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Other entities represented in this entry:
HGNC Approved Gene Symbol: SLC22A18
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:2,899,691-2,925,246 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Breast cancer, somatic | 114480 | 3 | |
| Lung cancer, somatic | 211980 | 3 | ||
| Rhabdomyosarcoma, somatic | 268210 | 3 |
Chromosome region 11p15.5 harbors a number of genes involved in neoplasms and in the genetic disease Beckwith-Wiedemann syndrome (BWS; 130650). By genomic analysis of a 170-kb region at 11p15.5 between loci D11S601 and D11S679, Schwienbacher et al. (1998) identified 6 transcriptional units. Three genes, NAP2 (601651), CDKN1C (600856), and KVLQT1 (607542), had been well characterized, whereas the other 3 genes were novel. The 3 additional genes were symbolized BWR1A, BWR1B (SLC22A1LS; 603240), and BWR1C (TSSC3; 602131), with BWR designating 'Beckwith-Wiedemann region.' Full-length cDNAs corresponding to these 3 genes were cloned and nucleotide sequences were determined. Schwienbacher et al. (1998) cloned the full-length BWR1A cDNA from a human fetal liver cDNA library. The open reading frame encodes a protein of 424 amino acids. BWR1A cDNA probes recognized a 1.7-kb transcript with highest expression in liver, heart, and kidney.
A megabase-scale region on 11p15.5 in humans and the corresponding area of distal chromosome 7 in mice contains at least 6 imprinted genes: IGF2 (147470), H19 (103280), ASCL2 (601886), p57(KIP2) (CDKN1C), KVLQT1, IPL (BWR1C), and in the mouse Ins2. A subset of these genes regulate fetal and/or placental growth, and the H19, IGF2, and p57(KIP2) genes show dysregulated expression and, in the case of H19, pathologic biallelic hypermethylation in human embryonal tumors. Dao et al. (1998) described the identification, structural characterization, and allelic expression analysis of mouse and human versions of a novel imprinted gene, IMPT1 (imprinted multimembrane-spanning polyspecific transporter-like gene-1) (GenBank AF028738), located in the 11p15.5 region between IPL and p57(KIP2). The gene encodes a predicted protein with multiple membrane-spanning segments that belongs to the polyspecific transporter/multidrug resistance gene family. The fact that Impt1 is relatively repressed on the mouse paternal allele, together with data from other imprinted genes, allowed a statistical conclusion that the primary effect of the human chromosome 11p15.5/mouse distal chromosome 7 imprinting is domainwide relative repression of genes on the paternal homolog. Dosage regulation of the metabolite transporter gene(s) by imprinting may regulate placental and fetal growth.
Cooper et al. (1998) identified the organic-cation transporter-like-2 (ORCTL2) (GenBank AF037064) and ORCTL2-antisense (ORCTL2S, or SLC22A1LS) genes by sequencing overlapping PAC clones from the BWS region in 11p15.5 and identifying matching ESTs. Northern blot analysis indicated that the ORCTL2 and ORCTL2S genes are predominantly expressed in fetal and adult liver and kidney. The authors isolated full-length human and mouse ORCTL2 cDNAs; these are approximately 75% identical through the open reading frames. The ORCTL2 gene exhibits 'leaky' imprinting in both human fetal kidney and fetal liver, whereas the Orctl2 gene is specifically and completely expressed from the maternal allele in mouse fetal liver.
Morisaki et al. (1998) isolated the human and mouse ITM, or SLC22A1L, genomic sequences and corresponding full-length cDNAs. They suggested that translation begins at the second methionine codon in the open reading frame, which would result in a 408-amino acid human ITM protein. Exon 1 of the mouse Itm gene is alternatively spliced. Morisaki et al. (1998) found that the mouse Itm gene is preferentially expressed from the maternal allele in fetal, newborn, and most adult tissues, but is biallelically expressed in adult kidney and liver, where its expression is highest.
Lee et al. (1998) isolated an SLC22A1L cDNA, which they called TSSC5, located within a subchromosomal transferable fragment from 11p15.5. TSSC5 was found to encode a predicted protein of 424 amino acids, and sequence analysis suggested that it is a membrane protein with 10 transmembrane segments. The TSSC5 gene is located between 2 imprinted genes, p57(KIP2) and TSSC3. Northern blot analysis detected a 1.6-kb transcript in multiple adult tissues and in fetal liver and kidney, consistent with a potential role in embryonal tumors. Lee et al. (1998) found that TSSC5 is imprinted with preferential expression from the maternal chromosome.
