ABCC8 p.Cys418Arg
| Predicted by SNAP2: | A: D (75%), D: D (75%), E: D (95%), F: D (59%), G: D (66%), H: D (63%), I: N (61%), K: D (66%), L: D (53%), M: N (53%), N: N (53%), P: D (80%), Q: D (53%), R: D (95%), S: N (57%), T: N (72%), V: N (82%), W: D (85%), Y: D (66%), |
| Predicted by PROVEAN: | A: N, D: N, E: N, F: D, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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[hide] Noninvasive diagnosis of focal hyperinsulinism of ... Diabetes. 2006 Jan;55(1):13-8. Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekstrom K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H
Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography.
Diabetes. 2006 Jan;55(1):13-8., [PMID:16380471]
Abstract [show]
Congenital hyperinsulinism of infancy (CHI) is characterized by severe hypoglycemia due to dysregulated insulin secretion, associated with either focal or diffuse pathology of the endocrine pancreas. The focal condition is caused by a paternally inherited mutation in one of the genes encoding the subunits of the beta-cell ATP-sensitive potassium channel (SUR1/ABCC8 or Kir6.2/KCNJ11) and somatic loss of maternal 11p15 alleles within the affected area. Until now, preoperative diagnostics have relied on technically demanding and invasive catheterization techniques. 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). To reduce bias in PET image interpretation, quantitative means for evaluation of pancreatic [(18)F]-DOPA uptake were established. Five patients had a visually apparent focal accumulation of [(18)F]-DOPA and standardized uptake value (SUV) >50% higher (mean 1.8-fold) than the maximum SUV of the unaffected part of the pancreas. When these patients were operated on, a focus of 4-5 x 5-8 mm matching with the PET scan was found, and all were normoglycemic after resection of the focus. The remaining nine patients had diffuse accumulation of [(18)F]-DOPA in the pancreas (SUV ratio <1.5). Diffuse histology was verified in four of these, and pancreatic catheterization was consistent with diffuse pathology in four cases. In conclusion, [(18)F]-DOPA PET is a promising noninvasive method for the identification and localization of the focal form of CHI.
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No. Sentence Comment
109 However, in one patient (no. 13), the only mutation identified (C418R) was inherited from the maternal side.
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ABCC8 p.Cys418Arg 16380471:109:64
status: NEW141 Thus, the mutation C418R was apparently not expressed within the lesion and is likely not of functional importance.
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ABCC8 p.Cys418Arg 16380471:141:19
status: NEW100 In one of these (case no. 7), a pancreatic biopsy with diffuse-type pathol- TABLE 1 Clinical and genetic characteristics of the patients, together with the findings in PET scan, pancreatic catheterization, surgery, and histology Patient Age at diagnosis/PET ABCC8 mutation Response to medication Glucose need (mg/kg/min) PET PVS/PACS Surgery/histology 1 Neonatal/6 months V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 12.3 focal/head focal/head focal resection/posterior neck PAD: focus 6.8 afb; 4 mm 2 4 months/13 months V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 9.5 focal/body focal/body focal resection/body PAD: focus 5 afb; 4 mm 3 Neonatal/6 months G1469V (4408Gb0e;T) (Paternal) Dzxafa;, Octr af9; 12.7 focal/head focal/head focal resection/head PAD: focus 8 afb; 5 mm 4 Neonatal/3.5 years V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 12.7 diffuse diffuse* ND 5 Neonatal/6 months A113V (338Cb0e;T) (Paternal) Dzxafa;, Octr af9; 12.7 diffuse diffuse Near-total pancreatectomy PAD: diffuse histology 6 Neonatal/5 years No mutations Dzx af9; 6.5 diffuse diffuse* ND 7 3 months/4 years No mutations Dzx af9; 6.5 diffuse ND Pancreas biopsy PAD: diffuse histology 8 Neonatal/9 months G92D (275Gb0e;A) Dzxafa;, Octr af9; 10.3 diffuse ND Near-total pancreatectomy PAD: diffuse histology 9 Neonatal/1 month V187D (561Tb0e;A) (Paternal) Dzxafa;, Octrafa; 20 focal/head ND focal resection/uncinate process PAD: focus 8 afb; 4 mm 10 Neonatal/2 months No mutations Dzx partial, Octr af9; 6.2 diffuse ND ND 11 5 months/13 months V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 6.4 diffuse diffuse ND 12 Neonatal/1.5 months G474A (de novo) Dzxafa;, Octr af9; 15.9 diffuse ND Near-total pancreatectomy PAD diffuse; 13 Neonatal/3 months C418R (1252Tb0e;C) (Maternal) Dzxafa;, Octr af9; 26 focal/body ND focal resection/body PAD: focus 10 afb; 6 mm 14 Neonatal/6 months A113V (338Cb0e;T) (Paternal) Dzxafa;, Octr af9; 13 diffuse ND ND The glucose need refers to the glucose infusion rate that was required to maintain normoglycemia at the time of the PET scan.
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ABCC8 p.Cys418Arg 16380471:100:1837
status: NEW110 However, in one patient (no. 13), the only mutation identified (C418R) was inherited from the maternal side.
