ABCMdb

PMID: 22132963

Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Takada Y, Okada C, Sakurai Y, Hosoya T, Kanai Y, Suzuki H, Shinomiya N
Identification of ABCG2 dysfunction as a major factor contributing to gout.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1098-104., [PubMed]

Sentences

No. Mutations Sentence Comment

16 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Login to comment 17 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Login to comment 18 ABCG2 p.Gln141Lys ABCG2 p.Gln126* As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. Login to comment 36 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment 45 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg The following six non-synonymous mutations, V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, were found (Figure 1A), and the first three mutations were SNPs. Login to comment 46 ABCG2 p.Gln141Lys Maekawa et al.[5] reported that allele frequencies for these SNPs, which are quite common in the Japanese population, were 31.9% for Q141K, 19.2% for FIGURE 1 Non-synonymous ABCG2 mutations in hyperuricemia patients. Login to comment 49 ABCG2 p.Val12Met ABCG2 p.Gln126* Results are expressed as means ± SD. V12M, and 2.8% for Q126X. Login to comment 50 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Gln126* With the Hardy-Weinberg equilibrium and the data reported by Maekawa et al. of the Japanese population,[5] we calculated estimates of the minor allele frequencies of Japanese individuals to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment 52 ABCG2 p.Gln141Lys ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg The ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X, G268R, S441N, and F506SfsX4 mutants (Figure 1B). Login to comment 53 ABCG2 p.Val12Met The V12M variant did not show any changes in urate transport relative to wild-type ABCG2. Login to comment 54 ABCG2 p.Gln126* Additional genotyping of ABCG2 SNPs was performed for 228 Japanese men with hyperuricemia (including 161 men with gout) and identified Q126X homozygous (N = 2) and heterozygous (N = 24) mutations. Login to comment 55 ABCG2 p.Gln126* Two patients with Q126X homozygous mutations showed very high SUA (>10 mg/dl) before they were treated for hyperuricemia. Login to comment 56 ABCG2 p.Gln141Lys ABCG2 p.Gln126* A total of 871 TABLE 1 Association analysis of ABCG2 genotype combination in gout patients Genotype Number Estimated transport Q126X Q141K Gout Control p value OR* 95% CI* ≤1/4 function T/T C/C 16 8 3.39 × 10-21 25.8 10.3-64.6 T/C A/C - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1/2 function T/C C/C 37 110 2.23 × 10-9 4.34 2.61-7.24 C/C A/A - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3/4 function C/C A/C 72 308 2.29 × 10-7 3.02 1.96-4.65 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Full function C/C C/C 34 439 1.00 *OR = odds ratio; 95% CI = 95% confidence interval. Login to comment 57 ABCG2 p.Gln141Lys ABCG2 p.Gln126* OR is obtained by comparing the non-risk genotype combination C/C (Q126X) and C/C (Q141K). Login to comment 58 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Risk alleles for Q126X and Q141K are underlined. Login to comment 60 ABCG2 p.Gln126* The association study showed that the risk of hyperuricemia was increased by Q126X (odds ratio [OR], 3.61; 95% confidence interval [CI], 2.14-6.08; p = 2.91 × 10-7 ). Login to comment 61 ABCG2 p.Gln126* ABCG2 p.Gln126* There were Q126X homozygous (N = 1) and heterozygous (N = 21) mutations among the 161 patients with gout, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; p = 3.04 × 10-8 ). Login to comment 62 ABCG2 p.Gln141Lys The half-functional SNP Q141K also increased gout (OR, 2.23; 95% CI, 1.75-2.87; p = 5.54 × 10-11 ). Login to comment 63 ABCG2 p.Gln141Lys ABCG2 p.Gln126* The haplotype frequency analysis revealed no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype. Login to comment 64 ABCG2 p.Gln126* The haplotype with Q126X was present in up to 13.5% of gout patients, and markedly increased gout risk (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) compared with non-risk haplotypes. Login to comment 65 ABCG2 p.Gln126* Our data also revealed enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment 66 ABCG2 p.Gln126* Thus, the Q126X mutation of the ABCG2 gene is identified as a major contributing factor in Japanese gout patients. Login to comment 67 ABCG2 p.Gln126* Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment 68 ABCG2 p.Val12Met ABCG2 p.Val12Met Our findings showed that V12M is exclusively assigned to a non-risk haplotype and that the V12M variant does not exhibit altered urate transport activity (Figure 1B). Login to comment 69 ABCG2 p.Val12Met These findings may help explain why V12M decreases gout risk (OR, 0.68; 95% CI, 0.49-0.94; p = 0.02). Login to comment 70 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Because the nonfunctional variant Q126X and half-functional variant Q141K are assigned to different risk haplotypes, their genotype combinations are divided into four functional groups on the basis of the estimated ABCG2 transport functions, i.e., full function, 3/4 function, 1/2 function, and ≤1/4 function (Table 1). Login to comment 79 ABCG2 p.Gln126* We also demonstrated that the nonfunctional ABCG2 variant Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment 83 ABCG2 p.Gln126* Our approach reported here revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment 84 ABCG2 p.Gln126* ABCG2 p.Gln126* The disease haplotype with the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) is present in up to 13.5% of primary gout patients in our population, suggesting that Q126X may well be a major causative mutation for gout. Login to comment 91 ABCG2 p.Gln141Lys They also found that Q141K was associated with self-reported gout in Caucasians (OR, 1.74; 95% CI, 1.51-1.99), which is consistent with our findings from clinically diagnosed Japanese gout patients. Login to comment 92 ABCG2 p.Gln141Lys A meta-analysis of GWAS in European descent also revealed that the nine loci, including GLUT9 and ABCG2, influence SUA, which confirms the findings of Dehghan et al.[3] The authors[6] and Woodward et al.[7] independently found a urate transport ability via ABCG2 to transport urate and characterized the effects of dysfunctional variant Q141K using different methods. Login to comment 93 ABCG2 p.Gln141Lys ABCG2 p.Gln126* In our study, we also identified several nonfunctional ABCG2 mutations including Q126X which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0). Login to comment 94 ABCG2 p.Gln126* [3] There is a possibility that these dysfunctional mutations, including Q126X, are specific to the Japanese or Asian population, or alternatively, there may be nonfunctional mutations in the ABCG2 gene that increase the incidence of gout in Caucasians and other groups. Login to comment