ABCC8 p.Gln474Arg
Predicted by SNAP2: | A: D (71%), C: D (59%), D: D (59%), E: D (66%), F: D (80%), G: D (53%), H: D (71%), I: D (75%), K: D (75%), L: D (80%), M: D (63%), N: N (93%), P: D (85%), R: D (75%), S: N (66%), T: D (59%), V: D (71%), W: D (85%), Y: D (80%), |
Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Diazoxide-unresponsive congenital hyperinsulinism ... Diabetes. 2011 Jun;60(6):1797-804. Epub 2011 May 2. Macmullen CM, Zhou Q, Snider KE, Tewson PH, Becker SA, Aziz AR, Ganguly A, Shyng SL, Stanley CA
Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the beta-cell sulfonylurea receptor SUR1.
Diabetes. 2011 Jun;60(6):1797-804. Epub 2011 May 2., [PMID:21536946]
Abstract [show]
OBJECTIVE: Congenital hyperinsulinemic hypoglycemia is a group of genetic disorders of insulin secretion most commonly associated with inactivating mutations of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (SUR1) and KCNJ11 (Kir6.2). Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with diazoxide, a channel agonist. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. We hypothesized that some medically uncontrollable cases with only one K(ATP) mutation might have dominant, diazoxide-unresponsive disease. RESEARCH DESIGN AND METHODS: Mutations of the K(ATP) genes were identified by sequencing genomic DNA. Effects of mutations on K(ATP) channel function in vitro were studied by expression in COSm6 cells. RESULTS: In 15 families with diazoxide-unresponsive diffuse hyperinsulism, we found 17 patients with a monoallelic missense mutation of SUR1. Nine probands had de novo mutations, two had an affected sibling or parent, and four had an asymptomatic carrier parent. Of the 13 different mutations, 12 were novel. Expression of mutations revealed normal trafficking of channels but severely impaired responses to diazoxide or MgADP. Responses were significantly lower compared with nine SUR1 mutations associated with dominant, diazoxide-responsive hyperinsulinism. CONCLUSIONS: These results demonstrate that some dominant mutations of SUR1 can cause diazoxide-unresponsive hyperinsulinism. In vitro expression studies may be helpful in distinguishing such mutations from dominant mutations of SUR1 associated with diazoxide-responsive disease.
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No. Sentence Comment
148 Parent of origin Family 1 II-1 LGA 1 No Diffuse Q474R De novo Family 2 II-1 LGA 1 No Diffuse A478D Maternal Family 2 II-2 AGA 1 No Diffuse A478D Maternal Family 3 II-1 AGA 1 No Diffuse V715A Maternal Family 3 II-2 LGA 1 No No surgery V715A Maternal Family 4 II-1 LGA 1 No No surgery V715G Not maternal Family 5 II-1 LGA 1 No Diffuse V715G De novo Family 6 II-1 LGA 42 No Diffuse V715G De novo Family 7 II-1 LGA 5 No Diffuse G716D Not maternal Family 8 II-1 AGA 3 No Diffuse T888P De novo Family 9 II-1 AGA 2 No Diffuse G1384E De novo Family 10 II-1 LGA 1 No Diffuse S1387F De novo Family 11 II-1 LGA 1 No Diffuse S1387Y De novo Family 12 II-1 LGA 1 No Diffuse S1389Y De novo Family 13 II-1 SGA 180 No Diffuse A1458T Paternal Family 14 II-1 LGA 88 No Diffuse Q1459H De novo Family 15 II-1 AGA 167 No Diffuse E1517K Maternal Dominant diazoxide-unresponsive (n = 17) 65% LGA median 1 day range (1-180 days) 100% no Diffuse 5 of 17 maternal 1 of 17 paternal 9 of 17 de novo 2 of 17 not maternal Dominant diazoxide-responsive (n = 13) 77% LGA median 30 days range (1-1,215 days) 100% yes Diffuse 5 of 13 maternal 4 of 13 paternal 4 of 13 de novo Recessive (n = 48) 87% LGA median 1 day range (1-9 days) 100% no Diffuse 48 of 48 biallelic LGA, AGA, SGA 5 large, appropriate, small for gestational age.
