ABCC4 p.Arg531Gln
| Predicted by SNAP2: | A: D (71%), C: D (66%), D: D (91%), E: D (85%), F: D (80%), G: D (59%), H: N (72%), I: D (75%), K: N (61%), L: D (75%), M: D (66%), N: D (75%), P: D (91%), Q: D (71%), S: D (80%), T: D (80%), V: D (75%), W: D (85%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, 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] Pharmacogenomics of MRP transporters (ABCC1-5) and... Drug Metab Rev. 2008;40(2):317-54. Gradhand U, Kim RB
Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2).
Drug Metab Rev. 2008;40(2):317-54., [PMID:18464048]
Abstract [show]
Elucidation of the key mechanisms that confer interindividual differences in drug response remains an important focus of drug disposition and clinical pharmacology research. We now know both environmental and host genetic factors contribute to the apparent variability in drug efficacy or in some cases, toxicity. In addition to the widely studied and recognized genes involved in the metabolism of drugs in clinical use today, we now recognize that membrane-bound proteins, broadly referred to as transporters, may be equally as important to the disposition of a substrate drug, and that genetic variation in drug transporter genes may be a major contributor of the apparent intersubject variation in drug response, both in terms of attained plasma and tissue drug level at target sites of action. Of particular relevance to drug disposition are members of the ATP Binding Cassette (ABC) superfamily of efflux transporters. In this review a comprehensive assessment and annotation of recent findings in relation to genetic variation in the Multidrug Resistance Proteins 1-5 (ABCC1-5) and Breast Cancer Resistance Protein (ABCG2) are described, with particular emphasis on the impact of such transporter genetic variation to drug disposition or efficacy.
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191 MRP4 protein has been detected in human kidney (van Aubel et al., 2002), lung (Torky et al., 2005), liver (Rius et al., 2003), prostate (Lee et al., 2000), brain (Nies et al., 2004), pancreas (König et al., 2005), lymphocytes (Schuetz et al., 1999), and platelets Figure 4 Predicted membrance topology of MRP4 (ABCC4) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 4 for allele frequencies and description of funtional consequences. NH2 COOH NBD NBD Val854Phe Ile18Leu Ile866Val Arg531Gln Tyr556Cys Thr1142Met Glu757Lys Val776Ile Gly187Trp Lys304Asn in out Membrane Cys171Gly Pro403Leu Lys498Glu Met744Val Met1272Val MRP4 (ABCC4) COOH NBD NBD Val854Phe Ile866Val Arg531Gln Tyr556Cys Thr1142Met Glu757Lys Val776Ile Gly187Trp Lys304AsnCys171Gly Pro403Leu Lys498Glu Met744Val Met1272Val COOH NBD NBD Val854Phe Ile866Val Arg531Gln Tyr556Cys Thr1142Met Glu757Lys Val776Ile Gly187Trp Lys304AsnCys171Gly Pro403Leu Lys498Glu Met744Val Met1272Val (Jedlitschky et al., 2004).
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ABCC4 p.Arg531Gln 18464048:191:554
status: NEWX
ABCC4 p.Arg531Gln 18464048:191:738
status: NEWX
ABCC4 p.Arg531Gln 18464048:191:892
status: NEW216 Polymorphisms in exons 1, 5, 12, 13, 19, 21, and 28 leading to the following amino acid exchanges Ile18Leu, Gly187Trp, Arg531Gln, Tyr556Cys, Val776Ile, Val854Phe, Ile866Val, and Thr1142Met were analysed in relation to expression and localization of MRP4 in human liver.
