ABCMdb

PMID: 26395522

Slomka M, Sobalska-Kwapis M, Korycka-Machala M, Bartosz G, Dziadek J, Strapagiel D
Genetic variation of the ABC transporter gene ABCC1 (Multidrug resistance protein 1-MRP1) in the Polish population.
BMC Genet. 2015 Sep 23;16(1):114. doi: 10.1186/s12863-015-0271-3., [PubMed]

Sentences

No. Mutations Sentence Comment

120 ABCC1 p.Ser199Leu 21 SNPs were located in exons and 11 of them change amino acid sequence as non-synonymous variants, including one novel polymorphic variant detected in this study: c.596C > T (p.Ser199Leu) with MAF = 0.003. Login to comment 121 ABCC1 p.Gly671Val Among all detected non-synonymous variants, only one, c.2012G > T (p.Gly671Val), occurred as a homozygote with estimated MAF = 0.077. Login to comment 134 ABCC1 p.Gly671Val We found statistically significant difference in MAF values obtained in the both our studies for only two loci - c.1062 T > C (p.Asn354+) and c.2012G > T (p.Gly671Val). Login to comment 136 ABCC1 p.Arg433Ser ABCC1 p.Ser199Leu ABCC1 p.Pro272Ser ABCC1 p.Arg1066Trp Variants c.596C > T (p.Ser199Leu) and c.814C > T (p.Pro272Ser) were located in the third intracellular loop (between TM5 and TM6), variant c.1299G > T (p.Arg433Ser) in the fourth intracellular loop, variant c.3196C > T (p.Arg1066Trp) in the seventh intracellular loop (between TM7 and TM8). Login to comment 137 ABCC1 p.Arg723Gln ABCC1 p.Gly671Val ABCC1 p.Arg633Gln ABCC1 p.Lys959Arg Additional four variants located in the loop containing NBD1 alter amino acids sequence: c.1898G > A (p.Arg633Gln) and c.2012G > T (p.Gly671Val) are located 44 and 6 amino acids upstream of the Walker A motif, respectively, while c.2168G > A (p.Arg723Gln) and c.2876A > G (p.Lys959Arg) are located 37 amino acids downstream of this motif, respectively. Login to comment 138 ABCC1 p.Arg1301Cys ABCC1 p.Arg1296Trp ABCC1 p.Asp1365Asn Similarly, three variants changing amino acids in the loop containing NBD2 were detected: c.3886C > T (p.Arg1296Trp) and c.3901C > T (p.Arg1301Cys) are located 30 and 25 amino acids upstream of the Walker A motif, respectively, while c.4093G > A (p.Asp1365Asn) is located 30 amino acids downstream of the motif. Login to comment 140 ABCC1 p.Arg723Gln ABCC1 p.Pro272Ser ABCC1 p.Asp1365Asn Analysis of all the non-synonymous variants detected in this study by the PolyPhen-2 tool (data in Additional file 3) showed for HumDiv-trained model that five of them: c.814C > T (p.Pro272Ser), c.1898G > A (p.Arg633 Gln), c.2168G > A (p.Arg723Gln), c.2876A > G (p.Lys 959Arg), the novel one c.4093G > A (p.Asp1365Asn), probably have benign influence on the functioning of the protein. Login to comment 141 ABCC1 p.Arg1066Trp For one polymorphism, c.3196C > T (p.Arg1066Trp) a possibly damaging effect on protein activity was expected. Login to comment 142 ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Arg1301Cys ABCC1 p.Ser199Leu The novel variant c.596C > T (p.Ser199Leu) was estimated as a probably damaging substitution, likewise as four others: c.1299G > T (Arg433 Ser), c.2012G > T (p.Gly671Val), c.3886C > T (p.Arg 1296Trp) and c.3901C > T (p.Arg1301Cys). Login to comment 143 ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Arg1301Cys ABCC1 p.Ser199Leu ABCC1 p.Arg1296Cys On the other hand, analysis for HumVar-trained model indicated that three polymorphisms: c.1299G > T (Arg433Ser), c.2012G > T (p.Gly671Val), c.3901C > T (p.Arg1301Cys), lead to probably damaging substitutions and two others, c.596C > T (p.Ser199Leu) and c.3886C > T (p.Arg1296Cys), are possibly damaging variants. Login to comment 144 ABCC1 p.Arg723Gln ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Arg633Gln ABCC1 p.Arg1301Cys ABCC1 p.Ser199Leu ABCC1 p.Pro272Ser ABCC1 p.Arg1066Trp ABCC1 p.Lys959Arg ABCC1 