Polyspecific organic-cation transporters located at the apical and basolateral surfaces of renal epithelial cells mediate kinetically distinct excretion of several endogenous and exogenous compounds. Reece et al. (1998) investigated the transport properties of ORCTL2 and showed that it confers resistance to chloroquine and quinidine when overexpressed in bacteria. Immunohistochemistry analyses on human renal sections indicated that ORCTL2 is localized on the apical membrane surface of the proximal tubules. The authors suggested that ORCTL2 may play a role in the transport of chloroquine- and quinidine-related compounds in the kidney. Recombinant ORCTL2 expressed in mammalian cells had an apparent molecular mass of approximately 40 kD by Western blot analysis.
Onyango et al. (2002) found that 3 imprinted genes, TSSC5, H19, and SNRPN (182279), show monoallelic expression in in vitro differentiated human cells derived from embryonic germ cells, and that a fourth gene, IGF2, shows partially relaxed imprinting at a ratio from 4:1 to 5:1, comparable to that found in normal somatic cells. In addition, they found normal methylation of an imprinting control region (ICR) that regulates H19 and IGF2 imprinting, suggesting that imprinting may not be a significant epigenetic barrier to human embryonic germ cell transplantation. Onyango et al. (2002) constructed an in vitro mouse model of genomic imprinting by generating germ cells from 8.5-day embryos of an interspecific cross, in which undifferentiated cells showed biallelic expression and acquired preferential parental allele expression after differentiation. They suggested that the model should allow experimental manipulation of epigenetic modifications of cultured embryonic germ cells that may not be possible in human stem cell studies. Commenting on this work, Sapienza (2002) pointed out that embryonic stem cells may not be the best source of therapeutic material for transplantation therapy.
Gallagher et al. (2006) found a nonimprinted profile for SLC22A18AS in normal adult breast tissue. A proportion of malignant breast tissues and fibroadenomas showed gain of imprinting at both the SLC22A18 and SLC22A18AS loci. One sample that showed gain of imprinting for SLC22A18 was unaltered at the SLC22A18AS locus.
By bacterial 2-hybrid screening with RING105 (RNF167; 610431) as bait, Yamada and Gorbsky (2006) identified an interaction with TSSC5, which, like RING105, localized to cytoplasmic membranes. Immunoprecipitation and immunoblot analyses with truncated forms of TSSC5 demonstrated that TSSC5 was polyubiquitylated on its sixth hydrophilic loop in an accelerated manner in the presence of RING105 and UBCH6 (UBE2E1; 602916). Yamada and Gorbsky (2006) proposed that UBCH6 and RING105 may define a ubiquitin-proteasome pathway that targets TSSC5.
Schwienbacher et al. (1998) determined that the BWR1A gene consists of 11 exons spanning a genomic area of 23 kb.
Cooper et al. (1998) found that the ORCTL2 and ORCTL2S genes overlap in their 5-prime regions in divergent orientations, with the first exon of ORCTL2S sharing 31 bp with the second exon of ORCTL2.
The SLC22A18 gene was identified on chromosome 11p15.5, within the Beckwith-Wiedemann syndrome (BWS; 130650) critical region, by several groups (Schwienbacher et al., 1998; Dao et al., 1998; Cooper et al., 1998; Morisaki et al., 1998; Lee et al., 1998).
Cooper et al. (1998) mapped the mouse Orctl2 gene to chromosome 7 by hybridization to PAC clones.
Lee et al. (1998) identified an arg309-to-gln mutation in the TSSC5 gene in a Wilms tumor, the matched normal kidney, and in the patient's mother. It was unclear whether this was a rare polymorphism or a tumor-predisposing mutation, because the mutant allele was of maternal origin and preferentially expressed in the patient's tissue. A second mutation, ser233 to phe (602631.0003), was identified in a lung cancer (211980). This substitution was absent from the matched normal tissue and thus represented a somatic mutation. Lee et al. (1998) also found loss of heterozygosity in the lung cancer, suggesting that TSSC5 may be a conventional tumor suppressor gene in the adult human lung and an imprinted tumor suppressor gene in the fetal kidney.
Cooper et al. (1998) did not detect disease-associated mutations in the ORCTL2 genes of 62 Wilms tumor (WT; see 194071) patients or 10 BWS patients.
Schwienbacher et al. (1998) carried out a mutation analysis of the BWR1A coding region in tumor cell lines and BWS samples, with identification of genetic alterations in the BWR1A gene in 2 cases (602631.0001, 602631.0002).
