ABCMdb

PMID: 12884082

Wakusawa S, Machida I, Suzuki S, Hayashi H, Yano M, Yoshioka K
Identification of a novel 2026G-->C mutation of the MRP2 gene in a Japanese patient with Dubin-Johnson syndrome.
J Hum Genet. 2003;48(8):425-9. Epub 2003 Jul 22., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC2 p.Gly676Arg The 2026G fi C mutation was a novel mutation in exon 16 affecting the conversion of Gly676 to Arg676 (G676R) in the MRP2 protein, and was not detected in fifty healthy volunteers. Login to comment 5 ABCC2 p.Gly676Arg The G676R mutation was located in the Walker A motif of the first nucleotide binding domain in the MRP2 protein, and it was suggested that the mutation induced the dysfunction of the MRP2 protein. Login to comment 13 ABCC2 p.Gly676Arg In the present study, we conducted a mutational analysis in three Japanese DJS patients and found two known deletion mutations (c.1901del67, c.2272del168) and a novel missense mutation of G676R in the first nucleotide-binding domain (NBD1) in the MRP2 protein. Login to comment 40 ABCC2 p.Gly676Arg In addition, sequencing analysis of exons 16 and 1 detected a novel missense mutation of 2026G fi C (G676R) in the first Walker A motif (Fig. 2) and a single nucleotide polymorphism (SNP) of )24C fi T in the non-coding region of exon 1 (Fig. 3). Login to comment 43 ABCC2 p.Arg1150His ABCC2 p.Arg1066* ABCC2 p.Ile1173Phe ABCC2 p.Gln1382Arg ABCC2 p.Arg1310* With respect to the polymorphism )24C fi T, we also employed a restriction enzyme assay with BbsI; the results showed that his spouse and one daughter were heterozygous for this SNP, but other Table 1 Mutations of MRP2 in Dubin-Johnson syndrome (DJS) Nucleotide mutation Predicted effects References Splice site mutation 1815+2T fi A 1669del147 (exon13 skipping) Wada et al. 1998 1967+2T fi C 1901del67 (exon15 skipping) Kajihara et al. 1998 2439+2T fi C 2272del168 (exon18 skipping) Toh et al. 1999 Deletion mutation Del4170-5 Del R1392 , M1393 Tsujii et al. 1999 Missense mutation 2302C fi T R768 W Wada et al. 1998 3449G fi A R1150H Mor-Cohen et al. 2001 3517A fi T I1173F Mor-Cohen et al. 2001 4145A fi G Q1382R Toh et al. 1999 Nonesense mutation 3196C fi T R1066X Paulusma et al. 1997 3928C fi T R1310X Tate et al. 2002 family members did not possess it (Fig. 4). Login to comment 48 ABCC2 p.Gly676Arg Discussion In the present study, we have found a novel missense mutation that is predicted to affect the substitution of glycine676 with arginine676 (G676R), together with two known deletion mutations. Login to comment 51 ABCC2 p.Gln1382Arg ABCC2 p.Gly676Arg One of these mutations (R768 W) is located within the first Walker C motif, and the other (Q1382R) lies within the second ABC (Toh Table 2 Mutations of the MRP2 gene in DJS patients and family members (wild wild-type, nd not determined) a C child, S siblings Patients and family Bilirubin (mg/dl) Alteration in MRP2 gene Predicted effects membersa Total Conjugated 1 DJ1 2.7 1.8 2439+2T fi C/2439+2T fi C 2272del168/2272del168 DJ1/C1 0.6 0.2 2439+2T fi C/wild 2272del168/wild DJ1/C2 0.6 0.2 2439+2T fi C/wild 2272del168/wild 2 DJ2 3.0 2.4 1967+2T fi C/1967+2T fi C 1901del67/1901del67 DJ2/S1 0.4 0.1 1967+2T fi C/wild 1901del67/wild DJ2/S2 0.5 0.2 Wild/wild ) DJ2/C1 0.8 0.2 1967+2T fi C/wild 1901del67/wild 3 DJ3 3.4 2.8 1967+2T fi C/2026G fi C 1901del67/G676R DJ3/S1 0.8 0.3 Wild/wild ) DJ3/S2 0.9 0.3 Wild/wild ) DJ3/S3 0.9 0.3 Wild/wild ) DJ3/S4 0.9 0.3 1967+2T fi C/wild 1901del67/wild DJ3/S5 0.3 0.1 Wild/wild ) DJ3/S6 1.3 0.6 1967+2T fi C/wild 1901del67/wild DJ3/C1 nd nd 1967+2T fi C/wild 1901del67/wild DJ3/C2 0.7 0.3 1967+2T fi C/wild 1901del67/wild Fig. 2 Sequencing analysis of exon 16 in the MRP2 gene from DJ3 (arrow site of the heterozygous missense mutation 2026G fi C). Login to comment 57 ABCC2 p.Gly676Arg The G676R conversion is the first reported mutation of the Walker A motif in MRP2 protein. Login to comment 59 ABCC2 p.Gly676Arg The G676R mutation is located at the 5`-flanking end of lysine, an amino acid shown to bind the c-phosphate of ATP (Konig et al. 2003) in NBD1. Login to comment 62 ABCC2 p.Lys677Arg Hashimoto et al. (2002) have reported that the artificial mutation K677R of the MRP2 gene and the missense mutation R768 W cause deficient maturation and impaired sorting. Login to comment 63 ABCC2 p.Gly676Arg The G676R mutation is associated with a change of hydrophobicity and electronic charge. Login to comment 64 ABCC2 p.Gly676Arg It has been speculated that G676R causes two basic amino acids, arginine and lysine, to interact and/or a change in the conformation of NBD1. Login to comment 69 ABCC2 p.Gly676Arg Because the parents and one sibling were deceased, the genetic route and correct segregation of the G676R mutation remain unclear. Login to comment 71 ABCC2 p.Gly676Arg In conclusion, a novel disease-associated mutation, 2026G fi C, which is predicted to cause a G676R conversion in the MRP2 protein, has been detected in a DJS patient. Login to comment