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ABCC8 p.Gln474Arg 21536946:148:48
status: NEW189 The important distinction between dominant and recessive missense mutations of the ABCC8 gene that cause hyperinsulinism appears to be whether they produce SUR1 subunits that can combine with Kir6.2 and then be trafficked to the TABLE 2 Mutant protein biogenesis and activity Surface expression (% of wild-type channel level) MgADP stimulation (% current in 0.1 mmol/L ATP plus 0.5 mmol/L ADP) Diazoxide stimulation (% current in 0.1 mmol/L ATP plus 0.2 mmol/L diazoxide) Mutation 1) Q474R 119.12 6 13.87 3.16 6 1.34 (n = 3) 2.03 6 0.77 (n = 3) 2) A478D 83.67 6 5.33 0.69 6 0.27 (n = 6) 3.14 6 1.37 (n = 3) 3) V715A 83.00 6 5.29 0.53 6 0.28 (n = 3) 1.73 6 0.53 (n = 4) 4) V715G 96.33 6 3.18 0.28 6 0.16 (n = 3) 2.35 6 1.99 (n = 3) 5) G716D 66.67 6 5.24 2.39 6 1.90 (n = 6) 2.37 6 1.32 (n = 4) 6) T888P 54.33 6 5.33 0.38 6 0.30 (n = 3) 1.30 6 0.44 (n = 3) 7) G1384E 101.80 6 8.50 0.17 6 0.09 (n = 4) 1.64 6 0.49 (n = 4) 8) S1387F 83.91 6 5.30 0.84 6 0.17 (n = 4) 4.05 6 1.34 (n = 4) 9) S1387Y 83.13 6 5.38 2.46 6 0.96 (n = 4) 2.44 6 0.42 (n = 4) 10) S1389Y 70.00 6 7.81 1.26 6 0.73 (n = 4) 1.65 + 0.63 (n = 3) 11) A1458T 94.33 6 10.48 0.52 6 0.21 (n = 3) 1.06 6 0.37 (n = 3) 12) Q1459H 91.00 6 2.31 0.69 6 0.39 (n = 3) 1.32 6 0.29 (n = 3) 13) E1517K 72.88 6 5.85 1.73 6 0.39 (n = 3) 1.96 6 0.55 (n = 4) Mean of dominant diazoxide-unresponsive SUR1 mutations 84.6 6 4.64 (n = 13) 1.42 6 0.35 (n = 13)* 1.83 6 0.18 (n = 13)† Mean of dominant diazoxide-responsive SUR1 mutations 93.68 6 5.07 (n = 10) 14.52 6 5.15 (n = 10) 18.33 6 6.06 (n = 10) Wild type 100 61.19 6 5.53 (n = 11) 77.8 6 2.2 (n = 9) Data are means 6 SE.
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ABCC8 p.Gln474Arg 21536946:189:484
status: NEW[hide] Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A... Endocr J. 2014;61(9):901-10. Epub 2014 Jul 8. Sang Y, Xu Z, Liu M, Yan J, Wu Y, Zhu C, Ni G
Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A and GCK genes in 30 Chinese patients with congenital hyperinsulinism.
Endocr J. 2014;61(9):901-10. Epub 2014 Jul 8., [PMID:25008049]
Abstract [show]
We conducted a cohort study to elucidate the molecular spectrum of congenital hyperinsulinism (CHI) in Chinese pediatric patients. Thirty Chinese children with CHI were chosen as research subjects, 16 of whom were responsive to diazoxide and 13 of whom were not (1 patient was not given the drug for medical reasons). All exons of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) genes KCNJ11 and ABCC8, the hepatocyte nuclear factor 4 alpha (HNF4A) gene, and the Glucokinase (GCK) gene as well as exons 6 and 7 and 10-12 of the glutamate dehydrogenase 1 (GLUD1) gene were amplified from genomic DNA and directly sequenced. Mutations were identified in 14 of 30 patients (47%): 3 in GLUD1 (10%) and 11 in the KATP channel genes (37%). Six patients had paternally derived monoallelic KATP channel mutations predictive of the focal CHI form. We found a novel de novo ABCC8 mutation, p. C1000*, a novel paternally inherited ABCC8 mutation, D1505H, and a dominantly inherited ABCC8 mutation, R1217K. The GLUD1 activating mutation R269H was found in 2 patients: 1 de novo and the other paternally inherited. A de novo S445L mutation was found in 1 patient. No significant HNF4A or GCK mutations were found. CHI has complex genetic onset mechanisms. Paternally inherited monoallelic mutations of ABCC8 and KCNJ11 are likely the main causes of KATP-CHI in Chinese patients. Glutamate dehydrogenase-CHI is the second most common cause of CHI, while HNF4A and GCK are rare types of CHI in Chinese patients.
