Genomic Structure of the Canalicular Multispecific Organic Anion–Transporter Gene (MRP2/cMOAT) and Mutations in the ATP-Binding–Cassette Region in Dubin-Johnson Syndrome

Toh, Shoichi; Wada, Morimasa; Uchiumi, Takeshi; Inokuchi, Akihiko; Makino, Yoshinari; Horie, Yutaka; Adachi, Yukihiko; Sakisaka, Shotaro; Kuwano, Michihiko

doi:10.1086/302292

Cited by 215 publications

(165 citation statements)

References 29 publications

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“…We compared sequences and mutations in ABCC6/MRP6 with ABCC2, ABCC8, ABCC7, and ABCR, which are implicated in, respectively, Dubin-Johnson syndrome, familial persistent hyperinsulinaemic hypoglycaemia of infancy, cystic fibrosis, and Stargardt disease or perhaps even age-related macula degeneration. [23][24][25][26][27] As we expected, a number of similar mutations occurred in conserved regions of the ABC proteins or even in the same conserved residues. In all proteins, a large number of mutations implicated in disease occurred in the NBF1 and NBF2 domains.…”

Section: Pxe Mutations -Functional Consequencessupporting

confidence: 63%

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

Plomp

Wijnholds

et al. 2003

Eur J Hum Genet

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Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.

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Section: Pxe Mutations -Functional Consequencessupporting

confidence: 63%

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

Plomp

Wijnholds

et al. 2003

Eur J Hum Genet

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“…7 The extended fragments of the primary PCR product were purified from non-incorporated nucleotides and primers through Microcon Centrifugal Filter Devices (Millipore, Molsheim France) and sequenced with the Big Dye Terminator cycle Sequencing Reading Reaction kit (PE, Applied Biosystems, Applera, Milan, Italy). The second PCR amplification was performed by adding 4.…”

Section: Methodsmentioning

confidence: 99%

A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus

et al. 2006

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“…ABCC2 is structurally and functionally very distinct from MDR1 P-glycoprotein (ABCB1), which belongs to a different subfamily of ABC transporters with which ABCC2 shares only about 26% amino acid sequence identity. The human ABCC2 gene is located on chromosome 10q24 [165], spans about 65 kilobase pairs, and consists of 32 exons with a high proportion of class 0 introns [168,170].…”

Section: Molecular Characterization Of Abcc2mentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

357

255

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ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

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Genomic Structure of the Canalicular Multispecific Organic Anion–Transporter Gene (MRP2/cMOAT) and Mutations in the ATP-Binding–Cassette Region in Dubin-Johnson Syndrome

Cited by 215 publications

References 29 publications

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus

The apical conjugate efflux pump ABCC2 (MRP2)

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