p.Arg1296Trp Table 2 Summary of ABCC1 variants detected during scanning by HRM Exon scanned by HRM dbSNP ID Variant position NM_004996.3: Intron/amino acid residue NP_004987.2: Observed genotypesa, b (n) HWE exact test P-valuec MAFd R/R R/V V/V 2 rs8187843 c.225 + 26G > A Intron 164 25 0 1 (A) 0.066 4 rs587783373* c.352-79G > A Intron 185 1 0 1 (A) 0.003 4 rs4148337 c.352-66 T > C Intron 15 80 91 0.727 (T) 0.296 5 rs483352860* c.596C > T p.Ser199Leu 186 1 0 1 (T) 0.003 6 rs8187846 c.677 + 17C > T Intron 188 1 0 1 (T) 0.003 7 rs483352864* c.809 + 16C > T Intron 188 1 0 1 (T) 0.003 7 rs45609533 c.809 + 31G > T Intron 183 5 0 1 (T) 0.013 7 rs903880 c.809 + 54C > A Intron 112 65 11 0.684 (A) 0.231 7 rs246232 c.809 + 64C > G Intron 84 90 14 0.174 (G) 0.314 8 rs546943313 c.810-73C > T Intron 187 1 0 1 (T) 0.003 8 rs200194736 c.814C > T p.Pro272Ser 187 1 0 1 (T) 0.003 8 rs2230669 c.816G > A p.Pro272= 172 16 0 1 (A) 0.043 8 rs246221 c.825 T > C p.Val275= 84 92 12 0.059 (C) 0.309 8 rs587783372* c.855G > A p.Pro285= 187 1 0 1 (A) 0.003 9 rs35587 c.1062 T > C p.Asn354= 78 91 16 0.185 (C) 0.332 9 rs35588 c.1218 + 8A > G Intron 82 91 16 0.245 (G) 0.327 9 rs483352877* c.1218 + 9C > T Intron 188 1 0 1 (T) 0.003 10 rs60782127 c.1299G > T p.Arg433Ser 186 2 0 1 (T) 0.005 12 rs17265551 c.1677 + 56C > T Intron 162 27 0 0.604 (T) 0.072 13 rs35604 c.1678-37G > A Intron 2 45 142 0.745 (G) 0.130 13 rs483352863* c.1678-34G > A Intron 188 1 0 1 (A) 0.003 13 rs35605 c.1684 T > C p.Leu562= 2 45 142 0.745 (T) 0.130 13 rs8187858 c.1704C > T p.Tyr568= 157 31 1 1 (T) 0.088 14 rs112282109 c.1898G > A p.Arg633Gln 187 1 0 1 (A) 0.003 16 rs8187863 c.2001C > T p.Ser667= 187 1 0 1 (T) 0.003 16 rs45511401 c.2012G > T p.Gly671Val 161 25 2 0.296 (T) 0.077 17 rs4148356 c.2168G > A p.Arg723Gln 181 9 0 1 (A) 0.024 19 rs45607032 c.2461-39_2461-38delAT Intron 179 9 0 1 (delAT) 0.024 19 rs2074087 c.2461-30C > G Intron 0 44 144 0.083 (C) 0.117 19 rs45492500 c.2461-27G > A Intron 172 14 2 0.056 (A) 0.048 21 rs11075296 c.2871 + 26C > T Intron 0 0 189 1 - 22 rs768191257 c.2876A > G p.Lys959Arg 187 1 0 1 (G) 0.003 22 rs3851716 c.3079 + 10G > A Intron 0 0 188 1 - 22 rs34794353 c.3079 + 24C > T Intron 187 1 0 1 (T) 0.003 22 rs3887893 c.3079 + 62 T > C Intron 67 96 25 0.358 (C) 0.388 23 rs191017838 c.3171G > A p.Leu1057= 187 2 0 1 (A) 0.005 23 rs199773531 c.3196C > T p.Arg1066Trp 188 1 0 1 (T) 0.003 25 rs41278168 c.3591-5C > T Intron 187 1 0 1 (T) 0.003 27 rs200922662 c.3886C > T p.Arg1296Trp 187 1 0 1 (T) 0.003 27 rs201533167 c.3901C > T p.Arg1301Cys 187 1 0 1 (T) 0.003 Linkage disequilibrium analysis Based on full genotype sets of 44 polymorphic variants confirmed by Hardy-Weinberg equilibrium exact test (Table 2), linkage disequilibrium analysis using r2 and |D`| statistics was performed (Additional file 4). Login to comment 151 ABCC1 p.Asp1365Asn Small areas of low |D`| values, and hence weak or lacking of linkage, were defined between polymorphisms from group: c.225 + 26G > A, c.352-66 T > C, c.809 + 31G > T, c.809 + 54C > A, c.809 + 64C > G, c.816G > A, c.825 T > C, c.1062 T > C, c.1218 + 8A > G, c.1677 + 56C > T, and those from group: c.1678-37G > A, c.1684 T > C, Table 2 Summary of ABCC1 variants detected during scanning by HRM (Continued) 28 rs2230671 c.4002G > A p.Ser1334= 102 68 18 0.202 (A) 0.277 28 rs188980645 c.4093G > A p.Asp1365Asn 187 1 0 1 (A) 0.003 29 rs212087 c.4126-45G > A Intron 62 85 42 0.239 (A) 0.447 30 rs212088 c.4487 + 18G > A Intron 136 47 5 0.775 (A) 0.148 31 rs587783374* c.4551G > A p.Gln1517= 186 1 0 1 (A) 0.003 31 rs373453875 c. Login to comment 154 ABCC1 p.Arg723Gln ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Cys1047Ser ABCC1 p.Val353Met ABCC1 p.Ala989Thr ABCC1 p.Val1146Ile ABCC1 p.Thr1337Ala ABCC1 