ABCC8 p.Lys1521Asn
| Predicted by SNAP2: | A: N (87%), C: N (78%), D: N (82%), E: N (87%), F: D (53%), G: N (82%), H: N (87%), I: N (82%), L: N (87%), M: N (87%), N: N (87%), P: N (57%), Q: N (93%), R: N (93%), S: N (93%), T: N (93%), V: N (87%), W: D (63%), Y: D (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, E: N, F: D, G: D, H: D, I: D, L: D, M: D, N: N, P: D, Q: N, R: N, S: N, T: D, V: D, W: D, Y: D, |
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[hide] A rare mutation in ABCC8/SUR1 leading to altered A... Diabetes. 2008 Jun;57(6):1595-604. Epub 2008 Mar 17. Tarasov AI, Nicolson TJ, Riveline JP, Taneja TK, Baldwin SA, Baldwin JM, Charpentier G, Gautier JF, Froguel P, Vaxillaire M, Rutter GA
A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.
Diabetes. 2008 Jun;57(6):1595-604. Epub 2008 Mar 17., [PMID:18346985]
Abstract [show]
OBJECTIVE: ATP-sensitive K(+) channels (K(ATP) channels) link glucose metabolism to the electrical activity of the pancreatic beta-cell to regulate insulin secretion. Mutations in either the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes only in adults. RESEARCH DESIGN AND METHODS: Recombinant K(ATP) channel subunits were expressed using pIRES2-based vectors in human embryonic kidney (HEK) 293 or INS1(832/13) cells and the subcellular distribution of c-myc-tagged SUR1 channels analyzed by confocal microscopy. K(ATP) channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca(2+)] was imaged using Fura-Red. RESULTS: A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning alpha-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single K(ATP) channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC(50) = 24 and 95 micromol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg(2+), suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca(2+) concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants. CONCLUSIONS: An ABCC8/SUR1 mutation with relatively minor effects on K(ATP) channel activity and beta-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.
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No. Sentence Comment
83 (E), wild type; (F), Y356C; (f), K1521N; (Ⅺ), H1023Y; (Œ), R248Q; (‚), L582V; (ૺ), R1379C.
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ABCC8 p.Lys1521Asn 18346985:83:33
status: NEW117 The two other ABCC8 mutations that we found to be associated with adult-onset diabetes were R248Q (type 2 diabetic patient diagnosed at age 39 years without familial cosegregation) (online appendix Fig. 1) and K1521N (two type 2 diabetic patients diagnosed at age 37 and 42 years).
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ABCC8 p.Lys1521Asn 18346985:117:210
status: NEW120 To test whether the mutations associated with type 2 diabetes might affect stimulus-secretion coupling in beta-cells, we next measured the sensitivity to ATP of recombinant KATP channels carrying SUR-Y356C, -R248Q, and -K1521N and compared these to the ATP sensitivity of TND-associated mutants (4), L582V, H1023Y, and R1379C.
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ABCC8 p.Lys1521Asn 18346985:120:220
status: NEW125 The concentration-inhibition curves for KATP channels carrying SUR1-R248Q and SUR1-K1521N were practically identical to the wild type, suggesting either that these mutations affected other properties of the channel or were not responsible for diabetes (Fig. 1C).
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ABCC8 p.Lys1521Asn 18346985:125:83
status: NEW126 KATP channel conductance of the inside-out patches expressing SUR1-K1521N was not different from wild type (11.3 Ϯ 5.6 ns and 12.5 Ϯ 5.9 ns, respectively), as measured in nucleotide-free solution.
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ABCC8 p.Lys1521Asn 18346985:126:67
status: NEW187 INS1(832/13) cells overexpressing SUR1-K1521N channels showed an unchanged [Ca2ϩ ]cyt response to glucose compared with wild-type cells (Fig. 5B and C).
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ABCC8 p.Lys1521Asn 18346985:187:39
status: NEW