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No. Sentence Comment
63 A paternally inherited mutation, p.C1000*, was found in patient 21 (Supplementary Fig. 1D), whereas the de novo mutations D1505H, Q474R and p.R598* were found in patient 22 (Supplementary Fig. 1E), 26 (Supplementary Fig. 1F) and 30 (Supplementary Fig. 1G), respectively.
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ABCC8 p.Gln474Arg 25008049:63:130
status: NEW76 Parent of origin Mutations 1* F 1 4.7 2.02 14.33 38 N N N P629PfsX17 Parental ABCC8 -C1887delc 2 M 3 3.5 1.52 17.4 128 N - - - - - 3 M 1 5.2 2.45 16.69 29 N - - - - - 4* M 1 4.4 2.54 34.96 128 N N N p.W288* Paternal ABCC8 -c.863G>A 5* F 165 4.2 1.8 9 77 N N Y A640V De Novo ABCC8 -c.1919C>T p.Q1196* Paternal ABCC8 -c.3286C>T 6* M 180 3.6 1.45 10.47 111 Y Y Y R269H De Novo GLUD1 -c.978G>A 7 M 76 4.2 1.8 43.51 95 N - - - - - 8 F 120 4.3 2.4 9.65 31 N - - - - - 9 F 2 2.3 1.6 5.34 47 N - - - - - 10 M 180 2.7 1.37 17.45 22 Y - - - - - 11 M 120 3.5 2.29 16.92 17 Y - - - - - 12* M 240 3.5 2.17 8.1 88 Y Y Y S445L De NovoGLUD1 -c.1506C>T 13* M 150 3.2 1.9 8.7 175 Y Y Y R269H Paternal GLUD1 -c.978G>A 14* F 1 4.2 2.01 9.18 44 Y N Y R1217K MaternalABCC8 -c.3650G>A 15* F 120 3.6 1.82 0.87 31 Y Y N R1493Q Paternal ABCC8 -C4487G>A 16* M 45 4.2 1.7 17.4 44 N Y N Q235E Paternal KCNJ11 -C703C>G 17 F 1 4.9 3.43 10.9 35 Y - - - - - 18 M 120 2.8 0.79 16.54 41 Y - - - - - 19 M 90 2.9 2.42 8.3 58 Y - - - - - 20* M 330 3.2 2.5 12.8 175 Not Used N Not Used R495Q Paternal ABCC8 -c.1484G>A 21* M 80 3.4 0.67 3.1 36 N Y N p.C1000* Paternal ABCC8 -c.3000C>A 22* F 1 5.28 1.04 22.94 46 N Y N D1505H De NovoABCC8 -c.4513G>C 23 F 240 3.25 2.24 4.69 26 Y - - - - - 24 M 240 3.5 1.9 12.96 31 Y - - - - - 25 F 1 3.6 1.06 30.8 54 Y - - - - - 26* F 2 4.5 1.5 8.8 38 N Y N Q474R De NovoABCC8 -c.1421A>G 27 F 30 3.5 1.03 10.37 27 Y - - - - - 28 M 120 5.45 1.36 11.48 48 N - - - - - 29 M 720 4.3 2.2 8.3 21 Y - - - - - 30* F 1 4.05 1.96 1.41 62 N Y N p.R598* De Novo ABCC8 -c.1792C>T * Patients with mutation results mutation in KCNJ11.
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ABCC8 p.Gln474Arg 25008049:76:1351
status: NEW109 In addition, 3 patients were found to carry de novo ABCC8 mutations, D1505H, Q474R and p.R598*.
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ABCC8 p.Gln474Arg 25008049:109:77
status: NEW145 A) Patient 5 showed a c.4487 G>A mutation (R1493Q); B) patient 20 showed a c.1484 G>A mutation (R495Q); C) patient 14 showed a c.3650G>A mutation (R1217K); D) patient 21 showed a c.3000C>A mutation (p.C1000*); E) patient 22 showed a c.4513G>C mutation (D1505H); F) patient 26 showed a c.1421A>G mutation (Q474R); G) patient 30 showed a c.1792C>T mutation (p.R598*).
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ABCC8 p.Gln474Arg 25008049:145:305
status: NEW