsky, S., Crane, A., Cosgrove, K.E., Hussain, K., Lavie, J., Heyman, M., Nesher, Y., Kuchinski, N., Ben-Shushan, E., Shatz, O., Nahari, E., Potikha, T., Zangen, D., Tenenbaum-Rakover, Y., de Vries, L., Argente, J., Gracia, R., Landau, H., Eliakim, A., Lindley, K., Dunne, M.J., Aguilar-Bryan, L., Glaser, B. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  4. CFTR is a conductance regulator as well as a chloride channel. Schwiebert, E.M., Benos, D.J., Egan, M.E., Stutts, M.J., Guggino, W.B. Physiol. Rev. (1999) [Pubmed]
  5. Toward understanding the assembly and structure of KATP channels. Aguilar-Bryan, L., Clement, J.P., Gonzalez, G., Kunjilwar, K., Babenko, A., Bryan, J. Physiol. Rev. (1998) [Pubmed]
  6. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Bitner-Glindzicz, M., Lindley, K.J., Rutland, P., Blaydon, D., Smith, V.V., Milla, P.J., Hussain, K., Furth-Lavi, J., Cosgrove, K.E., Shepherd, R.M., Barnes, P.D., O'Brien, R.E., Farndon, P.A., Sowden, J., Liu, X.Z., Scanlan, M.J., Malcolm, S., Dunne, M.J., Aynsley-Green, A., Glaser, B. Nat. Genet. (2000) [Pubmed]
  7. Linkage-disequilibrium mapping without genotyping. Cheung, V.G., Gregg, J.P., Gogolin-Ewens, K.J., Bandong, J., Stanley, C.A., Baker, L., Higgins, M.J., Nowak, N.J., Shows, T.B., Ewens, W.J., Nelson, S.F., Spielman, R.S. Nat. Genet. (1998) [Pubmed]
  8. Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor. Magge, S.N., Shyng, S.L., MacMullen, C., Steinkrauss, L., Ganguly, A., Katz, L.E., Stanley, C.A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  9. Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate. Homolya, L., Váradi, A., Sarkadi, B. Biofactors (2003) [Pubmed]
  10. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Thomas, P., Ye, Y., Lightner, E. Hum. Mol. Genet. (1996) [Pubmed]
  11. Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. Tanizawa, Y., Matsuda, K., Matsuo, M., Ohta, Y., Ochi, N., Adachi, M., Koga, M., Mizuno, S., Kajita, M., Tanaka, Y., Tachibana, K., Inoue, H., Furukawa, S., Amachi, T., Ueda, K., Oka, Y. Diabetes (2000) [Pubmed]
  12. Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. Hansen, J.B. Current medicinal chemistry. (2006) [Pubmed]
  13. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Gloyn, A.L., Weedon, M.N., Owen, K.R., Turner, M.J., Knight, B.A., Hitman, G., Walker, M., Levy, J.C., Sampson, M., Halford, S., McCarthy, M.I., Hattersley, A.T., Frayling, T.M. Diabetes (2003) [Pubmed]
  14. Sur domains that associate with and gate KATP pores define a novel gatekeeper. Babenko, A.P., Bryan, J. J. Biol. Chem. (2003) [Pubmed]
  15. PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. Béguin, P., Nagashima, K., Nishimura, M., Gonoi, T., Seino, S. EMBO J. (1999) [Pubmed]
  16. Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes. Elbein, S.C., Sun, J., Scroggin, E., Teng, K., Hasstedt, S.J. Diabetes Care (2001) [Pubmed]
  17. Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Suchi, M., MacMullen, C.M., Thornton, P.S., Adzick, N.S., Ganguly, A., Ruchelli, E.D., Stanley, C.A. Mod. Pathol. (2006) [Pubmed]
  18. Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Suchi, M., MacMullen, C., Thornton, P.S., Ganguly, A., Stanley, C.A., Ruchelli, E.D. Pediatr. Dev. Pathol. (2003) [Pubmed]
  19. Molecular biology of adenosine triphosphate-sensitive potassium channels. Aguilar-Bryan, L., Bryan, J. Endocr. Rev. (1999) [Pubmed]
  20. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Otonkoski, T., Näntö-Salonen, K., Seppänen, M., Veijola, R., Huopio, H., Hussain, K., Tapanainen, P., Eskola, O., Parkkola, R., Ekström, K., Guiot, Y., Rahier, J., Laakso, M., Rintala, R., Nuutila, P., Minn, H. Diabetes (2006) [Pubmed]
  21. ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. Darendeliler, F., Fournet, J.C., Baş, F., Junien, C., Gross, M.S., Bundak, R., Saka, N., Günöz, H. Journal of pediatric endocrinology & metabolism : JPEM. (2002) [Pubmed]
  22. Four novel splice variants of sulfonylurea receptor 1. Hambrock, A., Preisig-Müller, R., Russ, U., Piehl, A., Hanley, P.J., Ray, J., Daut, J., Quast, U., Derst, C. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  23. Inhibitory effect of protopine on K(ATP) channel subunits expressed in HEK-293 cells. Jiang, B., Cao, K., Wang, R. Eur. J. Pharmacol. (2004) [Pubmed]
  24. Genome-wide scan to identify quantitative trait loci for baseline resting heart rate and its response to endurance exercise training: the HERITAGE Family Study. An, P., Rice, T., Rankinen, T., Leon, A.S., Skinner, J.S., Wilmore, J.H., Bouchard, C., Rao, D.C. International journal of sports medicine. (2006) [Pubmed]
  25. Properties of a Ca(2+)-activated large conductance K(+) channel with ATP sensitivity in human renal proximal tubule cells. Hirano, J., Nakamura, K., Kubokawa, M. Jpn. J. Physiol. (2001) [Pubmed]
  26. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Inagaki, N., Gonoi, T., Clement, J.P., Namba, N., Inazawa, J., Gonzalez, G., Aguilar-Bryan, L., Seino, S., Bryan, J. Science (1995) [Pubmed]
  27. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. Chutkow, W.A., Pu, J., Wheeler, M.T., Wada, T., Makielski, J.C., Burant, C.F., McNally, E.M. J. Clin. Invest. (2002) [Pubmed]
  28. Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor. Katz, L.E., Ferry, R.J., Stanley, C.A., Collett-Solberg, P.F., Baker, L., Cohen, P. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  29. Syntaxin-1A actions on sulfonylurea receptor 2A can block acidic pH-induced cardiac K(ATP) channel activation. Kang, Y., Ng, B., Leung, Y.M., He, Y., Xie, H., Lodwick, D., Norman, R.I., Tinker, A., Tsushima, R.G., Gaisano, H.Y. J. Biol. Chem. (2006) [Pubmed]
  30. Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses. van Dam, R.M., Hoebee, B., Seidell, J.C., Schaap, M.M., de Bruin, T.W., Feskens, E.J. Diabet. Med. (2005) [Pubmed]
  31. Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels. Hussain, K., Cosgrove, K.E., Shepherd, R.M., Luharia, A., Smith, V.V., Kassem, S., Gregory, J.W., Sivaprasadarao, A., Christesen, H.T., Jacobsen, B.B., Brusgaard, K., Glaser, B., Maher, E.A., Lindley, K.J., Hindmarsh, P., Dattani, M., Dunne, M.J. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
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