ABCMdb

PMID: 16696816

Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Variola A, Tommasi AM, Marchesoni D, Braghin C, Mazzella G
Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations.
Aliment Pharmacol Ther. 2006 Jun 1;23(11):1649-53., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCB4 p.Glu528Asp ABCB4 p.Arg549His ABCB4 p.Gly536Arg Results Three novel non-synonymous heterozygous mutations in exon 14 were found (4%; E528D, R549H, G536R) among the 80 intrahepatic cholestasis of pregnancy patients, whereas the pregnant controls were all negative for exon 14 polymorphisms. Login to comment 35 ABCB4 p.Ser320Phe ABCB4 p.Gly535Asp ABCB4 p.Ala546Asp ABCB4 p.Arg957* ABCB4 p.Gly762Glu ABCB4 p.Arg150Lys ABCB4 p.Arg144* MDR3 mutations reported in the literature Mutation (codon) Exon Reference (R144X) 6 Gendrot et al.5 481G>A (R150K) 6 Mu¨llenbach et al.6 426-432del (132) 6 DeVree et al.13 959C>T (S320F) 9 Rosmordurc et al.,14 Pauli-Magnus et al.9 (G535D) 14 Lucena et al.7 1669 C>A (A546D) 14 Dixon et al.4 1712 del T (571) 14 Jacquemin et al.8, 15 2285 G>A (G762E) 18 Pauli-Magnus et al.9 2901 C>T (R957X) 23 DeVree et al.13 conditions included an initial denaturation step at 94 °C for 5 min, followed by 40 cycles of denaturation at 94 °C for 30 s, annealing at 55 °C for 30 s and extension at 72 °C for 30 s. Login to comment 51 ABCB4 p.Gly536Arg Patient #3 had a heterozygous mutation (GGG-AGG) in codon 536 with a consequent substitution of the wild-type glycine with mutant arginine (G536R). Login to comment 68 ABCB4 p.Gly536Arg ATP-binding and hydrolysis are mediated by NBDs, which are characterized as in all ABC transporters, by three consensus motifs: the Walker A, Walker B and a linker region (ABC signature dodecapeptide) just upstream from the Walker B domain).10 The G536R mutation is located in the linker region of the NBD1. Login to comment 69 ABCB4 p.Glu528Asp The E528D mutation is located in the central part of the NBD1, close to the linker region. Login to comment 70 ABCB4 p.Arg549His The R549H mutation is located between the linker region and the Walker B domain. Login to comment 72 ABCB4 p.Glu528Asp ABCB4 p.Arg549His ABCB4 p.Gly536Arg Patient #1 E528D mutation Patient #3 G536R mutation Patient #2 R549H mutation Figure 1. Login to comment 75 ABCB4 p.Glu528Asp ABCB4 p.Arg549His ABCB4 p.Gly536Arg Clinical details of ICP patients with heterozygous mutations Patient #1 E528D Patient #2 R549H Patient #3 G536R Onset of pruritus 3rd trimester 3rd trimester 3rd trimester Parity 0002 0001 0001 Previous ICP No Yes Yes Peak of AST (U/L) 163 88 129 Peak of ALT (U/L) 98 121 137 Bilirubin (mg/dL) 0.60 0.61 0.89 Peak of GGT (U/L) 8 15 19 Cholesterol lithiasis No Yes No Total bile salts (lM/L) 3.3 6.3 10.1 Delivery Vaginal Vaginal Caesarean ICP, intrahepatic cholestasis of pregnancy; AST, aspartate aminotransferase; ALT, alanine aminotransferase. A drawback of our study lies is not having sequenced the whole MDR3 gene, as our study design only involved sequencing exon 14; may also consequently underestimate the real prevalence of MDR3 mutations in ICP patients. Login to comment