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ABCC4 p.Arg531Gln 18464048:216:119
status: NEW236 Following the discovery and Table 4 MRP4 (ABCC4) Single nucleotide polymorphisms. Location, allele frequency and functional effects. Position in coding sequence Amino acid exchange Location Allele frequency Effect NCBI ID ReferenceAf Ca Jp others 52A>C Ile18Leu Exon 1 - 1.1 [1] 0 [2] - No influence on expression and localization in liver [1] rs11568681 511T>G Cys171Gly Exon 4 - 0 [1] [2] - - rs4148460 559G>T Gly187Trp Exon 5 - 2.2 [1] 0 [2] - No influence on expression and localization in liver [1] rs11568658 912G>T Lys304Asn Exon 8 - 9.9 [1] [2] - No influence on expression and localization in liver [1] rs2274407 1208T>C Pro403Leu Exon 9 - - - - - rs11568705 1492A>G Lys498Glu Exon 11 - - - - - rs11568669 1592G>A Arg531Gln Exon 12 - 0.6 [1] 0 [2] - No influence on expression and localization in liver [1] 1667A>G Tyr556Cys Exon 13 - 0.6 [1] 0 [2] - No influence on expression and localization in liver [1] 2230A>G Met744Val Exon 18 - - - - - rs9282570 2269G>A Glu757Lys Exon 18 - 0.6 [1] [2] - No influence on expression and localization in liver [1] rs3765534 2326G>A Val776Ile Exon 19 - 0.6 [1] 0 [2] - No influence on expression and localization in liver [1] 2560G>T Val854Phe Exon 21 - 1.7 [1] 0 [2] - No influence on expression and localization in liver [1] rs11568694 2596A>G Ile866Val Exon 21 - 2.8 [1] 0 [2] - No influence on expression and localization in liver [1] 3425C>T Thr1142Met Exon 27 - 1.6 [1] 0 [2] - No influence on expression and localization in liver [1] rs11568644 3814A>G Met1272Val Exon 30 - - - - - rs1134217 Reference without frequency means that SNP was detected but no frequency determined.
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ABCC4 p.Arg531Gln 18464048:236:723
status: NEW[hide] 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl)... Hum Mutat. 2008 May;29(5):659-69. Janke D, Mehralivand S, Strand D, Godtel-Armbrust U, Habermeier A, Gradhand U, Fischer C, Toliat MR, Fritz P, Zanger UM, Schwab M, Fromm MF, Nurnberg P, Wojnowski L, Closs EI, Lang T
6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4.
Hum Mutat. 2008 May;29(5):659-69., [PMID:18300232]
Abstract [show]
Multiple drug resistance protein 4 (MRP4, ABCC4) belongs to the C subfamily of the ATP-binding cassette (ABC) transporter superfamily and participates in the transport of diverse antiviral and chemotherapeutic agents such as 6-mercaptopurine (6-MP) and 9-(2-phosphonyl methoxyethyl) adenine (PMEA). We have undertaken a comprehensive functional characterization of protein variants of MRP4 found in Caucasians and other ethnicities. A total of 11 MRP4 missense genetic variants (nonsynonymous SNPs), fused to green fluorescent protein (GFP), were examined in Xenopus laevis oocytes for their effect on expression, localization, and function of the transporter. Radiolabeled 6-MP and PMEA were chosen as transport substrates. All MRP4 protein variants were found to be expressed predominantly in the oocyte membrane. A total of four variants (Y556C, E757 K, V776I, and T1142 M) exhibited a 20% to 40% reduced expression level compared to the wild type. Efflux studies showed that 6-MP is transported by MRP4 in unmodified form. Compared to wild-type MRP4, the transmembrane variant V776I, revealed a significant lower activity in 6-MP transport, while the amino acid exchange Y556C in the Walker(B) motif displayed significantly higher transport of PMEA. The transport properties of the other variants were comparable to wild-type MRP4. Our study shows that Xenopus oocytes are well suited to characterize MRP4 and its protein variants. Carriers of the rare MRP4 variants Y556C and V776I may have altered disposition of MRP4 substrates.
