* 601107

ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 2; ABCC2


Alternative titles; symbols

MULTISPECIFIC ORGANIC ANION TRANSPORTER, CANALICULAR; CMOAT
MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2; MRP2


HGNC Approved Gene Symbol: ABCC2

Cytogenetic location: 10q24.2     Genomic coordinates (GRCh38): 10:99,782,640-99,852,594 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
10q24.2 Dubin-Johnson syndrome 237500 AR 3

TEXT

Description

ABCC2 is a 190-kD integral membrane glycoprotein expressed mainly in the canalicular (apical) membrane of liver cells. It belongs to the ATP-binding cassette transporter superfamily and transports endogenous and exogenous anionic conjugates from hepatocytes to bile. ABCC2 is also involved in resistance of cancer cells to chemotherapeutic drugs (summary by Mor-Cohen et al., 2001).


Cloning and Expression

Paulusma et al. (1996) used the animal model of Dubin-Johnson syndrome (DJS; 237500), the TR- rat, to elucidate the canalicular multispecific organic anion transporter (cMOAT), which mediates hepatobiliary excretion of numerous organic anions. From studies of the cDNA for rat cmoat, which is similar to human multidrug resistance protein (MRP; 158343), they presented evidence suggesting that MRP and cMOAT are expressed in the basolateral and canalicular (apical) parts of the hepatocyte, respectively, and that cMOAT but not MRP is involved in biliary organic anion transport. They also showed that the 2 proteins are encoded by 2 different genes. In the TR- rat, a single nucleotide deletion in the cmoat gene resulted in reduced mRNA and absent protein.


Gene Function

Evers et al. (1998), who referred to cMOAT as multidrug resistance-associated protein-2 (MRP2), studied its drug export activity in polarized kidney in MDCK cells. In contrast to MRP1 (158343), cMOAT was found predominantly intracellularly in nonpolarized cells, suggesting the cMOAT requires a polarized cell for plasma membrane routing. They found that when kidney epithelial MDCK cells were grown in a monolayer, cMOAT localized to the apical plasma membrane. Their studies demonstrated that cMOAT causes transport of organic anions, including a substrate not shown to be transported by organic anion transporters previously. Transport was inhibited only inefficiently by compounds known to block MRP1. They also showed that cMOAT caused transport of the anticancer drug vinblastine to the apical side of a cell monolayer. They concluded that cMOAT is a 5-prime-adenosine triphosphate binding cassette transporter that may be involved in drug resistance in mammalian cells.

Using microarray analysis and quantitative RT-PCR, Xu et al. (2012) found that expression of microRNA-297 (MIR297; 615520) was downregulated in chemotherapy-resistant human colorectal carcinoma cell lines compared with their parental cell lines. Downregulation of MIR297 was inversely proportional to expression of a putative target, MRP2. Quantitative RT-PCR and Western blot analyses revealed that expression of MIR297 and MRP2 progressively decreased and increased, respectively, with clinical stage in human colorectal carcinomas. Reporter gene assays confirmed that MRP2 was a direct target of MIR297. Expression of an MIR297 mimic increased cell sensitivity to anticancer drugs and induced apoptosis in colorectal cancer cells in vitro and in vivo following injection into nude mice.


Gene Structure

Toh et al. (1999) determined the exon/intron structure of the human MRP2/CMOAT gene. They found that the human gene contains 32 exons and spans 200 kb or more genomic DNA.


Mapping

By fluorescence in situ hybridization (FISH), Taniguchi et al. (1996) mapped the human CMOAT gene to 10q24. Also by FISH, van Kuijck et al. (1997) mapped the CMOAT gene to human 10q24 and mouse 19D2. Gopalan et al. (1998) likewise mapped the cmoat gene to mouse chromosome 19.


