ABCMdb

PMID: 16394881

Kubitz R, Keitel V, Scheuring S, Kohrer K, Haussinger D
Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump.
J Clin Gastroenterol. 2006 Feb;40(2):171-5., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCB11 p.Val444Ala ABCB11 p.Glu186Gly One mutation (E186G) had been described in one BRIC-2 case; the second mutation (V444A) is more frequent and has been linked to intrahepatic cholestasis of pregnancy. Login to comment 72 ABCB11 p.Glu297Gly Mutations connected to BRIC-2 involve less important structures than PFIC-2 mutations.5 Only the mutation E297G was detected in patients with either PFIC-2 or BRIC-2.5,24 Nine of the 10 BRIC-2 patients who have been described so far by van Mil et al5 had homozygous or compound heterozygous BSEP mutations. Login to comment 73 ABCB11 p.Glu186Gly Only 1 patient carried the mutation E186G as a single heterozygous BSEP mutation. Login to comment 74 ABCB11 p.Val444Ala The same mutation was detected in our patient together with the polymorphism V444A. Login to comment 75 ABCB11 p.Val444Ala This latter polymorphism has an allele frequency of 51% in a normal female population, who did not develop intrahepatic cholestasis of pregnancy (ICP) compared with 83% in females with ICP.8 The association of V444A to ICP suggests that this polymorphism/ mutation might become disease relevant in certain conditions such as pregnancy. Login to comment 80 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly This might include protein misfolding and increased ER-associated degradation of BSEP as shown for some frequent BSEP mutations underlying PFIC-2.28,29 Other possibilities of reduced protein amounts of BSEP are an increased retention of BSEP within the secretory pathway11 or an increased vesicular retrieval of BSEP from the canalicular membrane as described in animal models of cholestasis.30,31 Targeting defects might be even more important than alteration in transporter activity as shown for the most frequent PFIC-2 mutations E297G and D482G.32 Cholestatic episodes of the patient were triggered by infections.16,33,34 These infections might induce cell stress,35,36 which might be the reason for protein instability and improper trafficking. Login to comment 81 ABCB11 p.Val444Ala ABCB11 p.Glu186Gly The immunofluorescence findings suggest that either BSEP mutation of our patient (E186G and V444A) predisposes for these mechanisms during cholestatic episodes. Login to comment