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No. Sentence Comment
34 We also sequenced large regions of the MRP4 gene of these individuals and identified 74 genetic variations, among them 10 missense mutations (I18L, G187W, K304N, R531Q, Y556C, E757 K, V776I, V854F, I866 V, and T1142 M).
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ABCC4 p.Arg531Gln 18300232:34:162
status: NEW[hide] Variability in human hepatic MRP4 expression: infl... Pharmacogenomics J. 2008 Feb;8(1):42-52. Epub 2007 Apr 3. Gradhand U, Lang T, Schaeffeler E, Glaeser H, Tegude H, Klein K, Fritz P, Jedlitschky G, Kroemer HK, Bachmakov I, Anwald B, Kerb R, Zanger UM, Eichelbaum M, Schwab M, Fromm MF
Variability in human hepatic MRP4 expression: influence of cholestasis and genotype.
Pharmacogenomics J. 2008 Feb;8(1):42-52. Epub 2007 Apr 3., [PMID:17404579]
Abstract [show]
The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5'-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299+/-138 vs 100+/-60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.
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45 Table 2 Genetic variations identified in the MRP4 gene among 95 Caucasian individuals Variant ID Sequence context 50 Systematic name Sequence context 30 Genetic element Effect Frequency (%) Heterozygous Homozygous NCBI SNP ID HW HW 1 GAACTCCTGA g.-2174C4G GTCAGGTGAT Promoter 23.7 28.5 5.4 3.0 2 CACCTGCCTC g.-2152A4G GCCTCCCAGA Promoter 2.2 2.2 0.0 0.0 3 TGGGCTAAAG g.-2055C4A CATCCTCCTG Promoter 40.9 47.9 39.8 36.3 rs2389235 4 CTAAAGCCAT g.-2051C4T CTCCTGTCTC Promoter 38.7 45.1 46.2 43.0 rs1764419 5 ATTTTTAAAA g.-1980-1981insA CTTTTGGTAG Promoter 39.8 45.5 45.2 42.3 6 CACTATGCTG g.-1949G4C CTAGCCTGTG Promoter 1.1 1.1 0.0 0.0 7 CATCTATAAA g.-1508G4A TAAGGATAAC Promoter 12.6 11.8 0.0 0.4 rs868853 8 AAATTATCAG g.-1235T4C ATTTGAACTT Promoter 2.1 2.1 0.0 0.0 9 TACTTAAACT g.-1130G4A AGTTGGGAGG Promoter 42.4 46.3 15.2 13.3 rs2993579 10 CCATGGCACC g.-642G4C TCGTTTGGTC Promoter 41.9 46.7 41.9 39.6 rs869951,39 11 CGCGTCTCCT g.-289C4G CCGCCGCGTC Promoter 2.2 2.2 0.0 0.0 12 CCGCGGCCAC g.