Molecular Genetics

Zimniak (1993) suggested that the defect in Dubin-Johnson syndrome may reside in the CMOAT gene. Dubin-Johnson syndrome is an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, an increase in the urinary excretion of coproporphyrin isomer I, deposition of melanin-like pigment in hepatocytes, and prolonged retention of sulfobromophthalein, but otherwise normal liver function. Consistent with findings of defects in the homologous cmoat gene in 2 rat models of hyperbilirubinemia (Paulusma et al., 1996, Ito et al., 1997), Wada et al. (1998) reported 2 deletions and a missense mutation in the active transport family signature region in the CMOAT gene in patients with DJS.

In a 63-year-old Japanese man with DJS, born of first-cousin parents, Kajihara et al. (1998) identified homozygosity for a splice site mutation in the ABCC2 gene (601107.0006).

Toh et al. (1999) identified 3 mutations, 2 of which were novel, in the MRP2/CMOAT gene in DJS patients (601107.0001 and 601107.0003-601107.0004, respectively).

All mutations identified to that time were in the cytoplasmic domain, which includes 2 ATP-binding cassettes and the linker region, or in the adjacent putative transmembrane domain.

Mor-Cohen et al. (2001) analyzed the ABCC2 gene in 35 Israeli DJS patients from 24 unrelated families, most of whom were ascertained previously by Shani et al. (1970) and had been followed for more than 3 decades, including 22 DJS patients from 13 Iranian Jewish families, 5 from 4 Moroccan Jewish families, 2 from mixed Moroccan and Iranian families, 3 of Ashkenazi Jewish origin, and 3 of Turkish, Kurdish, and Afghan Jewish origin, respectively. All 22 Iranian Jewish patients were homozygous for an I1173F mutation (601107.0007) in ABCC2, and all 5 Moroccan Jewish patients were homozygous for an R1150H mutation (601107.0008). Both mutations were unique to those specific populations.

In 2 brothers with neonatal-onset DJS, Pacifico et al. (2010) identified compound heterozygosity for an R768W mutation (601107.0001) and a nonsense mutation (R1066X; 601107.0009) in ABCC2. Both mutations had previously been found in adult patients, although compound heterozygosity for the 2 mutations was novel.


ALLELIC VARIANTS ( 9 Selected Examples):

.0001 DUBIN-JOHNSON SYNDROME

ABCC2, ARG768TRP
  
RCV000008923...

In 3 patients with Dubin-Johnson syndrome (DJS; 237500), 2 of whom were brothers, Wada et al. (1998) demonstrated a C-to-T transition at nucleotide 2302 in the CMOAT gene, resulting in an arg768-to-trp (R768W) substitution. This mutation was homozygous in genomic DNA of a severely affected patient and heterozygous in the 2 brothers and their father. The second alteration in the 2 brothers with DJS was 2272del168 (601107.0002), a deletion of 168 nucleotides from 2272 to 2439 in the PCR product. Thus the brothers were compound heterozygotes, whereas the parents, who had both been diagnosed as carriers by urinary excretion of coproporphyrin I, were heterozygous for one or the other of these mutations. A sister had neither mutation.

In an 81-year-old Japanese man with DJS, Toh et al. (1999) found homozygosity for the R768W mutation. The man was unrelated to the patients studied by Wada et al. (1998).

Materna and Lage (2003) identified the R768W mutation in homozygous state in a female Caucasian (Turkish) patient with DJS.

In 2 brothers with neonatal-onset DJS, Pacifico et al. (2010) identified compound heterozygosity for R768W and a 3196C-T transition in exon 23 of the ABCC2 gene, resulting in an arg1066-to-ter (R1066X; 601107.0009) substitution predicted to result in a protein lacking 4 membrane-spanning domains and the complete second ATP cassette.


.0002 DUBIN-JOHNSON SYNDROME

ABCC2, 168-BP DEL, NT2272
  
RCV000008924

For discussion of the 168-bp deletion (2272del168) in the ABCC2 gene that was found in 2 brothers with Dubin-Johnson syndrome (DJS; 237500) by Wada et al. (1998), see 601107.0001.


