Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11†

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing #

“…D482G is one of the most common PFIC missense mutations in European patients, and in vitro studies have differed in their conclusions on its effect on protein trafficking and protein function. 11,13,14,60 The altered pre-mRNA splicing of this mutant allele observed in this study (Fig. 3B) generates an mRNA template that on translation would result in the introduction of 14 novel amino acids followed by a stop codon.…”

“…Indeed, subsequent studies have shown differing results with respect to membrane localization and taurocholate transport for several mutations, depending on whether rat or human proteins were expressed. [11][12][13][14][15] It cannot necessarily be assumed that a missense mutation causes disease by exchanging an important amino acid in a protein; the primary defect may actually be at the level of the production or stability of the gene's messenger RNA (mRNA). 16,17 Evidence has emerged that missense mutations located in the middle of exons, and therefore well away from the classical intron-exon boundaries, can cause altered splicing events.…”

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

“…These variable findings argue that multiple expression systems (cells, and/or different species of BSEP/Bsep as templates for introducing of mutation) should be used before firm conclusions can be drawn regarding the mechanism underlying pathophysiology in the human disease. Different in vitro phenotyping studies (table 5) from several groups using different BSEP mutants demonstrated alterations in BSEP targeting [115,256], a shortening of the half life of BSEP in the plasma membrane [115] and differences in ubiquitin dependent BSEP turnover [114]. It was recently observed that the severity of BSEP deficiency syndrome phenotype in humans correlates with membrane expression and protein stability of the BSEP mutants in heterologous expression systems [144,182].…”

The bile salt export pump

“…It should, however, be noted that such studies on the functional impact of the human mutations based on heterologous expression systems may lead to conflicting results suggesting species-specific effects on transport function [81,97]. Therefore, directly testing the human mutated forms of BSEP in vivo seems to be an important prerequisite to obtain insights into the functional consequences of BSEP mutations [37,70].…”