ABCC8 p.Arg1493Gln
| Predicted by SNAP2: | A: D (91%), C: D (85%), D: D (95%), E: D (91%), F: D (95%), G: D (91%), H: D (85%), I: D (91%), K: D (80%), L: D (91%), M: D (91%), N: D (85%), P: D (91%), Q: D (85%), S: D (85%), T: D (85%), V: D (91%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Functional hot spots in human ATP-binding cassette... Protein Sci. 2010 Nov;19(11):2110-21. Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, Sali A
Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
Protein Sci. 2010 Nov;19(11):2110-21., [PMID:20799350]
Abstract [show]
The human ATP-binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small alpha-helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease-associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.
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No. Sentence Comment
50 Disease-associated nsSNPs at Three Structural Hotspots in Human ABC Transporter NBDs Gene Disease Position ARA motif ABCB11 BRIC2 A570T ABCD1 X-ALD A616V CFTR CF A559T ABCC6 PXE R765Q ABCC8 HHF1 R841G ABCC8 HHF1 R1493Q ABCC8 HHF1 R1493W ABCD1 X-ALD R617C ABCD1 X-ALD R617G ABCD1 X-ALD R617H CFTR CF R560K CFTR CF R560S CFTR CF R560T ABCA1 HDLD1 A1046D ABCB4 ICP A546D C-loop 1 motif ABCC8 HHF1 D1471H ABCC8 HHF1 D1471N CFTR CBAVD G544V ABCC8 HHF1 G1478R C-loop2 motif ABCA4 STGD1 H2128R ABCC8 HHF1 K889T ABCD1 X-ALD R660P ABCD1 X-ALD R660W ABCA1 HDLD2 M1091T ABCA4 STGD1 E2131K ABCA12 LI2 E1539K ABCA4 STGD1 and CORD3 E1122K CFTR CF L610S ABCC8 HHF1 L1543P ABCA1 Colorectal cancer sample; somatic mutation A2109T ABCC9 CMD1O A1513T ABCD1 X-ALD H667D CFTR CF A613T ABCA1 HDLD2 D1099Y ABCD1 X-ALD T668I CFTR CF D614G ABCA4 STGD1 R2139W ABCA4 STGD1 R1129C ABCA4 ARMD2, STGD1, and FFM R1129L Disease abbreviations are as follows: BRIC2, benign recurrent intrahepatic cholestasis type 2; X-ALD, X-linked adrenoleukodystrophy; CF, cystic fibrosis; PXE, Pseudoxanthoma elasticum; HHF1, familial hyperinsulinemic hypoglycemia-1; HDLD1, high density lipoprotein deficiency type 1; ICP, intrahepatic cholestasis of pregnancy; CBAVD, congenital bilateral absence of the vas deferens; STGD1, Stargardt disease type 1; HDLD2, high density lipoprotein deficiency type 2; LI2, ichthyosis lamellar type 2; CORD3, cone-rod dystrophy type 3; CMD1O, cardiomyopathy dilated type 1O; ARMD2, age-related macular degeneration type 2; FFM, fundus flavimaculatus.
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ABCC8 p.Arg1493Gln 20799350:50:212
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
60 Patients 15 and 20 carry mutations in R1493Q and R495Q mutations, respectively (Supplementary Fig. 1A and 1B, respectively).
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ABCC8 p.Arg1493Gln 25008049:60:38
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.Arg1493Gln 25008049:76:795
status: NEW107 Five patients carried paternally inherited ABCC8 mutations including P629PfsX17, p.W288*, R495Q, R1493Q and p.C1000*.
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ABCC8 p.Arg1493Gln 25008049:107:97
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.Arg1493Gln 25008049:145:43
status: NEW