.0003 DUBIN-JOHNSON SYNDROME

ABCC2, 147-BP DEL, NT1669
  
RCV000008925

In a patient with Dubin-Johnson syndrome (DJS; 237500), Wada et al. (1998) found apparent homozygosity for a 1669del147 mutation, a deletion of 147 nucleotides from 1669 to 1815 in the PCR product. The genomic sequence indicated that the deletion junction was at an exon-intron boundary. A T-to-A transversion 2 bases after the 3-prime boundary of the corresponding exon (the splice donor site) was identified in genomic DNA isolated from the patient.


.0004 DUBIN-JOHNSON SYNDROME

ABCC2, IVS18DS, T-C, +2
  
RCV000008926...

In a Japanese family segregating Dubin-Johnson syndrome (DJS; 237500), Toh et al. (1999) found that affected individuals were homozygous for a 2439+2T-C transition 2 bases 3-prime of exon 18. This involved a conserved splice donor site and was predicted to cause deletion of 168 nucleotides at positions 2272-2439 in the cDNA.


.0005 DUBIN-JOHNSON SYNDROME

ABCC2, GLN1382ARG
  
RCV000008927...

In a patient with Dubin-Johnson syndrome (DJS; 237500), Toh et al. (1999) identified compound heterozygosity for 2 mutations in the CMOAT gene: 2439+2T-C (601107.0004) and an A-to-G transition at nucleotide 4145 that resulted in a gln1382-to-arg (Q1382R) substitution.


.0006 DUBIN-JOHNSON SYNDROME

ABCC2, 67-BP DEL, IVSDS, T-C, +2
  
RCV000008928...

Kajihara et al. (1998) identified a single nucleotide substitution at an exon-intron junction of the CMOAT gene which generated liver cDNA with a 67-bp exon deletion. The exon skipping was due to a GT-to-GC change in the splice donor site of the 3-prime flanking intron. The patient was a 63-year-old Japanese man, the offspring of first-cousin parents. He had had a history of jaundice since childhood. Dubin-Johnson syndrome (DJS; 237500) was diagnosed on the basis of chronic conjugated hyperbilirubinemia, and delayed clearance and secondary rise at 90 minutes of intravenously injected bromosulfophthalein. Hepatic tissue was macroscopically black, and hyperpigmented liver parenchymal cells were demonstrated.


.0007 DUBIN-JOHNSON SYNDROME

ABCC2, ILE1173PHE
  
RCV000008929...

In 22 Iranian Jewish patients with Dubin-Johnson syndrome (DJS; 237500) from 13 unrelated families, Mor-Cohen et al. (2001) screened all 32 exons and adjacent regions of the MRP2 gene and identified homozygosity for a 3517A-T transversion in exon 25, predicting an ile1173-to-phe (I1173F) substitution. Use of 4 intragenic dimorphisms and haplotype analyses disclosed a specific founder effect. The mutation was introduced into an MRP2 expression vector by site-directed mutagenesis, transfected into HEK293 cells, and analyzed by a fluorescence transport assay, immunoblot, and immunocytochemistry. The studies demonstrated that the mutation impaired the transport activity of MRP2. Immunoblot analysis and immunocytochemistry showed that expression of the mutation was low and mislocated to the endoplasmic reticulum of the transfected cells.


.0008 DUBIN-JOHNSON SYNDROME

ABCC2, ARG1150HIS
  
RCV000008930...

In 5 Moroccan patients with Dubin-Johnson syndrome (DJS; 237500) from 4 unrelated families, Mor-Cohen et al. (2001) screened all 32 exons and adjacent regions of the MRP2 gene and identified homozygosity for a 3449G-A transition in exon 25, predicting an arg1150-to-his (R1150H) substitution. The mutation impaired the transport activity of MRP2. The mutant MRP2 matured properly and localized at the plasma membrane of transfected cells.


.0009 DUBIN-JOHNSON SYNDROME

ABCC2, ARG1066TER
  
RCV000024307...

For discussion of the arg1066-to-ter (R1066X) mutation in the ABCC2 gene that was found in compound heterozygous state in patients with neonatal-onset Dubin-Johnson syndrome (DJS; 237500) by Pacifico et al. (2010), see 601107.0001.