-49C4T GCCGCCTGAT 50 UTR/ Exon 1 1.1 1.1 0.0 0.0 rs3751333,39 13 TGCCCGTGTA g.15C4T CAGGAGGTGA Exon 1 synonymous 1.1 1.1 0.0 0.0 14 GGACGCGAAC g.52A4C TCTGCTCACG Exon 1 I18L 2.2 2.2 97.8 97.8 rs11568681 15 GGTGAGTGTC g.84C4T CCGCCCGAAA Intron 1 2.2 2.1 0.0 0.0 rs11568682 16 CACTCTCCCG g.138G4C GGCCGCGCCC Intron 1 1.1 1.0 0.0 0.0 17 ACCCATGGAG g.53498G4A TAGGAGTCTA Intron 1 46.7 47.4 15.2 14.9 rs9556466 18 TTTTTCCTCAT g.54215T4C GTAGGTTCTG Intron 2 46.7 47.0 14.4 14.3 rs4148437,39 19 AGCATGGGTG g.66387A4G CAGAGCAAGC Intron 3 11.9 11.2 0.0 0.4 39 20 GGTAAGTGAC g.66715A4G TTCAGCATTA Intron 4 2.2 2.2 0.0 0.0 rs11568637 21 CATGGCCATG g.90561G4T GGAAGACAAC Exon 5 G187W* 4.3 4.2 0.0 0.0 rs11568658 22 CACCCCTCTT g.90673T4C CCCCTTTTAT Intron 5 25.3 23.7 73.6 74.4 rs899496,39 23 TTTCTGGAGG g.90696C4T AGGGGCTCAC Intron 5 38.9 37.5 5.6 6.3 rs4148472,39 24 GCAGGGGCTC g.90705-90708delACTC TGTTCACACT Intron 5 44.9 47.7 38.2 36.8 rs3046400 25 TGTGTTCTTA g.91667C4T TGGTTTTGCT Intron 5 1.1 1.1 0.0 0.0 26 TGCAGGCGAT g.91765C4T GCAGTGACTG Exon 6 synonymous 19.4 19.2 1.1 1.2 rs899494,39 27 GTTGTCGGAA g.93281G4T CAAAAGCGCT Intron 6 43.5 41.5 48.9 49.9 rs2274410,39 28 GGCTGTGATC g.93355G4A CTCAGGCTCA Intron 6 15.2 17.7 2.2 1.0 rs2274409,39 29 CTCATCTCCC g.93372G4A TGTCTGGTTC Intron 6 2.2 2.2 0.0 0.0 rs11568683 30 AAGTTTTACT g.93595A4G TGTTTTCACA Intron 7 43.5 41.5 48.9 49.9 rs2274408,39 31 TCTCTTTCAG g.94534G4T AAGGAGATTT Exon 8 K304N 17.6 17.8 1.1 1.0 rs2274407,39 32 CCTGCCTCAG g.94573G4A GGGATGAATT Exon 8 synonymous 47.2 42.3 6.7 9.2 rs2274406,39 33 ATTTGGCTTC g.94591G4A TTTTTCAGTG Exon 8 synonymous 47.2 42.3 6.7 9.2 rs2274405,39 34 CAGGTTGGTG g.94791T4A CAGATGCCAT Intron 8 4.4 4.3 0.0 0.0 rs11568702 35 CACTATGTTC g.94865C4G AGTGTAATGA Intron 8 47.2 42.3 46.1 48.5 rs3818494,39 36 TGACATTTAA g.94883C4T TCTCTCATAA Intron 8 47.2 42.3 46.1 48.5 rs3818494,39 37 TAGAGAATTT g.106549T4C GAGGTGTTAC Intron 9 55.6 49.9 24.4 27.3 rs2274403,39 38 GCATTGCAGT g.114366G4A GCTTATTCTT Intron 10 9.8 9.3 0.0 0.2 rs4148487,39 39 CTCTGAAAAA g.114614G4A GTGAGTGATG Exon 11 synonymous 1.1 1.1 0.0 0.0 40 ATAGGAGATC g.123270G4A GGGAACCACG Exon 12 R531Q 1.1 1.1 0.0 0.0 41 GCTGACATCT g.123548A4G TCTCCTGGAC Exon 13 Y556C* 1.1 1.1 0.0 0.0 42 GAGGTCTCCC g.130808G4A AACTTGCAAG Intron 14 24.4 23.1 1.1 1.8 rs11568663 43 TGCCTGTTTC g.136709C4T CCACAGCTTT Intron 15 18.2 16.5 0.0 0.8 rs4148501,39 44 GTTTTCAGGC g.136862C4T TATAAGAATT Exon 16 synonymous 2.1 2.1 0.0 0.0 rs11568666 45 ATGTATGAAA g.137735T4C ACTCCAAAAT Intron 17 16.1 14.8 83.9 84.5 rs11568650 46 GGTTCATTTT g.138034T4C AAAAAAATGT Intron 17 20.7 20.3 1.1 1.3 39 47 AAATGTAACC g.138154G4A AGAAGCTAGA Exon 18 E757K 1.1 1.1 0.0 