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ABCC8 p.Cys418Arg 16380471:110:64
status: NEW142 Thus, the mutation C418R was apparently not expressed within the lesion and is likely not of functional importance.
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ABCC8 p.Cys418Arg 16380471:142:19
status: NEW[hide] Clinical and metabolic features of adult-onset dia... Diabetes Care. 2012 Feb;35(2):248-51. Epub 2011 Dec 30. Riveline JP, Rousseau E, Reznik Y, Fetita S, Philippe J, Dechaume A, Hartemann A, Polak M, Petit C, Charpentier G, Gautier JF, Froguel P, Vaxillaire M
Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations.
Diabetes Care. 2012 Feb;35(2):248-51. Epub 2011 Dec 30., [PMID:22210575]
Abstract [show]
OBJECTIVE: Gain-of-function ABCC8/sulfonylurea (SU) receptor 1 mutations cause neonatal diabetes mellitus (NDM) or late-onset diabetes in adult relatives. Given the effectiveness of SU treatment in ABCC8-NDM patients, we further characterized late-onset ABCC8-associated diabetes. RESEARCH DESIGN AND METHODS: Seven adult subjects from three NDM families and one family with type 2 diabetes were studied. Insulin secretion and insulin sensitivity were assessed using clamp techniques. We screened 139 type 2 diabetic patients who were well controlled by SU for ABCC8 mutations. RESULTS: ABCC8 mutation carriers exhibited glucose intolerance, frank diabetes, or insulin-requiring diabetes since diagnosis. HbA(1c) improved in five SU-treated patients. Insulin secretion capacity was impaired in three patients compared with adult control subjects but was restored after a 4-week SU trial in two patients. Cohort screening revealed four SU-treated patients with ABCC8 mutations, two of which are likely causal. CONCLUSIONS: Although of rare occurrence, recognition of adult-onset ABCC8-associated diabetes may help in targeting patients for SU therapy.
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38 Three mutations were previously reported (c.2476C.T/p.R826W in transient NDM [TNDM] (3,4,13), c.1252T.C/p.C418R and c.1858C.T/ p.R620C in congenital hyperinsulinism [CHI] (14,15)), and one mutation is novel (c.601C.G/p.P201S).
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ABCC8 p.Cys418Arg 22210575:38:106
status: NEW42 Genotyping of C418R and R620C mutations in .4,000 normoglycemic individuals from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) cohort (18) identified five and one carrier, respectively, suggesting that they may represent rare variants (population carrier frequency of 0.06 and 0.012%) likely not related to disease.
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ABCC8 p.Cys418Arg 22210575:42:14
status: NEW51 We cannot exclude that two rare variants (C418R and R620C), as previously reported in CHI (14,15) and found here in two diabetic patients, are nonfunctional (i.e., nondeleterious).
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ABCC8 p.Cys418Arg 22210575:51:42
status: NEW44 1-II.1 2-II.1 3-II.1 3-II.2 4-II.1 4-III.1 4-III.2 D-1 D-2 D-3 D-4 Sex Female Male Male Male Male Female Male Female Male Male Female Mutation R1380H C435R L582 V L582 V Y356C Y356C Y356C P201S C418R R620C R826 W c.4139G.A c.1303T.C c.1744C.G c.1744C.G c.1067A.G c.1067A.G c.1067A.G c.601C.G c.1252T.C c.1858C.T c.2476C.T Previous report NDM (11) NDM (2) NDM (2) d Type 2 diabetes (7) d d None rs67254669* rs58241708* TNDM (4,6,13) Features at diagnosis or at ascertainment Status Diabetes Diabetes Diabetes Diabetes Diabetes Impaired glucose toleranceߤ Normal glucose toleranceߤ Type 2 diabetes Type 2 diabetes Type 2 diabetes Type 2 diabetes Age (years)/BMI (kg/m 2 ) 17/24 15/20 36/21 32/37 39/26 35/20 33/22 53/22 53/31 46/25 49/28 Symptoms Polyuria Polyuria None Obesity None None None Tiredness Hyperglycemia Polyuria None Features at last examination Age (years) 63 39 38 37 74 35 33 80 74 56 58 SU treatment 15 mg/day glyburidex 15 mg/day glyburidex 5 mg/day glyburide 160 mg/day gliclazide 3 mg/day glimepiride None None Glyburide| Glimepiride| Glypizide Glimepiride HbA 1c (%)ߥ 7.3 6.7 6.2 6.4 6.5 5.5 ND 7.4 6.2 6.8 6.2 C-peptide (pmol/mL) 0.08 0.14 ND ND 3.00 ND ND 1.17 2.08 1.90 3.80 All mutations were identified heterozygously in the patients.
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ABCC8 p.Cys418Arg 22210575:44:194
status: NEW59 We cannot exclude that two rare variants (C418R and R620C), as previously reported in CHI (14,15) and found here in two diabetic patients, are nonfunctional (i.e., nondeleterious).
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ABCC8 p.Cys418Arg 22210575:59:42
status: NEW