REFERENCES

  1. Evers, R., Kool, M., van Deemter, L., Janssen, H., Calafat, J., Oomen, L. C. J. M., Paulusma, C. C., Oude Elferink, R. P. J., Baas, F., Schinkel, A. H., Borst, P. Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. J. Clin. Invest. 101: 1310-1319, 1998. [PubMed: 9525973, related citations] [Full Text]

  2. Gopalan, G., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Donovan, P. J. Chromosome localization of two new mammalian kinases related to yeast and fly chromosome segregation-regulators. Mammalian Genome 9: 86-96, 1998. [PubMed: 9434955, related citations] [Full Text]

  3. Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., Sugiyama, Y. Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am. J. Physiol. 272: G16-G22, 1997. [PubMed: 9038871, related citations] [Full Text]

  4. Kajihara, S., Hisatomi, A., Mizuta, T., Hara, T., Ozaki, I., Wada, I., Yamamoto, K. A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome. Biochem. Biophys. Res. Commun. 253: 454-457, 1998. [PubMed: 9878557, related citations] [Full Text]

  5. Materna, V., Lage, H. Homozygous mutation arg(768)trp in the ABC-transporter encoding gene MRP2/cMOAT/ABCC2 causes Dubin-Johnson syndrome in a Caucasian patient. J. Hum. Genet. 48: 484-486, 2003. [PubMed: 12942343, related citations] [Full Text]

  6. Mor-Cohen, R., Zivelin, A., Rosenberg, N., Shani, M., Muallem, S., Seligsohn, U. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J. Biol. Chem. 276: 36923-36930, 2001. [PubMed: 11477083, related citations] [Full Text]

  7. 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 syndrome. (Letter) Clin. Genet. 78: 598-600, 2010. [PubMed: 21044052, related citations] [Full Text]

  8. Paulusma, C. C., Bosma, P. J., Zaman, G. J. R., Bakker, C. T. M., Otter, M., Scheffer, G. L., Scheper, R. J., Borst, P., Oude Elferink, R. P. J. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271: 1126-1128, 1996. [PubMed: 8599091, related citations] [Full Text]

  9. Shani, M., Seligsohn, U., Gilon, E., Sheba, C., Adam, A. Dubin-Johnson syndrome in Israel. I. Clinical, laboratory, and genetic aspects of 101 cases. Quart. J. Med. 39: 549-567, 1970. [PubMed: 5532959, related citations]

  10. Taniguchi, K., Wada, M., Kohno, K., Nakamura, T., Kawabe, T., Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., Kuwano, M. A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res. 56: 4124-4129, 1996. [PubMed: 8797578, related citations]

  11. Toh, S., Wada, M., Uchiumi, T., Inokuchi, A., Makino, Y., Horie, Y., Adachi, Y., Sakisaka, S., Kuwano, M. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am. J. Hum. Genet. 64: 739-746, 1999. [PubMed: 10053008, related citations] [Full Text]

  12. van Kuijck, M. A., Kool, M., Merkx, G. F. M., Geurts van Kessel, A., Bindels, R. J. M., Deen, P. M. T., van Os, C. H. Assignment of the canalicular multispecific organic anion transporter gene (CMOAT) to human chromosome 10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization. Cytogenet. Cell Genet. 77: 285-287, 1997. [PubMed: 9284939, related citations] [Full Text]

  13. Wada, M., Toh, S., Taniguchi, K., Nakamura, T., Uchiumi, T., Kohno, K., Yoshida, I., Kimura, A., Sakisaka, S., Adachi, Y., Kuwano, M. Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. Hum. Molec. Genet. 7: 203-207, 1998. [PubMed: 9425227, related citations] [Full Text]

  14. Xu, K., Liang, X., Shen, K., Cui, D., Zheng, Y., Xu, J., Fan, Z., Qiu, Y., Li, Q., Ni, L. miR-297 modulates multidrug resistance in human colorectal carcinoma by down-regulating MRP-2. Biochem. J. 446: 291-300, 2012. [PubMed: 22676135, related citations] [Full Text]

