ABCMdb

PMID: 20422495

Lam P, Soroka CJ, Boyer JL
The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease.
Semin Liver Dis. 2010 May;30(2):125-33. Epub 2010 Apr 26., [PubMed]

Sentences

No. Mutations Sentence Comment

39 ABCB11 p.Asp482Gly Independent and collaborative studies have identified more than 100 different BSEP variants worldwide and the more frequent mutations are grouped as missense, nonsense, deletions and insertions, and splice-site mutations.11,42-47 A common result of these various gene mutations is the reduction or total loss of expression of the BSEP protein on the canalicular membrane.47 In addition, aberrant pre-mRNA splicing and reduced levels of BSEP mRNA can result from BSEP mutations and single nucleotide polymorphisms (SNPs) in the BSEP gene.48,49 Heterogeneity in clinical phenotypes from a single gene mutation (p.D482G) suggests that additional modifiers may influence the severity of the disease phenotype.47 To date, 86 polymorphisms in BSEP have been described in a population of Caucasians, Koreans, and African Americans.50 These polymorphisms are located in exons and introns, as well as in 50 -flanking regions, but no effect on the mRNA or protein has been determined. Login to comment 40 ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Met677Val Two nonsynonymous SNPs, c.1331T>C (p.V444A) in exon 13 and c.2029A>G (p.M677V), have been consistently observed and patients with at least one c.1331T allele tended to have lower levels of BSEP expression.49,51 The V444A variant is also associated with ICP and drug-induced cholestasis,46,49,51-53 but functional activity is not affected.51 It should be noted that these polymorphisms in BSEP that have been associated with ICP and drug cholestasis will require further validation and functional analyses in a larger group of patients. Login to comment 47 ABCB11 p.Val444Ala ABCB11 p.Met677Val Two single nucleotide polymorphisms (SNPs; V444A and M677V, cross) are also represented and have been characterized by functional studies (gray star). Login to comment 49 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Asn591Ser ABCB11 p.Arg1050Cys Similar to the results of immunofluorescence studies in liver tissue from PFIC2 patients,47 when PFIC2 human mutations were expressed in model mammalian cell lines (MDCK, HEK293, HepG2), the proteins failed to reach or be maintained at the cell surface.54-57 When BSEP mutations that cause PFIC2 (D482G, E297G), BRIC2 (A590T, R1050C), and ICP (N591S) were compared, the clinical severity of these mutations tended to correlate inversely with the amount of protein expressed on the cell surface. Login to comment 51 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly For example, the PFIC2 mutant D482G`s protein half-life is short compared with the wild-type and is shortened further after ubiquitylation with E3 ubiquitin ligases.58 However, a small amount of this mutant protein can reach the plasma membrane where it is functional.58 Additional studies have shown that the resident time on the cell surface is greatly reduced with D482G and E297G mutant proteins as a result of accelerated internalization, reduced recycling, and/or targeting of endocytosed proteins for degradation.57,59 These studies suggest that the use of small molecules that modulate these pathways might be worthwhile therapeutic approaches in some of these cholestatic disorders. Login to comment 52 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly For example, 4-phenylbutyrate (4-PBA) can enhance cell surface expression of D482G and E297G proteins.60 Furthermore, administration of 4-PBA to normal rats enhances BSEP expression and bile salt secretion.60 Further studies are clearly needed in this area. Login to comment 77 ABCB11 p.Asp482Gly ABCB11 p.Arg1268Gln ABCB11 p.Gly238Val ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg Ubiquitylation is involved in the degradation of receptors, channels, and transporters from the endoplasmic reticulum and cell surface of yeast and higher eukaryotes.86-88 Wang et al, showed for the first time that specific E3 ubiquitin ligases are involved in Bsep degradation.58 Bsep mutants (p.G238V, p.D482G, p.G982R, p.R1153C, and p.R1268Q) were highly ubiquitinated following overexpression of different E3 ubiquitin ligases and were rapidly degraded by proteasomes resulting in shorter half-lives compared with the wild-type protein.58 This study suggests that stabilizing aberrant BSEP proteins by inactivating key E3 ubiquitin ligases might be a novel therapeutic approach, providing that global effects on proteasomal degradation can be avoided. Login to comment