0.0 rs3765534,39 48 TGTAGCTACC g.139997G4A TTCTTTTTGG Exon 19 V776I 1.1 1.1 0.0 0.0 49 ACCACTGACA g.185182T4G CGGCTTATTT Intron 19 46.7 49.9 29.3 27.8 rs1678394,39 50 TGAATAATAT g.185207A4G TTAAATACAT Intron 19 4.3 4.2 0.0 0.0 rs2296652 51 ATTTGCTGCC g.185369G4A CTGACGTTTT Exon 20 synonymous 1.1 1.1 0.0 0.0 52 ACAACTCATG g.217965C4A AAGTATTTTT Intron 20 6.7 6.4 93.3 93.4 rs1189437,39 53 GGTTGGTGTG g.218049G4T TCTCTGTGGC Exon 21 V854F* 3.3 3.3 0.0 0.0 rs11568694 54 TTGGATCGCA g.218085A4G TACCCTTGGT Exon 21 I866 V* 5.6 5.4 0.0 0.1 55 CTTGGGAGGC g.225708C4T GCAGGTTTTT Intron 21 28.0 25.8 1.2 2.3 rs11568672 Figure 3 Predicted two-dimensional protein structure of the MRP4 protein.
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ABCC4 p.Arg531Gln 17404579:45:3126
status: NEW52 MRP4 protein expression in samples carrying non-synonymous polymorphisms relative to the control group (n ¼ 8) was as follows: G187W 58% (n ¼ 2), K304N 54% (n ¼ 3), R531Q 20% (n ¼ 1), Y556C 60% (n ¼ 1), E757K 86% (n ¼ 1), V776I 161% (n ¼ 1), V854F 96% (n ¼ 1), I866V 78% (n ¼ 4) and T1142M 40% (n ¼ 2).
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ABCC4 p.Arg531Gln 17404579:52:180
status: NEW72 Prediction of functional effects of non-synonymous variations In silico analysis of all 10 detected amino acid exchanges revealed that five of them (I18L, K304N, R531Q, E757K, V776I) can be considered benign, whereas others especially near or within transmembrane regions or ATP-binding domains are possibly (G187W, Y556C, V854F, I866V) or in one case (T1142M) even very likely damaging for protein localization and/or function (Figure 3).
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ABCC4 p.Arg531Gln 17404579:72:162
status: NEW46 Table 2 Genetic variations identified in the MRP4 gene among 95 Caucasian individuals Variant ID Sequence context 50 Systematic name Sequence context 30 Genetic element Effect Frequency (%) Heterozygous Homozygous NCBI SNP ID HW HW 1 GAACTCCTGA g.-2174C4G GTCAGGTGAT Promoter 23.7 28.5 5.4 3.0 2 CACCTGCCTC g.-2152A4G GCCTCCCAGA Promoter 2.2 2.2 0.0 0.0 3 TGGGCTAAAG g.-2055C4A CATCCTCCTG Promoter 40.9 47.9 39.8 36.3 rs2389235 4 CTAAAGCCAT g.-2051C4T CTCCTGTCTC Promoter 38.7 45.1 46.2 43.0 rs1764419 5 ATTTTTAAAA g.-1980-1981insA CTTTTGGTAG Promoter 39.8 45.5 45.2 42.3 6 CACTATGCTG g.-1949G4C CTAGCCTGTG Promoter 1.1 1.1 0.0 0.0 7 CATCTATAAA g.