ABCMdb

ABCB4 p.Glu604Gln

Predicted by SNAP2:	A: N (82%), C: N (57%), D: N (97%), F: D (63%), G: N (78%), H: N (93%), I: D (59%), K: N (87%), L: D (63%), M: D (53%), N: N (61%), P: D (80%), Q: N (93%), R: N (78%), S: N (93%), T: N (53%), V: N (57%), W: D (66%), Y: D (53%),
Predicted by PROVEAN:	A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: D, S: N, T: D, V: D, W: D, Y: D,

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[hide] Significant association of ABCG5 604Q and ABCG8 D1... Br J Surg. 2008 Aug;95(8):1005-11. Kuo KK, Shin SJ, Chen ZC, Yang YH, Yang JF, Hsiao PJ
Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease.
Br J Surg. 2008 Aug;95(8):1005-11., [PMID:18457353]

Abstract [show]
BACKGROUND: Adenosine triphosphate-binding cassette (ABC) transporters ABCG5 and ABCG8 are sterol export pumps regulating biliary cholesterol excretion. The formation of gallstones, supersaturated with cholesterol in bile, is determined by genetic and environmental factors. The interaction of susceptible gene polymorphisms with age, sex and body mass index in gallstone disease is unclear. METHODS: In a cross-sectional study, 979 subjects (880 men and 99 women, mean(s.d.) age 47.7(10.4) years) were recruited from a hospital-based population. Of these, 74 were diagnosed with gallstone disease by abdominal ultrasonography. Five non-synonymous polymorphisms, E604Q (ABCG5), D19H, C54Y, T400K and A632V (ABCG8), were analysed using the TaqMan genotyping assay. RESULTS: The serum total cholesterol and both low- and high-density lipoprotein cholesterol levels were significantly lower in subjects with gallstones than in those without. 604Q (CC) and D19H (GC) genotypes were significantly associated with gallstone disease, even when adjusted for age, sex and body mass index. The genetic risk of developing gallstone disease was further stratified by age. The risk was greatly increased in subjects younger than 50 years with the D19H genotype and those of 50 years or more with the 604Q genotype. CONCLUSION: Carriers of ABCG5 604Q or ABCG8 D19H polymorphisms have an increased risk of gallstone disease independent of age, sex and body mass index.

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No. Sentence Comment
26 In previous studies, five non-synonymous polymorphisms in ABCG5 (E604Q) and ABCG8 (C54Y, D19H, T400K, A632V) have been linked to cholesterol homeostasis, especially in cholesterol absorption efficiency and cholesterol saturation of bile. Login to comment
44 Relevant non-synonymous polymorphisms of ABCG5 (E604Q) and ABCG8 (C54Y, D19H, T400K, A632V) associated with biliary cholesterol secretion were chosen for this study. Login to comment
46 The specific primers were designed using Primer 3 software according to SNP reference of GenBank mapping in the National Center for Biotechnology Information database (rs6720173 for E604Q, rs11887534 for D19H, rs4148211 for C54Y, rs4148217 for T400K, rs6544718 for A632V). Login to comment
56 Binary logistic regression gave odds ratios of having gallstones under the influence of genotypes E604Q (CC versus GG + GC), D19H (GC versus GG) and C54Y (AA versus GG + GA). Login to comment
57 For the crude odds ratio, the presence or absence of gallstones was the dependent variable, and the E604Q, D19H or C54Y genotype was the independent variable. Login to comment
67 Table 2 shows allele frequencies of the five nonsynonymous polymorphisms (ABCG5: E604Q; ABCG8: D19H, C54Y, T400K, A632V). Login to comment
75 There was a significant correlation of gallstone disease with the genotype distribution of E604Q, D19H and C54Y polymorphisms. Login to comment
76 The minor alleles of E604Q, D19H and C54Y polymorphisms were overexpressed in patients with gallstones compared with controls. Login to comment
77 For example, in the E604Q polymorphism, the frequency of the CC genotype was 4 per cent in the gallstone group compared with 0·7 per cent in the stone-free group, and the frequency of the D19H (GC) variant was 8 per cent in the gallstone group compared with 2·1 per cent in the group without gallstones. Login to comment
83 *Two-sample Student`s t test, except †Pearson χ2 test. Table 2 Allele frequencies of the polymorphisms in ABCG5 and ABCG8 genes in 979 subjects Gene Allele NCBI SNP reference Ratio Frequency (%) ABCG5: E604Q G1810C rs 6720173 G : C 89·5 : 10·5 ABCG8: D19H G55C rs 11887534 G : C 98·6 : 1·4 ABCG8: C54Y G161A rs 4148211 G : A 90·3 : 9·7 ABCG8: T400K C1199A rs 4148217 C : A 92·0 : 8·0 ABCG8: A632V T1895C rs 6544718 T : C 0 : 100 NCBI, National Center for Biotechnology Information; SNP, single nucleotide polymorphism. Login to comment
84 Table 3 Association of genotype frequency of ABCG5 and ABCG8 with gallstone development No stones (n = 905) Gallstones (n = 74) P* Power (%) ABCG5: E604Q (G1810C) Genotype GG 691 (79·2) 52 (74) 0·011 18 GC 175 (20·1) 15 (21) CC 6 (0·7) 3 (4) ABCG8: D19H (G55C) Genotype GG 851 (97·9) 66 (92) 0·001 79 GC 18 (2·1) 6 (8) ABCG8: C54Y (G161A) Genotype GG 747 (82·5) 54 (73) 0·041 53 GA 152 (16·8) 18 (24) AA 6 (0·7) 2 (3) ABCG8: T400K (C1199A) Genotype CC 739 (84·5) 58 (79) 0·463 22 CA 134 (15·3) 15 (21) AA 2 (0·2) 0 (0) Values in parentheses are percentages. Login to comment
85 *Pearson χ2 test. Table 4 Gallstone risk associated with ABCG5 and ABCG8 polymorphisms Genotype Crude odds ratio P† Adjusted odds ratio* P† E604Q GG + GC 1·0 CC 6·5 (1·6, 26·4) 0·009 4·7 (1·1, 21·1) 0·042 D19H GG 1·0 GC 4·3 (1·7, 11·2) 0·003 3·5 (1·2, 9·6) 0·018 C54Y GG + GA 1·0 AA 4·1 (0·8, 20·9) 0·085 3·2 (0·6, 17·3) 0·170 Values in parentheses are 95 per cent confidence intervals. Login to comment
95 Discussion This study found a significant correlation between the distribution of E604Q and D19H (GC) polymorphisms and gallstone disease in the Taiwanese population. Login to comment
98 The study also found that serum levels of total Table 5 Gallstone risk associated with ABCG5 and ABCG8 polymorphisms stratified by age Age < 50 years Age ≥ 50 years Genotype Crude odds ratio P‡ Adjusted odds ratio* P‡ Crude odds ratio P‡ Adjusted odds ratio* P‡ E604Q GG + GC 1·0 CC† 6·0 (1·3, 27·7) 0·022 6·4 (1·3, 30·7) 0·020 D19H GG 1·0 1·0 GC 6·4 (1·3, 32·7) 0·025 12·4 (1·7, 90·0) 0·013 2·8 (0·9, 9·2) 0·088 2·5 (0·8, 8·6) 0·133 Values in parentheses are 95 per cent confidence intervals. Login to comment
78 For further analysis of the odds ratios of minor genotypes with gallstone disease, carriers of GG and GC genotypes of E604Q and those of GG and GA genotypes of C54Y were combined. Login to comment