  15. Zimniak, P. Dubin-Johnson and Rotor syndromes: molecular basis and pathogenesis. Semin. Liver Dis. 13: 248-260, 1993. [PubMed: 8235715, related citations] [Full Text]


Matthew B. Gross - updated : 10/24/2016
Marla J. F. O'Neill - updated : 5/25/2012
Victor A. McKusick - updated : 12/23/2003
Victor A. McKusick - updated : 2/24/2003
Victor A. McKusick - updated : 4/12/1999
Victor A. McKusick - updated : 3/22/1999
Carol A. Bocchini - updated : 11/17/1998
Victor A. McKusick - updated : 4/16/1998
Victor A. McKusick - updated : 4/15/1998
Victor A. McKusick - updated : 2/19/1998
Victor A. McKusick - updated : 10/20/1997
Creation Date:
Victor A. McKusick : 3/7/1996
carol : 05/29/2019
mgross : 10/24/2016
carol : 09/16/2016
carol : 09/22/2015
carol : 6/10/2015
mcolton : 6/9/2015
mgross : 11/15/2013
terry : 11/15/2012
terry : 5/25/2012
tkritzer : 12/26/2003
terry : 12/23/2003
carol : 3/3/2003
tkritzer : 2/25/2003
terry : 2/24/2003
carol : 11/10/1999
carol : 11/9/1999
carol : 4/12/1999
carol : 4/5/1999
terry : 3/22/1999
terry : 11/17/1998
carol : 11/16/1998
dholmes : 5/11/1998
carol : 5/2/1998
terry : 4/16/1998
carol : 4/15/1998
terry : 4/15/1998
terry : 4/15/1998
terry : 2/19/1998
terry : 10/20/1997
mark : 3/9/1996
mark : 3/7/1996

* 601107

ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 2; ABCC2


Alternative titles; symbols

MULTISPECIFIC ORGANIC ANION TRANSPORTER, CANALICULAR; CMOAT
MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2; MRP2


HGNC Approved Gene Symbol: ABCC2

SNOMEDCT: 44553005;   ICD10CM: E80.6;  


Cytogenetic location: 10q24.2     Genomic coordinates (GRCh38): 10:99,782,640-99,852,594 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
10q24.2 Dubin-Johnson syndrome 237500 Autosomal recessive 3

TEXT

Description

ABCC2 is a 190-kD integral membrane glycoprotein expressed mainly in the canalicular (apical) membrane of liver cells. It belongs to the ATP-binding cassette transporter superfamily and transports endogenous and exogenous anionic conjugates from hepatocytes to bile. ABCC2 is also involved in resistance of cancer cells to chemotherapeutic drugs (summary by Mor-Cohen et al., 2001).


Cloning and Expression

Paulusma et al. (1996) used the animal model of Dubin-Johnson syndrome (DJS; 237500), the TR- rat, to elucidate the canalicular multispecific organic anion transporter (cMOAT), which mediates hepatobiliary excretion of numerous organic anions. From studies of the cDNA for rat cmoat, which is similar to human multidrug resistance protein (MRP; 158343), they presented evidence suggesting that MRP and cMOAT are expressed in the basolateral and canalicular (apical) parts of the hepatocyte, respectively, and that cMOAT but not MRP is involved in biliary organic anion transport. They also showed that the 2 proteins are encoded by 2 different genes. In the TR- rat, a single nucleotide deletion in the cmoat gene resulted in reduced mRNA and absent protein.


Gene Function

Evers et al. (1998), who referred to cMOAT as multidrug resistance-associated protein-2 (MRP2), studied its drug export activity in polarized kidney in MDCK cells. In contrast to MRP1 (158343), cMOAT was found predominantly intracellularly in nonpolarized cells, suggesting the cMOAT requires a polarized cell for plasma membrane routing. They found that when kidney epithelial MDCK cells were grown in a monolayer, cMOAT localized to the apical plasma membrane. Their studies demonstrated that cMOAT causes transport of organic anions, including a substrate not shown to be transported by organic anion transporters previously. Transport was inhibited only inefficiently by compounds known to block MRP1. They also showed that cMOAT caused transport of the anticancer drug vinblastine to the apical side of a cell monolayer. They concluded that cMOAT is a 5-prime-adenosine triphosphate binding cassette transporter that may be involved in drug resistance in mammalian cells.

