ABCMdb

PMID: 21044052

Pacifico L, Carducci C, Poggiogalle E, Caravona F, Antonozzi I, Chiesa C, Maggiore G
Mutational analysis of ABCC2 gene in two siblings with neonatal-onset Dubin Johnson syndrome.
Clin Genet. 2010 Dec;78(6):598-600. doi: 10.1111/j.1399-0004.2010.01497.x., [PubMed]

Sentences

No. Mutations Sentence Comment

27 ABCC2 p.Arg768Trp ABCC2 p.Arg1066* Mutation analysis showed that both siblings were compound heterozygous for missense mutation on exon 18: p.R768W (c.2302 C>T) and nonsense mutation on exon 23 p.R1066X (c.3196 C>T). Login to comment 28 ABCC2 p.Arg768Trp ABCC2 p.Arg1066* ABCC2 p.Gln1382Arg ABCC2 p.Arg393Trp ABCC2 p.Ser325* ABCC2 p.Tyr1275* ABCC2 p.Leu441Met ABCC2 p.Trp709Arg ABCC2 p.Thr1273Ala ABCC2 p.Gly676Arg ABCC2 p.Arg100* ABCC2 p.Glu1352Gln ABCC2 p.Arg1310* The study of allelic segregation in Letter to the Editor R100X R393W IVS6_IVS7del L441M IVS13 +2 T>A IVS15 +2 T>C G676R IVS18 +2 T>C R768W * 2748_2883del * R1066X * 3399_3400del L1173F 3615_3843del* Y1275X * R1310X Q1382R R1392_M1393del S325X W709R T1273A IVS8 +4 A>G 1256_1272delins CT 4292_4293delR1150H E1352Q * Exon 1 32 Fig. 1. Login to comment 37 ABCC2 p.Arg768Trp In particular, the missense mutation (p.R768W) has been identified in homozygosis as well as in compound heterozygosis in different populations (Japanese, Caucasian) (4, 11-15), suggesting that this is a common allele in the DJS patients. Login to comment 42 ABCC2 p.Arg768Trp The missense mutation R768W found in our patients is indeed located in the Walker C motif of the first ABC domain. Login to comment 43 ABCC2 p.Arg768Trp ABCC2 p.Arg768Trp Immunochemical data by Hashimoto et al. (16) in a DJS patient with the R768W mutation have shown that MRP2 protein could not be expressed in the canalicular membrane of hepatocytes of such patient Pulse chase analysis revealed that the precursor form of the wild-type MRP2 were converted to the mature form, which is resistant to endoglycosidase H in about 60 min while the precursor form of the R768W MRP2, which is sensitive to endoglycosidase H, was rapidly degraded within 120 min and did not mature to the fully glycosylated form (16). Login to comment 44 ABCC2 p.Arg768Trp Thus the mutation R768W MRP2 appears to block the maturation process of MRP2 protein during membrane sorting, plausibly from endoplasmic reticulum to the Golgi apparatus. Login to comment 45 ABCC2 p.Arg1066* The nonsense mutation p.R1066X is known in DJS and leads to the absence of four membrane-spanning domains and the complete second ATP cassette. Login to comment 47 ABCC2 p.Arg768Trp In this case our patients will result functionally hemyzygotes for R768W mutation. Login to comment 51 ABCC2 p.Arg768Trp In that vein, it may be of interest that Toh et al. found higher bilirubin levels in patients with R768W mutation compared to those with other mutations, and they also suggested that this mutation might cause more severe disruption of the transporter activity (4). Login to comment 101 ABCC2 p.Arg768Trp Materna V, Lage H. Homozygous mutation Arg768Trp in the ABC-transporter encoding gene MRP2/cMOAT/ABCC2 causes Dubin-Johnson syndrome in a Caucasian patient. Login to comment