p.Ala861Thr Bold variants signifies the ones which were validated by genotyping results Table 3 Summary of ABCC1 selected SNPs genotyping by HRM and comparing them with scanning results dbSNP ID Variant residue NM_004996.3: Intron/amino acid residue NP_004987.2: Observed genotypesa (n) HWE exact test P-valueb MAFc (genotyping) MAFc (scanning) Chi-square test P-valued R/R R/V V/V rs41395947 c.128G > C p.Cys43Se 380 0 0 1 - - - rs2230669 c.816G > A p.Pro272= 362 18 0 1 (A) 0.024 (A) 0.043 0.079 rs246221 c.825 T > C p.Val275 197 160 23 0.243 (C) 0.271 (C) 0.309 0.187 rs8187852 c.1057G > A p.Val353Met 379 0 0 1 - - - rs35587 c.1062 T > C p.Asn354= 204 142 33 0.247 (C) 0.274 (C) 0.332 0.044 rs35588 c.1218 + 8A > G Intron 190 160 30 0.709 (G) 0.289 (G) 0.325 0.214 rs60782127 c.1299G > T p.Arg433Ser 373 6 0 1 (T) 0.008 (T) 0.005 0.623 rs35605 c.1684 T > C p.Leu562= 13 105 262 0.588 (T) 0.172 (T) 0.130 0.063 rs8187858 c.1704C > T p.Tyr568= 325 55 0 0.242 (T) 0.072 (T) 0.087 0.374 rs45511401 c.2012G > T p.Gly671Val 346 28 3 0.007 (T) 0.045 (T) 0.077 0.038 rs4148356 c.2168G > A p.Arg723Gln 360 19 0 1 (A) 0.025 (A) 0.024 0.888 rs45517537 c.2581G > A p.Ala861Thr 380 0 0 1 - - - rs35529209 c.2965G > A p.Ala989Thr 378 0 0 1 - - - rs13337489 c.3140G > C p.Cys1047Ser 380 0 0 1 - - - rs28706727 c.3436G > A p.Val1146Ile 380 0 0 1 - - - rs2230671 c.4002G > A p.Ser1334= 204 140 32 0.296 (A) 0.271 (A) 0.277 0.850 rs28364006 c.4009A > G p.Thr1337Ala 380 0 0 1 - - - a Number of genotypes detected during this study, R - reference allele, V - variant allele. b P-value is consistent with Hardy-Weinberg equilibrium if P > 0.001. c Minor allele shown in brackets with its frequency. Login to comment 169 ABCC1 p.Gly671Val Marginal statistical significance (0.05 > P > 0.01) of difference between MAF values for scanning and targeted genotyping methods for two SNPs c.1062 T > C (p.Asn354=) and c.2012G > T (p.Gly671Val) is probably caused by sample size effect (there was no overlap between groups of individuals selected for both stages of the study). Login to comment 205 ABCC1 p.Gly671Val A similar observation was also reported previously for the SNP c.2012G > T (p.Gly671Val), detected also by us. Login to comment 207 ABCC1 p.Arg723Gln ABCC1 p.Gly671Val ABCC1 p.Arg633Gln Recently, other data confirmed these observations and none of the amino acid substitutions: p.Arg633Gln, p.Gly671Val, p.Arg723Gln, detected also in our study, was found to change functionality of MRP1 transporter. Login to comment 210 ABCC1 p.Arg723Gln Thus, it was demonstrated that variant c.2168G > A (p.Arg723Gln) reduced resistance activity of MRP1-overexpressing cells to drugs like daunorubicin, doxorubicin, etoposide, vinblastine and vincristine in vitro [36]. Login to comment 212 ABCC1 p.Gly671Val Two other polymorphic variants detected in this study c.825 T > C (p.Val275=) and c.2012G > T (p.Gly671Val), were correlated with febrile neutropenia as an effect of FEC-induced hematological toxicity in breast cancer patients [38]. Login to comment 215 ABCC1 p.Arg723Gln ABCC1 p.Gly671Val The discrepancy observed in different studies on clinical significance of c.2012G > T (p.Gly671Val) and c.2168G > A (p.Arg723Gln) is of unclear origin. Login to comment 220 ABCC1 p.Ser199Leu Therefore, novel variants like c.596C > T (p.Ser199Leu), detected in this study and qualified in silico as damaging, need to be checked in an experimental investigation. Login to comment 379 ABCC1 p.Gly671Val Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution. Login to comment 389 ABCC1 p.Arg723Gln 37. Yin JY, Han LF, Huang Q, Xu XJ, Zhou HH, Liu ZQ. ABCC1 polymorphism Arg723Gln (2168G > A) is associated with lung cancer susceptibility in a Chinese population. Login to comment