-1508G4A TAAGGATAAC Promoter 12.6 11.8 0.0 0.4 rs868853 8 AAATTATCAG g.-1235T4C ATTTGAACTT Promoter 2.1 2.1 0.0 0.0 9 TACTTAAACT g.-1130G4A AGTTGGGAGG Promoter 42.4 46.3 15.2 13.3 rs2993579 10 CCATGGCACC g.-642G4C TCGTTTGGTC Promoter 41.9 46.7 41.9 39.6 rs869951,39 11 CGCGTCTCCT g.-289C4G CCGCCGCGTC Promoter 2.2 2.2 0.0 0.0 12 CCGCGGCCAC g.-49C4T GCCGCCTGAT 50 UTR/ Exon 1 1.1 1.1 0.0 0.0 rs3751333,39 13 TGCCCGTGTA g.15C4T CAGGAGGTGA Exon 1 synonymous 1.1 1.1 0.0 0.0 14 GGACGCGAAC g.52A4C TCTGCTCACG Exon 1 I18L 2.2 2.2 97.8 97.8 rs11568681 15 GGTGAGTGTC g.84C4T CCGCCCGAAA Intron 1 2.2 2.1 0.0 0.0 rs11568682 16 CACTCTCCCG g.138G4C GGCCGCGCCC Intron 1 1.1 1.0 0.0 0.0 17 ACCCATGGAG g.53498G4A TAGGAGTCTA Intron 1 46.7 47.4 15.2 14.9 rs9556466 18 TTTTTCCTCAT g.54215T4C GTAGGTTCTG Intron 2 46.7 47.0 14.4 14.3 rs4148437,39 19 AGCATGGGTG g.66387A4G CAGAGCAAGC Intron 3 11.9 11.2 0.0 0.4 39 20 GGTAAGTGAC g.66715A4G TTCAGCATTA Intron 4 2.2 2.2 0.0 0.0 rs11568637 21 CATGGCCATG g.90561G4T GGAAGACAAC Exon 5 G187W* 4.3 4.2 0.0 0.0 rs11568658 22 CACCCCTCTT g.90673T4C CCCCTTTTAT Intron 5 25.3 23.7 73.6 74.4 rs899496,39 23 TTTCTGGAGG g.90696C4T AGGGGCTCAC Intron 5 38.9 37.5 5.6 6.3 rs4148472,39 24 GCAGGGGCTC g.90705-90708delACTC TGTTCACACT Intron 5 44.9 47.7 38.2 36.8 rs3046400 25 TGTGTTCTTA g.91667C4T TGGTTTTGCT Intron 5 1.1 1.1 0.0 0.0 26 TGCAGGCGAT g.91765C4T GCAGTGACTG Exon 6 synonymous 19.4 19.2 1.1 1.2 rs899494,39 27 GTTGTCGGAA g.93281G4T CAAAAGCGCT Intron 6 43.5 41.5 48.9 49.9 rs2274410,39 28 GGCTGTGATC g.93355G4A CTCAGGCTCA Intron 6 15.2 17.7 2.2 1.0 rs2274409,39 29 CTCATCTCCC g.93372G4A TGTCTGGTTC Intron 6 2.2 2.2 0.0 0.0 rs11568683 30 AAGTTTTACT g.93595A4G TGTTTTCACA Intron 7 43.5 41.5 48.9 49.9 rs2274408,39 31 TCTCTTTCAG g.94534G4T AAGGAGATTT Exon 8 K304N 17.6 17.8 1.1 1.0 rs2274407,39 32 CCTGCCTCAG g.94573G4A GGGATGAATT Exon 8 synonymous 47.2 42.3 6.7 9.2 rs2274406,39 33 ATTTGGCTTC g.94591G4A TTTTTCAGTG Exon 8 synonymous 47.2 42.3 6.7 9.2 rs2274405,39 34 CAGGTTGGTG g.94791T4A CAGATGCCAT Intron 8 4.4 4.3 0.0 0.0 rs11568702 35 CACTATGTTC g.94865C4G AGTGTAATGA Intron 8 47.2 42.3 46.1 48.5 rs3818494,39 36 TGACATTTAA g.94883C4T TCTCTCATAA Intron 8 47.2 42.3 46.1 48.5 rs3818494,39 37 TAGAGAATTT g.106549T4C GAGGTGTTAC Intron 9 55.6 49.9 24.4 27.3 rs2274403,39 38 GCATTGCAGT g.114366G4A GCTTATTCTT Intron 10 9.8 9.3 0.0 0.2 rs4148487,39 39 CTCTGAAAAA g.114614G4A GTGAGTGATG