ABCMdb

PMID: 20422496

Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E
The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.
Semin Liver Dis. 2010 May;30(2):134-46. Epub 2010 Apr 26., [PubMed]

Sentences

No. Mutations Sentence Comment

144 ABCB4 p.Arg652Gly Site-directed mutagenetic analysis of P-glycoprotein has shown that mutations in transmembrane domains are important for substrate specificity and that mutations localized near Walker motifs may disrupt the function of the transporter.88,91-93 Alternatively, missense mutations might result in intracellular misprocessing of MDR3 as shown for other ABC transporters.44,46,74,94 Indeed, such missense mutations were associated with a decreased level of MDR3 canalicular protein.4 Whatever the mechanism, a low level of biliary phospholipids found in patients with missense mutations demonstrates a functional MDR3 deficiency.4 Interestingly, some affected children had missense mutations that probably represented a polymorphism (p.R652G).4 It may be that this polymorphism has mild clinical consequences, explaining the favorable outcome of patients with this mutation following UDCA therapy, or that in certain circumstances such as pregnancy, may lead to clinical symptoms.6,22,63,82,95 In human liver, this polymorphism is associated with low expression of MDR3.95 It has been shown for MDR1 P-glycoprotein that amino acid polymorphisms may affect the protein function.96 Ideally, it would be desirable to have a functional means to distinguish disease mutations from normal variants.32,46,97,98 In our experience, in silico tools are useful to predict if an intronic mutation should lead to abnormal splicing.99 Compared with children who have ABCB4 mutations that lead to a truncated protein, children with ABCB4 missense mutations have a less severe disease, with a later onset in life and a slower progression, which can be favorably modified by chronic administration of UDCA in $50% of cases33 and be compatible with life until adolescence or early adulthood. Login to comment 148 ABCB4 p.Arg652Gly In our experience, the threshold percentage of biliary phospholipids that predicts a positive answer to UDCA Table 1 Genotype-Phenotype Correlations in PFIC3 Children with ABCB4 Mutations Patients Homozygous for a Mutation Leading to a Truncated Protein Patients Homozygous or Heterozygous for a mutation Leading to a Missense Protein N 12 34(4*) MDR3 canalicular staining 5 Patients tested: 8 Patients tested: negative in 5 negative in 3, faint in 3, positive in 2 Mean age at first symptoms (range) 9 Months 4 years (1-28) (1 month-20 years) Biliary phospholipid concentration 3 Patients tested: 6 Patients tested(1*): Mean % of total biliary lipid concentration (range) 0.05-0.13 mM 0.4-3 mM <2% 7.6% (3.3-14) Response to UDCA 7 Patients tested: 29 Patients tested: negative in 7 negative in 4, unknown in 8 (1*), positive in 183* Liver transplantation No: 1, alive at 3 years No: 23 (3*), alive at a mean age of 13 years (range: 2-33) Mean age at liver transplantation (range) Yes: 11 Yes: 10 (1*) 5.5 years Lost to follow-up: 1 (2.5-9) 14 years (5-30) (n*) Including n patients with the p.R652G amino acid polymorphism. Login to comment