ABCMdb

PMID: 16890614

Keitel V, Vogt C, Haussinger D, Kubitz R
Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy.
Gastroenterology. 2006 Aug;131(2):624-9., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCB4 p.Ser320Phe Gene sequencing revealed a homozygous MDR3 gene mutation (S320F). Login to comment 6 ABCB11 p.Val444Ala The patient was also homozygous for the common BSEP polymorphism V444A. Login to comment 9 ABCB11 p.Val444Ala The common BSEP polymorphism V444A accounts for the reduced canalicular BSEP expression. Login to comment 32 ABCB11 p.Val444Ala ABCB4 p.Ser320Phe A single nucleotide exchange from cytidine to thymidine at position 959 in exon 9 of MDR3 (959C¡T) led to a change from serine to phenylalanine (S320F) (Figure 2A), which has been described to be ICP specific.6 The second homozygous polymorphism was detected in the BSEP gene at the complementary DNA position 1331 with a thymidine replaced by a cytidine (1331T¡C), leading to an exchange of valine to alanine (V444A) (Figure 2B). Login to comment 35 ABCB4 p.Ser320Phe The patient`s mother and aunt (the mother`s sister) were heterozygous for the MDR3 mutation S320F. Login to comment 36 ABCB11 p.Val444Ala ABCB11 p.Val444Ala The mother was heterozygous for the BSEP polymorphism V444A, while the aunt was homozygous for V444A (Figure 2). Login to comment 58 ABCB11 p.Asn591Ser ABCB4 p.Ser320Phe ABCB4 p.Gly762Glu Two ICP-specific nonsynonymous SNPs were detected in the MDR3 gene (S320F and G762E).6 In the BSEP gene, one ICP-specific SNP was found (N591S).6 Another nucleotide exchange from T to C at position Figure 2. Login to comment 63 ABCB11 p.Val444Ala ABCB4 p.Ser320Phe The mutations found in this patient are within the fifth transmembrane domain (MDR3, S320F) and in the nucleotide binding fold (BSEP, V444A). Login to comment 65 ABCB11 p.Val444Ala 1331 of the BSEP complementary DNA results in an exchange from valine to alanine (V444A). Login to comment 66 ABCB11 p.Val444Ala This exchange is detected in 51.3% of alleles of healthy women, while it was found in 83.3% of alleles of patients with ICP.6 This difference in allele frequency was not statistically significant; however, the association of V444A with ICP suggests that this mutation may become disease relevant under certain conditions such as pregnancy. Login to comment 67 ABCB11 p.Val444Ala The patient described in this report was homozygous for V444A. Login to comment 68 ABCB11 p.Val444Ala The reduced amount of canalicular BSEP implies that homozygous V444A has a major impact on bile formation despite its frequent occurrence in the healthy population. Login to comment 70 ABCB11 p.Val444Ala ABCB11 p.Glu186Gly We have recently described a 16-year-old male pa- tient8 with BRIC-2.13 He was compound heterozygous for the BSEP mutations E186G and V444A. Login to comment 71 ABCB11 p.Val444Ala This patient also had reduced canalicular BSEP expression, emphasizing the association between the common variant V444A and a decrease in canalicular BSEP. Login to comment 73 ABCB11 p.Val444Ala ABCB11 p.Glu186Gly However, in the patient with BRIC-2 described previ- ously8 with the E186G/V444A genotype, the amount of BSEP messenger RNA was normal despite reduced canalicular BSEP expression. Login to comment 75 ABCB11 p.Val444Ala These possibilities include impaired protein maturation leading to increased ER-associated degradation as shown for some frequent BSEP mutations underlying PFIC-2.14 Furthermore, an increased retention of BSEP within the secretory pathway15 or reduced accessibility of BSEP from intracellular pools16 may be the result of the V444A polymorphism. Login to comment 79 ABCB11 p.Glu297Gly ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Arg432Thr In addition to changes in protein localization, V444A may alter transport activity as described recently for 2 BRIC-associated BSEP mutations (R432T and E297G).19 Another possibility of reduced transporter activity includes an increased susceptibility of V444A toward the inhibitory effect of estrogens.20 Homozygous V444A can be expected in 25% of the population, but homozygous V444A alone cannot explain the severity of ICP in our patient. Login to comment 81 ABCB4 p.Ser320Phe ABCB4 p.Ser320Phe The MDR3 mutation S320F has been shown to be specific for ICP.6 Strikingly, S320F does not result in an obvious decrease in MDR3 immunoreactivity as compared with BSEP. Login to comment 82 ABCB4 p.Ser320Phe This is in line with recent observations that at least 4 of the 18 published severe, PFIC-3-associated, MDR3 mutations do not alter MDR3 localization.10,21,22 In conclusion, the ICP-relevant mutation S320F probably alters the activity but not the localization of MDR3. Login to comment 83 ABCB11 p.Val444Ala It may be speculated that reduced activity of mutated MDR3 induces changes in the lipid composition of the canalicular membrane, which consecutively causes altered BSEP expression when the V444A polymorphism is present. Login to comment 92 ABCB4 p.Ser320Phe Treatment options for patients with ICP include cholestyramine and ursodeoxycholate.24 To date, ursodeoxycholate seems to represent the most effective therapy, which has a beneficial effect on pruritus and liver enzyme levels.24-26 Ursodeoxycholate may also improve fetal outcome by reducing the risk of preterm delivery.26 Typically, the total amount of serum bile salts (including ursodeoxycholate) is not significantly affected by ursodeoxycholate treatment.24 However, ursodeoxycholate replaces endogenous bile salts (by about 45%), thereby reducing the absolute (and relative) amount of endogenous bile salts by almost 60%.24 In patients with PFIC-3 with severe MDR3 mutations, residual MDR3 activity was shown to be essential for a response to ursodeoxycholate treatment.22,27 The remaining activity of MDR3 in our patient with the homozygous mutation S320F may account in part for the normalization of liver enzyme levels that was induced by UDCA. Login to comment 96 ABCB4 p.Ser320Phe Both the mother and aunt of our patient, who were heterozygous for the MDR3 mutation S320F, had a milder course of ICP, pointing to a genotype-phenotype relationship. Login to comment 97 ABCB11 p.Val444Ala ABCB4 p.Ser320Phe Homozygosity for both the S320F MDR3 mutation and the V444A BSEP mutation may account for the severity and early onset of ICP in our patient. Login to comment 99 ABCB11 p.Val444Ala Our findings show that the common BSEP polymorphism V444A becomes disease relevant when precipitating factors occur. Login to comment