ABCMdb

ABCB1 p.Gly1265Ser

Predicted by SNAP2:	A: D (71%), C: D (63%), D: D (59%), E: D (63%), F: D (80%), H: D (75%), I: D (80%), K: D (75%), L: D (80%), M: D (75%), N: D (63%), P: D (85%), Q: D (75%), R: D (80%), S: D (66%), T: D (75%), V: D (80%), W: D (85%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Naturally occurring mutations and functional polym... J Med Genet. 2002 May;39(5):340-6. Potocnik U, Ravnik-Glavac M, Golouh R, Glavac D
Naturally occurring mutations and functional polymorphisms in multidrug resistance 1 gene: correlation with microsatellite instability and lymphoid infiltration in colorectal cancers.
J Med Genet. 2002 May;39(5):340-6., [PMID:12011154]

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214 (A) Germline mutation in exon 28 of the MDR1 gene identified in tumour sample MSI 11. Arrow indicates G>A substitution at position 3793 resulting in an amino acid change at position 1265 from non-polar glycine to polar serine (G1265S). Login to comment
240 The germline G1265S substitution identified in sample MSI 11 was of special interest (fig 2). Login to comment
242 G1265S was also the only germline alteration that resulted in substitution of an amino acid conserved through species; in this case non-polar Gly is replaced by polar Ser. The G1265S substitution is located in the predicted IC12 domain after the ATP binding site. Login to comment
247 Table 1 Mutations and germline promoter functional polymorphism in the MDR1 gene identified in colorectal cancers with microsatellite instability Sample Origin Exon Nucleotide change Consequence Amino acid change Domain Consensus MSI 3 Germline Promoter +8 T>C* Somatic 25 3149 T>C I1050T Non-polar>polar IC6 Yes MSI 5 Germline Promoter +8 T>C* Somatic 4 209 T>C L70P Non-polar>non-polar TM1 Yes MSI 11 Somatic Promoter -14 G>T Germline 28 3793 G>A G1265S Non-polar>polar IC6 Yes MSI 19 Somatic Promoter -29 G>A Somatic 20 2422-2426 del A Frameshift IC4 MSI 22 Germline Promoter +8 T>C* MSI 34 Germline 8 729 A>G E243 no change / / / IC=intracelular domain, TM=transmembrane domain. Login to comment

[hide] Polymorphisms in multidrug resistance 1 (MDR1) gen... Genes Immun. 2004 Nov;5(7):530-9. Potocnik U, Ferkolj I, Glavac D, Dean M
Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis.
Genes Immun. 2004 Nov;5(7):530-9., [PMID:15505619]

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We used coding and noncoding polymorphisms evenly spaced across the ABCB1/MDR1 gene to perform association analysis in Slovenian patients with inflammatory bowel diseases and to obtain haplotype structure and patterns of linkage disequilibrium (LD) in the MDR1 gene. A disease association study was performed in 307 IBD patients, including 144 patients with ulcerative colitis (UC) and 163 patients with Crohn's disease (CD), and 355 healthy controls. Here we report an association between MDR1 alleles, polymorphisms and haplotypes and refractory CD patients, who do not respond to standard therapy, including patients who develop fistulas. We also report an association with UC and MDR1 polymorphisms in a Slovenian population. Haplotypes significantly associated with diseases were defined by single-nucleotide polymorphisms (SNPs) in exons 12 (1236 C>A), 21(A893S), and 26 (3435 C>T). In addition, two intronic SNPs in LD with the disease haplotype, one in intron 13 (rs2235035) and another in intron 16 (rs1922242), were significantly associated with refractory Crohn (P=0.026, odds ratio (OR) 2.7 and P=0.025, OR 2.8, respectively), as well as with UC (P=0.006, OR 1.8 and P=0.026, OR 1.9, respectively). Our results suggest that MDR1 is a potential target for therapy in refractory CD patients and in patients with UC.

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75 We previously identified G1265S in exon 28 in a patient with CRC.12,13 Neither of these two mutations was additionally identified in any other CRC or IBD patient nor in 355 healthy individuals. Login to comment