Using microarray analysis and quantitative RT-PCR, Xu et al. (2012) found that expression of microRNA-297 (MIR297; 615520) was downregulated in chemotherapy-resistant human colorectal carcinoma cell lines compared with their parental cell lines. Downregulation of MIR297 was inversely proportional to expression of a putative target, MRP2. Quantitative RT-PCR and Western blot analyses revealed that expression of MIR297 and MRP2 progressively decreased and increased, respectively, with clinical stage in human colorectal carcinomas. Reporter gene assays confirmed that MRP2 was a direct target of MIR297. Expression of an MIR297 mimic increased cell sensitivity to anticancer drugs and induced apoptosis in colorectal cancer cells in vitro and in vivo following injection into nude mice.


Gene Structure

Toh et al. (1999) determined the exon/intron structure of the human MRP2/CMOAT gene. They found that the human gene contains 32 exons and spans 200 kb or more genomic DNA.


Mapping

By fluorescence in situ hybridization (FISH), Taniguchi et al. (1996) mapped the human CMOAT gene to 10q24. Also by FISH, van Kuijck et al. (1997) mapped the CMOAT gene to human 10q24 and mouse 19D2. Gopalan et al. (1998) likewise mapped the cmoat gene to mouse chromosome 19.


Molecular Genetics

Zimniak (1993) suggested that the defect in Dubin-Johnson syndrome may reside in the CMOAT gene. Dubin-Johnson syndrome is an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, an increase in the urinary excretion of coproporphyrin isomer I, deposition of melanin-like pigment in hepatocytes, and prolonged retention of sulfobromophthalein, but otherwise normal liver function. Consistent with findings of defects in the homologous cmoat gene in 2 rat models of hyperbilirubinemia (Paulusma et al., 1996, Ito et al., 1997), Wada et al. (1998) reported 2 deletions and a missense mutation in the active transport family signature region in the CMOAT gene in patients with DJS.

In a 63-year-old Japanese man with DJS, born of first-cousin parents, Kajihara et al. (1998) identified homozygosity for a splice site mutation in the ABCC2 gene (601107.0006).

Toh et al. (1999) identified 3 mutations, 2 of which were novel, in the MRP2/CMOAT gene in DJS patients (601107.0001 and 601107.0003-601107.0004, respectively).

All mutations identified to that time were in the cytoplasmic domain, which includes 2 ATP-binding cassettes and the linker region, or in the adjacent putative transmembrane domain.

Mor-Cohen et al. (2001) analyzed the ABCC2 gene in 35 Israeli DJS patients from 24 unrelated families, most of whom were ascertained previously by Shani et al. (1970) and had been followed for more than 3 decades, including 22 DJS patients from 13 Iranian Jewish families, 5 from 4 Moroccan Jewish families, 2 from mixed Moroccan and Iranian families, 3 of Ashkenazi Jewish origin, and 3 of Turkish, Kurdish, and Afghan Jewish origin, respectively. All 22 Iranian Jewish patients were homozygous for an I1173F mutation (601107.0007) in ABCC2, and all 5 Moroccan Jewish patients were homozygous for an R1150H mutation (601107.0008). Both mutations were unique to those specific populations.

In 2 brothers with neonatal-onset DJS, Pacifico et al. (2010) identified compound heterozygosity for an R768W mutation (601107.0001) and a nonsense mutation (R1066X; 601107.0009) in ABCC2. Both mutations had previously been found in adult patients, although compound heterozygosity for the 2 mutations was novel.


