ABCMdb

PMID: 24287461

Ishikawa T, Aw W, Kaneko K
Metabolic Interactions of Purine Derivatives with Human ABC Transporter ABCG2: Genetic Testing to Assess Gout Risk.
Pharmaceuticals (Basel). 2013 Nov 4;6(11):1347-60. doi: 10.3390/ph6111347., [PubMed]

Sentences

No. Mutations Sentence Comment

81 ABCG2 p.Gln141Lys The SNP 421C>A is a non-synonymous polymorphism that leads to amino acid substitution; Gln to Lys (Q141K) in the intracellular loop containing an ATP-binding cassette (ABC). Login to comment 82 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys 608 592 603 592 Extracellular loop Outside Inside Plasma membrane 596 N-linked glycan Asn Cys ATP-binding cassette (ABC) Q141K Q141K 608 592 603 592 Extracellular loop Outside Inside Plasma membrane 596 N-linked glycan Asn Cys ATP-binding cassette (ABC) 608 592 603 592 Extracellular loop Outside Inside Plasma membrane 596 N-linked glycan Asn Cys 608 592 603 592 Extracellular loop Outside Inside Plasma membrane 596 N-linked glycan Asn Cys N-linked glycan Asn Cys ATP-binding cassette (ABC) Q141K Q141K ABCG2 expressed on the apical side of the proximal tubular cells in human kidney plays a pivotal role in renal excretion of serum uric acid. Login to comment 83 ABCG2 p.Gln141Lys Introduction of the mutation Q141K encoded by the common SNP (rs2231142) by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (p < 0.001). Login to comment 84 ABCG2 p.Gln141Lys The expression levels of the Q141K variant are reduced by ubiquitin-mediated proteasomal degradation [31-34] (Figure 5). Login to comment 85 ABCG2 p.Gln141Lys Thus, renal excretion of serum uric acid via ABCG2 is impaired in persons who are carrying the 421A allele (Q141K variant). Login to comment 88 ABCG2 p.Gln141Lys Effect of the SNP variant (Q141K) on the protein expression level and degradation of ABCG2. Login to comment 90 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys To assess the effect of Q141K variant on the protein expression level, Flp-In-293 cells expressing WT and the Q141K variant were incubated in the absence or presence of MG132 (2 bc;M) for 24 h. ABCG2 WT and Q141 variant proteins were analyzed by immunoblotting with the ABCG2-specific monoclonal antibody (BXP-21) after PNGase F treatment. Login to comment 94 ABCG2 p.Gln141Lys (B) Correctly processed ABCG2 WT protein is destined to reach the plasma membrane and is then degraded by the endosome-lysosome pathway after remaining in the plasma membrane domain for a certain period. In contrast, the ABCG2 Q141K variant protein is recognized as a misfolded form and then undergoes ubiquitination-mediated proteasomal degradation. Bafilomycin A1 (BMA) and MG132 inhibit lysosomal and proteasomal degradation, respectively. Login to comment 95 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Golgi Endosome ER Plasma membrane Folded ABCG2 Mature ABCG2 ATP ATP N N N C C Misfolded ABCG2 E3 E3 Ubiquitin Ubiquitin ligase Proteasome MG132 Cis Medial Trans CNX PDI Dol-P-P- Dol-P-P- BiP Chaperone proteins Ribosomes ERGIC Lysosome BMA H+ H+ Control MG132 Relative expression level 0 0.5 1.0 Lys141 (Q141K) Gln141 (WT) * Control MG132 Relative expression level 0 0.5 1.0 Lys141 (Q141K) Gln141 (WT) * A B 6. Login to comment 108 ABCG2 p.Gln141Lys The allele frequencies of 421C (WT) and 421A (Q141K) among different ethnic populations. Login to comment 110 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys 0 0.2 0.4 0.6 0.8 1 African African-American Mexican-American Caucasian Japanese Chinese ABCG2 allele frequency 421C (WT) 421A (Q141K) 0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 - - 0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 African African-American Mexican-American Caucasian Japanese Chinese ABCG2 allele frequency 421C (WT) 421A (Q141K) 0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 - - An investigation of the expression level of ABCG2 in 99 Japanese placenta samples revealed that individuals homozygous for the Q141K variant showed significantly lower expression levels of this transporter protein, while the heterozygous samples displayed intermediate expression levels [44]. Login to comment 111 ABCG2 p.Gln141Lys Based on those observations, it is assumed that the protein stability of the Q141K variant is significantly reduced without showing significant changes in its mRNA levels. Login to comment 112 ABCG2 p.Gln141Lys Evidence has been provided to show that the Q141K variant of ABCG2 is degraded via ubiquitin-mediated proteasomal degradation [31-35]. Login to comment 113 ABCG2 p.Gln141Lys The level of the Q141K variant protein could be recovered when proteosomal degradation was inhibited by MG132 in vitro (Figure 5A). Login to comment 114 ABCG2 p.Gln141Lys The Q141K mutation does not interfere with the nucleotide-binding domain/intracellular loop interactions but greatly affect the protein-protein interactions necessary for the dimerization of ABCG2. Login to comment 116 ABCG2 p.Gln141Lys In addition to the Q141K variant, a minor SNP in exon 4, 376C>T, substituting a stop codon for Gln126, was found in the Japanese population with an allele frequency of 2.4% [37]. Login to comment 118 ABCG2 p.Gln126* The variant Q126stop (376C>T) was consistently observed in certain Japanese cohorts; however, it was absent in Caucasian and African-American groups [39,41,44]. Login to comment 119 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Matsuo et al. [4] reported that the genotype combinations of Q126stop and Q141K are clinically important biomarkers to predict the possible risk of gout in the Japanese population. Login to comment 123 ABCG2 p.Gln141Lys Their data suggest that at least 10% of all gout cases in Caucasians are attributable to SNP 421C>A (Q141K). Login to comment