A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Starqardt macular dystrophy

Allikmets, Rando; Singh, Nanda; Sun, Hui; Shroyer, Noah F.; Hutchinson, Amy; Chidambaram, Abirami; Gerrard, Bernard; Baird, Lisa; Stauffer, Dora; Peiffer, Andy; Rattner, Amir; Smallwood, Philip M.; Li, Yixin; Anderson, K O; Lewis, Richard A.; Nathans, Jeremy; Leppert, M.; Dean, Michael; Lupski, James R.

doi:10.1038/ng0397-236

Cited by 1,240 publications

(743 citation statements)

References 58 publications

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“…In humans this superfamily is divided further into seven subfamilies (ABC-A to -G) based primarily on sequence similarity. Most ABC proteins from eukaryotes encode full transporters, consisting of two ATP-binding domains and 12 membrane-spanning regions or half transporters, which are presumed to dimerize (16,18). We described earlier that the sequence of MRP8, which is related closely to MRP5, belongs to the ABCC subfamily.…”

Section: Discussionmentioning

confidence: 99%

MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer

Bera

Iavarone

Kumar

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

110

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Combining a computer-based screening strategy and functional genomics, we previously identified MRP9 (ABCC12), a member of the ATP-binding cassette (ABC) superfamily. We now show that the gene has two major transcripts of 4.5 and 1.3 kb. In breast cancer, normal breast, and testis, the MRP9 gene transcript is 4.5 kb in size and encodes a 100-kDa protein. The protein is predicted to have 8 instead of 12 membrane-spanning regions. When compared with closely related ABC family members, it lacks transmembrane domains 3, 4, 11, and 12 and the second nucleotide-binding domain. In other tissues including brain, skeletal muscle, and ovary, the transcript size is 1.3 kb. This smaller transcript encodes a nucleotide-binding protein of Ϸ25 kDa in size. An in situ hybridization study shows that the 4.5-kb transcript is expressed in the epithelial cells of breast cancer. An antipeptide antibody designed to react with the amino terminus of the protein detects a 100-kDa protein in testis and the membrane fraction of a breast cancer cell line. Because the 4.5-kb RNA is highly expressed in breast cancer and not expressed at detectable levels in essential normal tissues, MRP9 could be a useful target for the immunotherapy of breast cancer. Because of the unusual topology of the two variants of MRP9, we speculate that they may have a different function from other family members.

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Section: Discussionmentioning

confidence: 99%

MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer

Bera

Iavarone

Kumar

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

110

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“…The fulllength cDNA coded for a novel 655 amino-acid protein with properties of a half-transporter, which is characteristic for members of the ABCG subfamily. A BLAST-N search of the nonredundant database of GenBank human expressed sequence tag (EST) entries for homology to the BCRP cDNA sequences revealed that a portion of the 3 0 end of BCRP cDNA had near identity to clone EST157481, one of 21 new genes predicted by Allikmets et al (1996) to be in the human ABC transporter family on the basis of EST database analysis.…”

Section: Identification Of the Bcrp Genementioning

confidence: 99%

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

2003

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Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential 'side population' stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.

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“…In humans, ABCA4 is associated with one of the more common forms of heritable blindness among children and young adults (Stargardt disease) (29,30), but a substantial number of disease alleles (Ͼ35%) in humans do not harbor plausible high-penetrance disease-causing variations in the ABCA4 coding sequences, suggesting that variations that affect gene expression may be involved in some cases (23). Opn1sw encodes the opsin that is found in the subset of cone photoreceptors that are maximally sensitive to blue light.…”

Section: Selection Of Inbred Rat Strainsmentioning

confidence: 99%

Regulation of gene expression in the mammalian eye and its relevance to eye disease

Scheetz

Kim

Swiderski

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

241

151

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We used expression quantitative trait locus mapping in the laboratory rat (Rattus norvegicus) to gain a broad perspective of gene regulation in the mammalian eye and to identify genetic variation relevant to human eye disease. Of >31,000 gene probes represented on an Affymetrix expression microarray, 18,976 exhibited sufficient signal for reliable analysis and at least 2-fold variation in expression among 120 F2 rats generated from an SR͞JrHsd ؋ SHRSP intercross. Genome-wide linkage analysis with 399 genetic markers revealed significant linkage with at least one marker for 1,300 probes (␣ ‫؍‬ 0.001; estimated empirical false discovery rate ‫؍‬ 2%). Both contiguous and noncontiguous loci were found to be important in regulating mammalian eye gene expression. We investigated one locus of each type in greater detail and identified putative transcription-altering variations in both cases. We found an inserted cREL binding sequence in the 5 flanking sequence of the Abca4 gene associated with an increased expression level of that gene, and we found a mutation of the gene encoding thyroid hormone receptor ␤2 associated with a decreased expression level of the gene encoding short-wavelength sensitive opsin (Opn1sw). In addition to these positional studies, we performed a pairwise analysis of gene expression to identify genes that are regulated in a coordinated manner and used this approach to validate two previously undescribed genes involved in the human disease Bardet-Biedl syndrome. These data and analytical approaches can be used to facilitate the discovery of additional genes and regulatory elements involved in human eye disease.bioinformatics ͉ expression quantitative trait locus analysis ͉ gene regulation ͉ ophthalmology

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A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Starqardt macular dystrophy

Cited by 1,240 publications

References 58 publications

MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer

MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Regulation of gene expression in the mammalian eye and its relevance to eye disease

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