ALLELIC VARIANTS 9 Selected Examples):

.0001   DUBIN-JOHNSON SYNDROME

ABCC2, ARG768TRP
SNP: rs56199535, gnomAD: rs56199535, ClinVar: RCV000008923, RCV000726727

In 3 patients with Dubin-Johnson syndrome (DJS; 237500), 2 of whom were brothers, Wada et al. (1998) demonstrated a C-to-T transition at nucleotide 2302 in the CMOAT gene, resulting in an arg768-to-trp (R768W) substitution. This mutation was homozygous in genomic DNA of a severely affected patient and heterozygous in the 2 brothers and their father. The second alteration in the 2 brothers with DJS was 2272del168 (601107.0002), a deletion of 168 nucleotides from 2272 to 2439 in the PCR product. Thus the brothers were compound heterozygotes, whereas the parents, who had both been diagnosed as carriers by urinary excretion of coproporphyrin I, were heterozygous for one or the other of these mutations. A sister had neither mutation.

In an 81-year-old Japanese man with DJS, Toh et al. (1999) found homozygosity for the R768W mutation. The man was unrelated to the patients studied by Wada et al. (1998).

Materna and Lage (2003) identified the R768W mutation in homozygous state in a female Caucasian (Turkish) patient with DJS.

In 2 brothers with neonatal-onset DJS, Pacifico et al. (2010) identified compound heterozygosity for R768W and a 3196C-T transition in exon 23 of the ABCC2 gene, resulting in an arg1066-to-ter (R1066X; 601107.0009) substitution predicted to result in a protein lacking 4 membrane-spanning domains and the complete second ATP cassette.


.0002   DUBIN-JOHNSON SYNDROME

ABCC2, 168-BP DEL, NT2272
SNP: rs2133078815, ClinVar: RCV000008924

For discussion of the 168-bp deletion (2272del168) in the ABCC2 gene that was found in 2 brothers with Dubin-Johnson syndrome (DJS; 237500) by Wada et al. (1998), see 601107.0001.


.0003   DUBIN-JOHNSON SYNDROME

ABCC2, 147-BP DEL, NT1669
SNP: rs387906395, gnomAD: rs387906395, ClinVar: RCV000008925

In a patient with Dubin-Johnson syndrome (DJS; 237500), Wada et al. (1998) found apparent homozygosity for a 1669del147 mutation, a deletion of 147 nucleotides from 1669 to 1815 in the PCR product. The genomic sequence indicated that the deletion junction was at an exon-intron boundary. A T-to-A transversion 2 bases after the 3-prime boundary of the corresponding exon (the splice donor site) was identified in genomic DNA isolated from the patient.


.0004   DUBIN-JOHNSON SYNDROME

ABCC2, IVS18DS, T-C, +2
SNP: rs200606989, gnomAD: rs200606989, ClinVar: RCV000008926, RCV003555980

In a Japanese family segregating Dubin-Johnson syndrome (DJS; 237500), Toh et al. (1999) found that affected individuals were homozygous for a 2439+2T-C transition 2 bases 3-prime of exon 18. This involved a conserved splice donor site and was predicted to cause deletion of 168 nucleotides at positions 2272-2439 in the cDNA.


.0005   DUBIN-JOHNSON SYNDROME

ABCC2, GLN1382ARG
SNP: rs72558202, gnomAD: rs72558202, ClinVar: RCV000008927, RCV003407306

In a patient with Dubin-Johnson syndrome (DJS; 237500), Toh et al. (1999) identified compound heterozygosity for 2 mutations in the CMOAT gene: 2439+2T-C (601107.0004) and an A-to-G transition at nucleotide 4145 that resulted in a gln1382-to-arg (Q1382R) substitution.


.0006   DUBIN-JOHNSON SYNDROME

ABCC2, 67-BP DEL, IVSDS, T-C, +2
SNP: rs387906396, gnomAD: rs387906396, ClinVar: RCV000008928, RCV002512922

Kajihara et al. (1998) identified a single nucleotide substitution at an exon-intron junction of the CMOAT gene which generated liver cDNA with a 67-bp exon deletion. The exon skipping was due to a GT-to-GC change in the splice donor site of the 3-prime flanking intron. The patient was a 63-year-old Japanese man, the offspring of first-cousin parents. He had had a history of jaundice since childhood. Dubin-Johnson syndrome (DJS; 237500) was diagnosed on the basis of chronic conjugated hyperbilirubinemia, and delayed clearance and secondary rise at 90 minutes of intravenously injected bromosulfophthalein. Hepatic tissue was macroscopically black, and hyperpigmented liver parenchymal cells were demonstrated.


