ABCMdb

PMID: 16529292

Li YH, Wang YH, Li Y, Yang L
MDR1 gene polymorphisms and clinical relevance.
Yi Chuan Xue Bao. 2006 Feb;33(2):93-104., [PubMed]

Sentences

No. Mutations Sentence Comment

39 ABCB1 p.Gln1107Pro Four SNPs are at wobble positions with no amino acid changes [C1236T (exon 12), C2650T (exon 21) and C343ST, C3396T (both in exon26)I. Subsequently, a screen of 461 German Caucasians for allele and genotype distribution further revealed two rare mutations (G2677A: Ala893Thr; and A3320C: Gln1107Pro) 13". Login to comment 40 ABCB1 p.Arg492Cys Additional mutations were identified in Asians including 5`-flanking A-41G, C-145G (exon la)"", as well as three nonsynonymous mutations (A548G: Asnl83Ser; C1474T: Arg492Cys; and T3421A: Serll41Thr) in different ethnic populations'". Login to comment 42 ABCB1 p.Ser400Asn ABCB1 p.Phe103Leu ABCB1 p.Ala999Thr ABCB1 p.Arg492Cys ABCB1 p.Met986Val Table 1 Geneticpolymorphismsin MDRl ~~~~~~~~~~ Position Location Effect C-l4SG T-l29C(T12C) C-4T G-IA A61C G.51-2ST G.51-3SC T307C C6/+139C A548G G119YA C1236T c12li44T C1474T TIlJ-76A A 17/+137G C26SOT G2677T A2956G G2995A A3320C C3396T T342l A C343ST T3421A C343ST G4030C A4036G Intron Exon la Exon 1b Exon 2 Exon 2 Exon 2 lntron Intron Exon 5 Intron Exon 7 Exon 11 Exon 12 lntron Exon 13 Intron Intron Exon 21 Exon 21 Exon 21 Exon 24 Exon 24 Exon 26 Exon 26 Exon 26 Exon 26 Exon 28 Exon 26 Non-coding Non-coding Non-coding Non-coding Non-coding Am21Asp Phe103Leu Asnl83Ser Ser400Asn Wobble(Gly412Gly) Arg492Cys Wobble(Leu884Leu) Ala893Thr Ala893Ser Met986Val Ala999Thr Gln1I 07Pro Wobble Serll41Thr Wobble(1le114SIIe) Silent Silent In recent years, most of the MDR1 SNPs were identified, with some resulting in changes in P-gp . Login to comment 43 ABCB1 p.Asn21Asp The A61G mutationexpression and function (Asn21Asp) may contribute to a net charge change (basic to acidic) close to the N-terminus of P-gp, which appears to be of minor functional importance '3y1. Login to comment 46 ABCB1 p.Ser400Asn ABCB1 p.Gln1107Pro The 16.18.19,35] B@%fW Acta Genetica Sinica Vo1.33 No.2 2006 nonsynonymous G1199A (Ser400Asn) in exon 11 brings about a significant size change, and depending on the pH and isoelectric environment of the residue, may lead to a charge change in the protein. Login to comment 47 ABCB1 p.Ala999Thr ABCB1 p.Arg492Cys This SNP is located on the cytoplasmic side just ahead of the first ATP-binding domain'291.C1236T in exon 12, the synonymous polymorphism, is one of the SNPs with the highest freq~encies[~".G2677T/A, a missense mutation in exon 21 that results in an amino acid change from Ala 893 to Ser or Thr, has also been associated with altered P-gp expre~sion"~,~~'.Another polymorphism, G2995A in exon 24 changes Ala 999 to Thr in the second transmembrance domain closer to the ATP-binding domain[361.Finally, MDR is another wobble mutation that doesn't alter the amino acid Ile at the position 1145.The potential functional significance of these polymorphisms can be deduced by pinpointingthem on the domain structureof P-gp. Login to comment 49 ABCB1 p.Ser400Asn ABCB1 p.Phe103Leu ABCB1 p.Ala999Thr ABCB1 p.Arg492Cys ABCB1 p.Met986Val Table 1 Geneticpolymorphismsin MDRl ~~~~~~~~~~ Position Location Effect C-l4SG T-l29C(T12C) C-4T G-IA A61C G.51-2ST G.51-3SC T307C C6/+139C A548G G119YA C1236T c12li44T C1474T TIlJ-76A A 17/+137G C26SOT G2677T A2956G G2995A A3320C C3396T T342l A C343ST T3421A C343ST G4030C A4036G Intron Exon la Exon 1b Exon 2 Exon 2 Exon 2 lntron Intron Exon 5 Intron Exon 7 Exon 11 Exon 12 lntron Exon 13 Intron Intron Exon 21 Exon 21 Exon 21 Exon 24 Exon 24 Exon 26 Exon 26 Exon 26 Exon 26 Exon 28 Exon 26 Non-coding Non-coding Non-coding Non-coding Non-coding Am21Asp Phe103Leu Asnl83Ser Ser400Asn Wobble(Gly412Gly) Arg492Cys Wobble(Leu884Leu) Ala893Thr Ala893Ser Met986Val Ala999Thr Gln1I 07Pro Wobble Serll41Thr Wobble(1le114SIIe) Silent Silent In recent years, most of the MDR1 SNPs were identified, with some resulting in changes in P-gp . Login to comment 50 ABCB1 p.Asn21Asp The A61G mutation expression and function (Asn21Asp) may contribute to a net charge change (basic to acidic) close to the N-terminus of P-gp, which appears to be of minor functional importance '3y1. Login to comment 52 ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Ala999Thr Furthermore, Kimchi-Sarfaty and his colleagues carried out a study to characterize the functional consequences of five coding SNPs (Asn21Asp,Phel03Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system, but it was found that the distribution and function of P-gp in the cells were similar to wild-type P-gp in the human body'431.The mechanism of these contradictory results regarding the C2677T/A and C3435T polymorphisms function is unclear until now. Login to comment 54 ABCB1 p.Ser400Asn The 16.18.19,35] B@%fW Acta Genetica Sinica Vo1.33 No.2 2006 nonsynonymous G1199A (Ser400Asn) in exon 11 brings about a significant size change, and depending on the pH and isoelectric environment of the residue, may lead to a charge change in the protein. Login to comment 58 ABCB1 p.Ala999Thr Another polymorphism, G2995A in exon 24 changes Ala 999 to Thr in the second transmembrance domain closer to the ATP-binding domain[361. Login to comment 64 ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Ala999Thr Furthermore, Kimchi-Sarfaty and his colleagues carried out a study to characterize the functional consequences of five coding SNPs (Asn21Asp,Phel03Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system, but it was found that the distribution and function of P-gp in the cells were similar to wild-type P-gp in the human body'431.The mechanism of these contradictory results regarding the C2677T/A and C3435T polymorphisms function is unclear until now. Login to comment