ABCMdb

ABCB4 p.Pro479Leu

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Publications

PMID: 24594635 [PubMed] Gordo-Gilart R et al: "Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity."

No. Sentence Comment

9 Results Eight distinct ABCB4 mutations were identified: one nonsense, one splicing and six missense mutations, four of which (G68R, T201M, P479L, D459H) affected MDR3 expression level. Login to comment
11 Phosphatidylcholine efflux assays indicated that T201M, P479L, S978P and E1118K mutations impaired MDR3 activity to variable degrees. Login to comment
79 Two of these variants, P479L and S978P , have been described previously in a child with PFIC319 and in an adult patient with cholangiocarcinoma,13 respectively; the other six mutations are novel. Login to comment
117 MDR3 was detected as a 140-150 kDa band, Table 2 ABCB4 mutations and MDR3 immunohistochemical analysis Mutation allele 1 Mutation allele 2 Patient n Nucleotide change Predicted effect Nucleotide change Predicted effect MDR3 staining 1 c.3559C>T p.R1187X c.3633+2 T>A Splicing defect ABSENT 2 c.202G>A p.G68R c.202G>A p.G68R ABSENT 3 c.202G>A p.G68R c.202G>A p.G68R NA 4 c.1375G>C p.D459H c.1436C>T p.P479L FAINT 5 c.602C>T p.T201M c.3352G>A p.E1118K NORMAL 6 c.2932T>C p.S978P ND NORMAL Immunostaining was carried out on liver biopsy specimens in patients 2-6 and in hepatectomy specimens in patient 1. Login to comment
122 (C) Faint staining in patient 4, who is compound heterozygous for two missense mutations (D459H and P479L). Login to comment
128 By contrast, expression levels of mutants G68R and D459H were markedly decreased (15% and 20% of wild-type, respectively), consistent with the fact that ER retention usually leads to a premature degradation of the proteins.32 T201M and P479L mutations also caused a significant reduction in the expression of MDR3 (60% and 65% of wild-type, respectively). Login to comment
138 The T201M, P479L and E1118K mutations reduced the release of labelled PC in the presence of the bile salt. Login to comment
140 At the time point of 3 h, the percentage of [3 H]-choline phospholipids effluxed in cells expressing mutants T201M, P479L and E1118K was 27%, 18% and 39% of that in cells expressing the wild-type protein, respectively (figure 4B). Login to comment
159 It seems likely that these mutations lead to misfolded proteins which, typically, exhibit abnormal trafficking and are prematurely degraded by the ER-associated protein degradation.32 This would raise the possibility that these mutants could be rescued to the cell surface by pharmacological chaperones, as has been shown for various other misfolded mutant membrane proteins.37 38 The T201M, P479L, S978P and E1118K mutations affect PC-translocating activity of MDR3, but to different extents. Login to comment
190 It must be taken into account that the T201M and P479L mutations also lowered the MDR3 protein levels, although the extent to which these levels were decreased did not parallel with the reductions in MDR3 activity obtained in the PC efflux assays. Login to comment
189 It must be taken into account that the T201M and P479L mutations also lowered the MDR3 protein levels, although the extent to which these levels were decreased did not parallel with the reductions in MDR3 activity obtained in the PC efflux assays. Login to comment