[hide] Mutational analysis of conserved carboxylate resid... Biochemistry. 2000 Nov 21;39(46):14138-49. Urbatsch IL, Julien M, Carrier I, Rousseau ME, Cayrol R, Gros P
Mutational analysis of conserved carboxylate residues in the nucleotide binding sites of P-glycoprotein.
Biochemistry. 2000 Nov 21;39(46):14138-49., [PMID:11087362]

Abstract [show]
Mutagenesis was used to investigate the functional role of six pairs of aspartate and glutamate residues (D450/D1093, E482/E1125, E552/E1197, D558/D1203, D592/D1237, and E604/E1249) that are highly conserved in the nucleotide binding sites of P-glycoprotein (Mdr3) and of other ABC transporters. Removal of the charge in E552Q/E1197Q and D558N/D1203N produced proteins with severely impaired biological activity when the proteins were analyzed in yeast cells for cellular resistance to FK506 and restoration of mating in a ste6Delta mutant. Mutations at other acidic residues had no apparent effect in the same assays. These four mutants were expressed in Pichia pastoris, purified to homogeneity, and biochemically characterized with respect to ATPase activity. Studies with purified proteins showed that mutants D558N and D1203N retained 14 and 30% of the drug-stimulated ATPase activity of wild-type (WT) Mdr3, respectively, and vanadate trapping of 8-azido[alpha-(32)P]nucleotide confirmed slower basal and drug-stimulated 8-azido-ATP hydrolysis compared to that for WT Mdr3. The E552Q and E1197Q mutants showed no drug-stimulated ATPase activity. Surprisingly, drugs did stimulate vanadate trapping of 8-azido[alpha-(32)P]nucleotide in E552Q and E1197Q at a level similar to that of WT Mdr3. This suggests that formation of the catalytic transition state can occur in these mutants, and that the bond between the beta- and gamma-phosphates is hydrolyzed. In addition, photolabeling by 8-azido[alpha-(32)P]nucleotide in the presence or absence of drug was also detected in the absence of vanadate in these mutants. These results suggest that steps after the transition state, possibly involved in release of MgADP, are severely impaired in these mutant enzymes.

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No. Sentence Comment
63 A similar strategy was used to create mutants D592N and E604Q. Login to comment
137 Single-point mutations D450N, E482Q, E552Q, D558N, D592N, and E604Q were introduced into the NB1 of Mdr3, and mutations D1093N, E1125Q, E1197Q, D1203N, D1237N, and E1249Q were introduced independently into the NB2. Login to comment
153 Cells expressing WT Mdr3 or the NB1 mutants D450N, E482Q, D592N, and E604Q (Figure 3A) or their NB2 counterparts D1093N, E1125Q, D1237N, and E1249Q (Figure 3B) were all resistant to FK506. Login to comment
169 Mating frequencies of mutants D450N (104%), E482Q (127%), D592N (22%), and E604Q (85%) in NB1 (Figure 4) or their counterparts D1093N (72%), E1125Q (101%), D1237N (68%), and E1249Q (118%) in NB2 (Figure 4) were similar to that of the Mdr3 WT control. Login to comment
259 Single-point mutations D450N, E482Q, D592N, and E604Q were introduced in NB1 and their homologous substitutions D1093N, E1125Q, D1237N, and E1249Q created in NB2, and the mutants were transformed in the yeast S. cereVisiae to assess their biological activity. Login to comment