ABCMdb

PMID: 16628674

Floreani A, Carderi I, Variola A, Rizzotto ER, Nicol J, Bergasa NV
A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus.
Hepatology. 2006 May;43(5):1152-4., [PubMed]

Sentences

No. Mutations Sentence Comment

30 ABCC2 p.Val1188Glu This mutation resulted from the substitution of valine by glutamate (V1188E) (Fig. 1). Login to comment 34 ABCC2 p.Val1188Glu V1188E was identified in 17 of 87 (19.5%) patients who reported pruritus, and in 7 of 90 patients who did not (7.8%) (P ϭ .02, RR ϭ 2.51, 95% CI: 1.13-5.69). Login to comment 35 ABCC2 p.Val1188Glu In the patients from Italy, the V1188E mutation was present in 13 of 39 (33.3%) patients with pruritus and in 6 of 62 (9.7%) patients without pruritus (P ϭ .003, RR ϭ 3.44, 95% CI: 1.47-8.20). Login to comment 37 ABCC2 p.Val1188Glu Discussion We identified a novel polymorphism in exon 25, in which valine was substituted by glutamate in position 1188 (V1188E) in the gene that codes for MRP2. Login to comment 41 ABCC2 p.Val1188Glu This mutation led to the substitution of valine by glutamate (V1188E). Login to comment 43 ABCC2 p.Val1188Glu Frequency of the V1188E Polymorphism in Patients With PBC From Italy and From the United States (US) and in Controls Wt/Mutation N/Total (%) US PBC 5/76 (6.6%)* Italian PBC 19/101 (18.8%) Italian controls 12/101 (11.9%) *US PBC vs. Italian PBC: P ϭ .02. Login to comment 45 ABCC2 p.Val1188Glu Frequency of the V1188E Polymorphism and Pruritus in Patients With PBC Symptom and Genotype Total PBC Population (N ‫؍‬ 177) PBC Patients From Italy (N ‫؍‬ 101) PBC Patients From the United States (N ‫؍‬ 76) Pruritus wt/m 17 (19.5%) 13 (33.3%) 4 (8.3%) wt/wt 70 (80.5%) 26 (66.7%) 44 (91.7%) Total 87 (100%) 39 (100%) 48 (100%) No pruritus wt/m 7 (7.8%) 6 (9.7%) 1 (3.6%) wt/wt 83 (92.2%) 56 (90.3%) 27 (96.4%) Total 90 (100%) 62 (100%) 28 (100%) RR (95%CI) 2.51 (1.13-5.69) 3.44 (1.47-8.20) 2.33 (0.37-15.4) P value (pruritus vs. no pruritus) .02 .003 .42 HEPATOLOGY, Vol. 43, No. Login to comment 47 ABCC2 p.Val1188Glu V1188E was associated with pruritus in the patients with PBC. Login to comment 48 ABCC2 p.Val1188Glu MRP2 is a membrane protein with 1,545 amino acids and contains 17 transmembrane (TM) segments organized into three membrane-spanning domains (MSD0, MSD1, MSD2).8 The V1188E polymorphism is located in the MSD2 membrane-spanning domain, in the cytoplasmic loop linking TM15 and TM16. Login to comment 50 ABCC2 p.Val1188Glu Although photoaffinity labeling studies have not as yet been reported forMRP2,inferencesaboutsubstratebindingsiteshavebeen made on the basis of site-directed mutagenesis.9 These studies indicate the involvement of several TM segments, including T16 in the human protein and in the rat.10,11 Finally, the novel V1188E mutation located in the cytoplasmic loop between T15 and T16 might reduce the ability of the protein to transport substrates. Login to comment 51 ABCC2 p.Val1188Glu A pathogenic role of this mutation alone is doubtful, as the frequency of V1188E in controls is similar to that of patients with PBC in the Italian group of subjects; however, the development of pruritus in any of these control subjects were they to develop cholestasis is unknown. Login to comment 54 ABCC2 p.Val1188Glu Possible mechanisms by which V1188E affects the development of pruritus of cholestasis include alterations in the transport of pruritogen(s) or its cofactors from the hepatocyte into bile or into the central nervous system. Login to comment