ABCMdb

ABCC8 p.Arg620Cys

Predicted by SNAP2:	A: N (78%), C: D (66%), D: D (63%), E: N (87%), F: N (53%), G: N (78%), H: N (87%), I: N (72%), K: N (87%), L: N (87%), M: N (72%), N: N (93%), P: N (82%), Q: N (87%), S: N (53%), T: N (87%), V: N (82%), W: D (53%), Y: N (57%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: N, W: N, Y: N,

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[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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No. Sentence Comment
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). Login to comment
42 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. Login to comment
51 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). Login to comment
44 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. Login to comment
59 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). Login to comment