In the breast cancer (114480) cell line BT549, Schwienbacher et al. (1998) identified an insertion that introduced a stop codon in the BWR1A gene. The insertion consisted of 111 nucleotides between nucleotides 1295 and 1296 of the cDNA sequence. These nucleotides represented the junction between exon 8 and exon 9 of the BWR1A gene. Therefore, this inserted segment behaved like a new exon. Indeed, the newly added 111-nucleotide segment was found within intron 8, at 331 nucleotides from the 3-prime end of exon 8. The presence of the canonical splicing sites at the boundaries of the genomic sequence confirmed that the segment had been inserted in the normal BWR1A transcript by an mRNA splicing event. Though it did not introduce a frameshift, it did introduce an in-frame stop codon after 18 nucleotides, removing the last 136 amino acids at the normal polypeptide sequence. This result indicated that the mRNA was aberrant and not a product of alternative splicing.
In the rhabdomyosarcoma (268210) cell line TE125.T, Schwienbacher et al. (1998) found a G-to-A transition at nucleotide 688 that introduced an arginine in place of a cysteine in the product of the BWR1A gene. The change was present in a homozygous state, suggesting that loss of the normal allele occurred during the tumorigenic conversion.
In a lung cancer (211980), Lee et al. (1998) identified an apparent somatic mutation, a C-to-T transition at nucleotide 892 of the SLC22A18 gene, resulting in a ser233-to-phe substitution. They also found loss of heterozygosity in the lung cancer, suggesting that SLC22A18 may be a conventional tumor suppressor gene in the adult human lung and an imprinted tumor suppressor gene in the fetal kidney.
Cooper, P. R., Smilinich, N. J., Day, C. D., Nowak, N. J., Reid, L. H., Pearsall, R. S., Reece, M., Prawitt, D., Landers, J., Housman, D. E., Winterpacht, A., Zabel, B. U., Pelletier, J., Weissman, B. E., Shows, T. B., Higgins, M. J. Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain. Genomics 49: 38-51, 1998. [PubMed: 9570947] [Full Text: https://doi.org/10.1006/geno.1998.5221]
Dao, D., Frank, D., Qian, N., O'Keefe, D., Vosatka, R. J., Walsh, C. P., Tycko, B. IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum. Molec. Genet. 7: 597-608, 1998. [PubMed: 9499412] [Full Text: https://doi.org/10.1093/hmg/7.4.597]
Gallagher, E., Mc Goldrick, A., Chung, W. Y., McCormack, O., Harrison, M., Kerin, M., Dervan, P. A., McCann, A. Gain of imprinting of SLC22A18 sense and antisense transcripts in human breast cancer. Genomics 88: 12-17, 2006. [PubMed: 16624517] [Full Text: https://doi.org/10.1016/j.ygeno.2006.02.004]
Lee, M. P., Reeves, C., Schmitt, A., Su, K., Connors, T. D., Hu, R.-J., Brandenburg, S., Lee, M. J., Miller, G., Feinberg, A. P. Somatic mutation of TSSC5, a novel imprinted gene from human chromosome 11p15.5. Cancer Res. 58: 4155-4159, 1998. [PubMed: 9751628]
Morisaki, H., Hatada, I., Morisaki, T., Mukai, T. A novel gene, ITM, located between p57(KIP2) and IPL, is imprinted in mice. DNA Res. 5: 235-240, 1998. [PubMed: 9802569] [Full Text: https://doi.org/10.1093/dnares/5.4.235]
Onyango, P., Jiang, S., Uejima, H., Shamblott, M. J., Gearhart, J. D., Cui, H., Feinberg, A. P. Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages. Proc. Nat. Acad. Sci. 99: 10599-10604, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 103: 14255 only, 2006. [PubMed: 12114541] [Full Text: https://doi.org/10.1073/pnas.152327599]
Reece, M., Prawitt, D., Landers, J., Kast, C., Gros, P., Housman, D., Zabel, B. U., Pelletier, J. Functional characterization of ORCTL2--an organic cation transporter expressed in the renal proximal tubules. FEBS Lett. 433: 245-250, 1998. [PubMed: 9744804] [Full Text: https://doi.org/10.1016/s0014-5793(98)00907-7]
Sapienza, C. Imprinted gene expression, transplantation medicine, and the 'other' human embryonic stem cell. Proc. Nat. Acad. Sci. 99: 10243-10245, 2002. [PubMed: 12149520] [Full Text: https://doi.org/10.1073/pnas.172384299]
Schwienbacher, C., Sabbioni, S., Campi, M., Veronese, A., Bernardi, G., Menegatti, A., Hatada, I., Mukai, T., Ohashi, H., Barbanti-Brodano, G., Croce, C. M., Negrini, M. Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples. Proc. Nat. Acad. Sci. 95: 3873-3878, 1998. [PubMed: 9520460] [Full Text: https://doi.org/10.1073/pnas.95.7.3873]
Yamada, H. Y., Gorbsky, G. J. Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105. Oncogene 25: 1330-1339, 2006. [PubMed: 16314844] [Full Text: https://doi.org/10.1038/sj.onc.1209167]