ABCMdb

ABCC8 p.Arg1530Cys

Predicted by SNAP2:	A: D (63%), C: D (59%), D: D (71%), E: D (66%), F: D (80%), G: D (71%), H: D (63%), I: D (75%), K: N (57%), L: D (75%), M: D (71%), N: D (53%), P: D (80%), Q: D (63%), S: N (53%), T: N (53%), V: D (75%), W: D (91%), Y: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D,

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[hide] Disease progression and search for monogenic diabe... BMC Endocr Disord. 2010 Sep 23;10:16. Porksen S, Laborie LB, Nielsen L, Louise Max Andersen M, Sandal T, de Wet H, Schwarcz E, Aman J, Swift P, Kocova M, Schonle EJ, de Beaufort C, Hougaard P, Ashcroft F, Molven A, Knip M, Mortensen HB, Hansen L, Njolstad PR
Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies.
BMC Endocr Disord. 2010 Sep 23;10:16., [PMID:20863361]

Abstract [show]
BACKGROUND: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. MATERIALS AND METHODS: In 261 newly diagnosed children with type 1 diabetes, we measured residual beta-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation. RESULTS: Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual beta-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide. CONCLUSION: GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.

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No. Sentence Comment
6 Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the KATP channel to inhibition by MgATP. Login to comment
89 We studied the functional effects of the SUR1-R1530C mutation by expressing recombinant KATP channels in Xenopus oocytes. Login to comment
91 In contrast, in oocytes expressing SUR1-R1530C mutant channels significant resting whole-cell KATP currents were present in the absence of metabolic inhibition (Fig. 2). Login to comment
107 Meal-stimulated GLP-1 and GIP did not differ between the subject carrying the R1530C mutation and non-carriers (data not shown). Login to comment
123 At study entry the diagnosis of wt R1531C azide Tolbutamide 0.5 µA 0.5 µA Figure 2 Tolbutamide response in SUR1-R1530C. Login to comment
124 Whole-cell currents recorded from Xenopus oocytes coexpressing Kir6.2 and either SUR1 (WT) or SUR1-R1530C in response to voltage steps of +20 mV from a holding potential of -10 mV. Login to comment
126 Figure 3 Tolbutamide response in SUR1-R1530C. Login to comment
137 We did not find pathogenic mutations in INS or KCNJ11, but one subject had a heterozygous mutation (R1530C) in SUR1 encoded by ABCC8. Login to comment
100 Although functional analyses showed that the mutant channel was highly sensitive to sulfonylureas, there was no clinical effect on metabolic control or insulin requirement after four weeks of glibenclamide treatment (1.0-1.2 mg/kg/24h) 8 years after Table 2 Clinical characteristics of the two study participants who tested negative for autoantibodies (GADA, IA-2A, and ICA) at 1 month and who converted to positivity for GADA (patient 2) at 12 months or IA-2A (patient 24 (carrier of the Arg1530Cys mutation of the ABCC8)) at 6 and 12 months after the diagnosis of type 1 diabetes Patient Age (years) Sex BMI (kg/m 2 ) HbA1C0 (%) IDAA1C 1 IDAA1C 6 IDAA1C 12 Ins dose1 (U/kg/day) ins dose6 (U/kg/day) Ins dose12 (U/kg/day) Cpep1 (pmol/L) Cpep6 (pmol/L) Cpep12 (pmol/L) BGstim1 (mmol/L) BGstim6 (mmol/L) BGstim12 (mmol/L) 2 16.3 female 17 10.9 Na 11.1 11.7 0.54 0.73 0.59 120 10 10 14.2 20.7 13.2 24 14 male 16.4 12.4 11.3 10.6 12.8 0.63 0.73 0.98 356 308 218 13.9 21 20.6 Abbreviations: Na, not available; BMI, body mass index; HBA1C0; HBA1C at diagnosis; IDAA1C 1, Insulin Dose Adjusted HbA1c (IDAA1C) at 1 month; IDAA1C 6, IDAA1C at 6 months; IDAA1C 12, IDAA1C at 12 months;; Ins dose1, insulin dose at 1 month; Ins dose6, insulin dose at 6 months; Ins dose12, insulin dose at 12 months; Cpep1, stimulated C-peptide at 1 month, Cpep6, stimulated C-peptide at 6 months; Cpep12, stimulated C-peptide at 12 months; BGstim1, 90 min glucose at 1 month; BGstim6, 90 min glucose at 6 months; BGstim12, 90 min glucose at 12 months; (HbA1c (%) + [4 x insulin dose (U/Kg/24h)) (pmol/L) A C E B D (pmol/L) Figure 1 Comparison of disease course in autoantibody-negative and autoantibody-positive children: A: 12 months after disease onset, the residual beta cell function in autoantibody-negative patients was twofold higher than in autoantibody-positive patients (p = 0.002). Login to comment