ABCMdb

ABCB4 p.Ser978Pro

None has been submitted yet.

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

11 Phosphatidylcholine efflux assays indicated that T201M, P479L, S978P and E1118K mutations impaired MDR3 activity to variable degrees. Login to comment
42 Plasmids and site-directed mutagenesis The plasmid pReceiver-M02-MDR3, containing the full open reading frame of ABCB4 (Capital Biosciences, Rockville, Maryland, USA) was used as a template for introducing the substitutions G68R, T201M, P352L, D459H, S978P and E1118K, by site-directed mutagenesis using the QuickChange II system (Agilent Technologies, Santa Clara, California, USA). 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
110 Mutants T201M, P479 L, S978P and E1118 K exhibited surface expression comparable to that of wild-type MDR3. 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
127 The changes S978P and E1118 K displayed protein levels comparable to the wild-type MDR3 (figure 3C). Login to comment
141 As mock-transfected cells, cells transfected with the S978P mutant yielded identical curves of radioactivity release in the presence or absence of NaTC, thus suggesting that this mutation completely abolishes MDR3 activity (figure 4A). 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
175 Along these lines, it has recently been reported that the mutation of another amino acid at the Q-loop of the NBD1 of MDR3, L481R, lowers MDR3 activity.26 The S978P mutation completely abrogated the PC translocation capacity of MDR3. Login to comment
186 binding and ATP hydrolysis.43 Of note, the equivalent residue in mouse Abcb1, S975, directly interacts with specific substrates, as revealed by crystallographic studies.41 Furthermore, a number of mutations within this transmembrane helix has been shown to dramatically affect ATPase activity of ABCB1.44 These observations concur with the complete loss of function of MDR3 caused by mutation S978P . Login to comment
197 In patient 6, a single heterozygous mutation, S978P , was detected despite extensive analysis by sequencing and MLPA. Login to comment
199 Indeed, the presence of the deleterious S978P mutation alone is not expected to trigger a progressive form of cholestatic liver disease in this patient, and a 'second hit` leading to hepatocellular damage can be suspected. Login to comment
174 Along these lines, it has recently been reported that the mutation of another amino acid at the Q-loop of the NBD1 of MDR3, L481R, lowers MDR3 activity.26 The S978P mutation completely abrogated the PC translocation capacity of MDR3. Login to comment
185 binding and ATP hydrolysis.43 Of note, the equivalent residue in mouse Abcb1, S975, directly interacts with specific substrates, as revealed by crystallographic studies.41 Furthermore, a number of mutations within this transmembrane helix has been shown to dramatically affect ATPase activity of ABCB1.44 These observations concur with the complete loss of function of MDR3 caused by mutation S978P . Login to comment
196 In patient 6, a single heterozygous mutation, S978P , was detected despite extensive analysis by sequencing and MLPA. Login to comment
198 Indeed, the presence of the deleterious S978P mutation alone is not expected to trigger a progressive form of cholestatic liver disease in this patient, and a 'second hit` leading to hepatocellular damage can be suspected. Login to comment