.0007   DUBIN-JOHNSON SYNDROME

ABCC2, ILE1173PHE
SNP: rs72558201, gnomAD: rs72558201, ClinVar: RCV000008929, RCV000727693

In 22 Iranian Jewish patients with Dubin-Johnson syndrome (DJS; 237500) from 13 unrelated families, Mor-Cohen et al. (2001) screened all 32 exons and adjacent regions of the MRP2 gene and identified homozygosity for a 3517A-T transversion in exon 25, predicting an ile1173-to-phe (I1173F) substitution. Use of 4 intragenic dimorphisms and haplotype analyses disclosed a specific founder effect. The mutation was introduced into an MRP2 expression vector by site-directed mutagenesis, transfected into HEK293 cells, and analyzed by a fluorescence transport assay, immunoblot, and immunocytochemistry. The studies demonstrated that the mutation impaired the transport activity of MRP2. Immunoblot analysis and immunocytochemistry showed that expression of the mutation was low and mislocated to the endoplasmic reticulum of the transfected cells.


.0008   DUBIN-JOHNSON SYNDROME

ABCC2, ARG1150HIS
SNP: rs72558200, gnomAD: rs72558200, ClinVar: RCV000008930, RCV003421913, RCV003574699

In 5 Moroccan patients with Dubin-Johnson syndrome (DJS; 237500) from 4 unrelated families, Mor-Cohen et al. (2001) screened all 32 exons and adjacent regions of the MRP2 gene and identified homozygosity for a 3449G-A transition in exon 25, predicting an arg1150-to-his (R1150H) substitution. The mutation impaired the transport activity of MRP2. The mutant MRP2 matured properly and localized at the plasma membrane of transfected cells.


.0009   DUBIN-JOHNSON SYNDROME

ABCC2, ARG1066TER
SNP: rs72558199, gnomAD: rs72558199, ClinVar: RCV000024307, RCV000725912, RCV003415739

For discussion of the arg1066-to-ter (R1066X) mutation in the ABCC2 gene that was found in compound heterozygous state in patients with neonatal-onset Dubin-Johnson syndrome (DJS; 237500) by Pacifico et al. (2010), see 601107.0001.


REFERENCES

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Contributors:
Matthew B. Gross - updated : 10/24/2016
Marla J. F. O'Neill - updated : 5/25/2012
Victor A. McKusick - updated : 12/23/2003
Victor A. McKusick - updated : 2/24/2003
Victor A. McKusick - updated : 4/12/1999
Victor A. McKusick - updated : 3/22/1999
Carol A. Bocchini - updated : 11/17/1998
Victor A. McKusick - updated : 4/16/1998
Victor A. McKusick - updated : 4/15/1998
Victor A. McKusick - updated : 2/19/1998
Victor A. McKusick - updated : 10/20/1997

Creation Date:
Victor A. McKusick : 3/7/1996

Edit History:
carol : 05/29/2019
mgross : 10/24/2016
carol : 09/16/2016
carol : 09/22/2015
carol : 6/10/2015
mcolton : 6/9/2015
mgross : 11/15/2013
terry : 11/15/2012
terry : 5/25/2012
tkritzer : 12/26/2003
terry : 12/23/2003
carol : 3/3/2003
tkritzer : 2/25/2003
terry : 2/24/2003
carol : 11/10/1999
carol : 11/9/1999
carol : 4/12/1999
carol : 4/5/1999
terry : 3/22/1999
terry : 11/17/1998
carol : 11/16/1998
dholmes : 5/11/1998
carol : 5/2/1998
terry : 4/16/1998
carol : 4/15/1998
terry : 4/15/1998
terry : 4/15/1998
terry : 2/19/1998
terry : 10/20/1997
mark : 3/9/1996
mark : 3/7/1996