A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome.

Tate, Genshu; Li, Min; Suzuki, Takao; Mitsuya, Toshiyuki

doi:10.1266/ggs.77.117

Cited by 29 publications

(11 citation statements)

References 24 publications

(26 reference statements)

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“…The mutations are different from those reported from Japanese patients. Most reported mutations of the ABCC2 gene in DJS involve one or both ABC (8). These ABC are important for ATP binding and are highly conserved (7,8).…”

Section: Discussionmentioning

confidence: 99%

“…Most reported mutations of the ABCC2 gene in DJS involve one or both ABC (8). These ABC are important for ATP binding and are highly conserved (7,8). From reviewing reported cases, almost all the patients diagnosed as DJS before 10 y of age have mutations involving one of the two ABC of the MRP2 protein whereas mutations involving domains other than ABC of the MRP2 protein are observed mostly in adults (see Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…The ABC are functional regions responsible for nucleotide binding and have three motifs: Walker A, Walker B, and the signature C motif. These motifs are important for ATP binding and are highly conserved among members of the ABC transporter superfamily (7,8).The human ABCC2 gene is localized to chromosome 10q24, spans about 45 kb, and contains 32 exons (9). The first mutation of ABCC2 gene responsible for DJS was detected in 1997 (10).…”

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Neonatal Dubin-Johnson Syndrome: Long-Term Follow-up and MRP2 Mutations Study

Lee

Chen

et al. 2006

Pediatr Res

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Neonatal Dubin-Johnson syndrome (DJS) is rarely diagnosed and mutational analysis of multidrug-resistance-associated protein 2 (MRP2) in such patients had not been reported. We aimed to investigate the possible correlations between genotype and phenotype of patients with DJS. Four cases of DJS, two diagnosed during the neonatal period and two diagnosed at adolescence, were followed for 5-20 y. Mutational analysis in the MRP2/ABCC2 gene was performed in all four cases. Biphasic pattern of jaundice attack was observed in one patient who was followed for 20 y, with jaundice subsiding before 1 y of age and recurring at adolescence. Six novel mutations in four patients were found, including deletions (2748del136, 3615del229, and Del3399-3400), and missense mutations (L441M and E1352Q) and nonsense mutation (Y1275X). The immunohistochemical staining in liver tissues from two patients with neonatal onset showed negative staining for MRP2. Reviewing previously reported cases, all patients diagnosed as DJS before 10 y of age have mutations involving one of the two ATP-binding cassettes (ABC) of the MRP2. This study suggests that long-term follow-up is indicated for neonatal DJS because of possible recurrence and/or second attacks of jaundice in later life, and that disruption of functionally important ABC domains in MRP2 may be related to the earlier onset of the disease. of chronic or intermittent conjugated hyperbilirubinemia, a defect in the excretion of anionic conjugate from the hepatocyte into the bile, delayed clearance of intravenous bromosulfophthalein (BSP), increased urinary excretion of coproporphyrin I, and hepatic histopathology of lysosomal accumulation of black pigment (1-3). Most patients are asymptomatic, although some patients presented with vague right-upper-quadrant abdominal pain, weakness, nausea, or vomiting. Physical examination is frequently normal or unremarkable. Jaundice is evident by the time of puberty in about half, and by the age of 20 in about two-thirds, of affected persons (1). Liver enzymes are usually within normal limits, although the bilirubin levels fluctuate (1).The molecular mechanism in DJS is impaired hepatobiliary excretion of anionic conjugate caused by the defects of MRP2 or cMOAT (4,5). The formal genetic name is ABCC2. MRP2 protein acts as an ATP-dependent export pump for anionic glutathione or glucuronate conjugate from hepatocyte into bile and is expressed at the apical/canalicular plasma membrane of hepatocyte (6). The MRP2 protein is a member of the ABC transporter superfamily. The predicted topology of the MRP2 protein contains three MSD and two ABC (7). The ABC are functional regions responsible for nucleotide binding and have three motifs: Walker A, Walker B, and the signature C motif. These motifs are important for ATP binding and are highly conserved among members of the ABC transporter superfamily (7,8).The human ABCC2 gene is localized to chromosome 10q24, spans about 45 kb, and contains 32 exons (9). The first mutation of ABCC2 gene responsible for D...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Neonatal Dubin-Johnson Syndrome: Long-Term Follow-up and MRP2 Mutations Study

Lee

Chen

et al. 2006

Pediatr Res

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“…Various polymorphisms in the MRP2 gene contribute to the etiology of the Dubin-Johnson syndrome (Paulusma et al, 1996;Wada et al, 1998;Tsujii et al, 1999;Mor-Cohen et al, 2001;Tate et al, 2002;Materna and Lage, 2003;Wakusawa et al, 2003). It was shown that single nucleotide changes like the 3517 A/T transition in exon 25 are associated with lower efflux of MRP2 substrates and altered distribution of the protein in transfected cells (Mor-Cohen et al, 2001;Keitel et al, 2003).…”

Section: Meyer Zu Schwabedissen Et Almentioning

confidence: 99%