Exon 11 synonymous 1.1 1.1 0.0 0.0 40 ATAGGAGATC g.123270G4A GGGAACCACG Exon 12 R531Q 1.1 1.1 0.0 0.0 41 GCTGACATCT g.123548A4G TCTCCTGGAC Exon 13 Y556C* 1.1 1.1 0.0 0.0 42 GAGGTCTCCC g.130808G4A AACTTGCAAG Intron 14 24.4 23.1 1.1 1.8 rs11568663 43 TGCCTGTTTC g.136709C4T CCACAGCTTT Intron 15 18.2 16.5 0.0 0.8 rs4148501,39 44 GTTTTCAGGC g.136862C4T TATAAGAATT Exon 16 synonymous 2.1 2.1 0.0 0.0 rs11568666 45 ATGTATGAAA g.137735T4C ACTCCAAAAT Intron 17 16.1 14.8 83.9 84.5 rs11568650 46 GGTTCATTTT g.138034T4C AAAAAAATGT Intron 17 20.7 20.3 1.1 1.3 39 47 AAATGTAACC g.138154G4A AGAAGCTAGA Exon 18 E757K 1.1 1.1 0.0 0.0 rs3765534,39 48 TGTAGCTACC g.139997G4A TTCTTTTTGG Exon 19 V776I 1.1 1.1 0.0 0.0 49 ACCACTGACA g.185182T4G CGGCTTATTT Intron 19 46.7 49.9 29.3 27.8 rs1678394,39 50 TGAATAATAT g.185207A4G TTAAATACAT Intron 19 4.3 4.2 0.0 0.0 rs2296652 51 ATTTGCTGCC g.185369G4A CTGACGTTTT Exon 20 synonymous 1.1 1.1 0.0 0.0 52 ACAACTCATG g.217965C4A AAGTATTTTT Intron 20 6.7 6.4 93.3 93.4 rs1189437,39 53 GGTTGGTGTG g.218049G4T TCTCTGTGGC Exon 21 V854F* 3.3 3.3 0.0 0.0 rs11568694 54 TTGGATCGCA g.218085A4G TACCCTTGGT Exon 21 I866 V* 5.6 5.4 0.0 0.1 55 CTTGGGAGGC g.225708C4T GCAGGTTTTT Intron 21 28.0 25.8 1.2 2.3 rs11568672 Figure 3 Predicted two-dimensional protein structure of the MRP4 protein.
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ABCC4 p.Arg531Gln 17404579:46:3126
status: NEW53 MRP4 protein expression in samples carrying non-synonymous polymorphisms relative to the control group (n &#bc; 8) was as follows: G187W 58% (n &#bc; 2), K304N 54% (n &#bc; 3), R531Q 20% (n &#bc; 1), Y556C 60% (n &#bc; 1), E757K 86% (n &#bc; 1), V776I 161% (n &#bc; 1), V854F 96% (n &#bc; 1), I866V 78% (n &#bc; 4) and T1142M 40% (n &#bc; 2).
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ABCC4 p.Arg531Gln 17404579:53:177
status: NEW73 Prediction of functional effects of non-synonymous variations In silico analysis of all 10 detected amino acid exchanges revealed that five of them (I18L, K304N, R531Q, E757K, V776I) can be considered benign, whereas others especially near or within transmembrane regions or ATP-binding domains are possibly (G187W, Y556C, V854F, I866V) or in one case (T1142M) even very likely damaging for protein localization and/or function (Figure 3).
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ABCC4 p.Arg531Gln 17404579:73:162
status: NEW