Disease relevance of SLC14A2

• Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma [1].
• A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations [2].
• A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis [2].
• Taken together, these data document the functional demonstration of a cellular protein binding to influenza virus RNAs and, importantly, suggest that influenza virus may recruit GRSF-1 to the 5' UTR to ensure preferential translation of viral mRNAs in infected cells [3].
• Using the 5' UTR of the influenza virus nucleocapsid protein (NP) mRNA as bait, we identified the cellular RNA-recognition motif containing RNA-binding protein G-rich sequence factor 1 (GRSF-1) as a positive-acting translational regulatory factor [3].

Psychiatry related information on SLC14A2

• Fragile X syndrome, the most common form of inherited mental retardation, is the result of an unstable expansion of a CGG trinucleotide repeat in the 5' UTR of the fragile X mental retardation-1 (FMR1) gene [4].
• Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study [5].
• Association of the 3' UTR transcription factor LBP-1c/CP2/LSF polymorphism with late-onset Alzheimer's disease [6].

High impact information on SLC14A2

• We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle [7].
• GRSF-1 also stimulated translation of an NP 5' UTR-driven template in HeLa cell extracts that were depleted of essential factors by addition of RNA oligonucleotides representing the viral 5' UTR RNA [3].
• We show that initiation factor 4B is essential for mRNAs that have even a rather moderate base pairing within their 5' UTRs (with the cumulative stability of the secondary structure within the entire 5' UTR < -13 kcal/mol) and not essential for beta-globin mRNA [8].
• We determined therefore whether nucleotide variation in the kidney-specific human urea transporter, HUT2, is associated with variation in BP [9].
• Two of the SNPs result in Val/Ile and Ala/Thr amino acid substitutions at positions 227 and 357 in the HUT2 open reading frame, respectively [9].

Chemical compound and disease context of SLC14A2

• The CDKN2a common variants: 148 Ala/Thr and 500 C/G in 3' UTR, and their association with clinical course of melanoma [10].

Biological context of SLC14A2

• We determined the organization of the human Slc14a2 gene and identified 20 exons distributed over approximately 67.5 kb on chromosome 18, from which hUT-A1 and the other human urea transporter, hUT-A2, are transcribed [11].
• By in situ hybridization, the gene encoding HUT2 has been assigned to chromosome 18q12.1-q21-1, as found previously for the Kidd/urea transporter HUT11, suggesting that both genes evolved from duplication of a common ancestor [12].
• The transcript encoding hUT-A6 contains a novel 129-bp exon, exon 5a, which, as a result of alternative splicing, introduces a unique 19-aa segment and a stop codon [13].
• Deletion of the two PKA consensus sites from murine UT-A3 (mUT-A3) did not affect the stimulatory response of PKA agonists, which, together with the lack of PKA consensus sites in hUT-A6, indicates that regulation of hUT-A6 and mUT-A3 is not mediated through a classic PKA phosphorylation consensus [13].
• Whereas para-chloromercuribenzene sulfonate inhibits HUT11 with an IC50 of 150 microM, it does not inhibit HUT2, whatever the concentration used [14].

Anatomical context of SLC14A2

• Functional expression studies in Xenopus oocytes demonstrated that HUT2-mediated urea transport was not inhibited by p-chloromercuribenzene sulfonate (pCMBS) which, however, inhibited the urea flux mediated by HUT11 [12].
• In this article, we report the characterization of a cDNA isolated from human colonic mucosa encoding a novel UT-A urea transporter, hUT-A6 [13].
• UT-A2 immunoreactivity was observed mainly on the basolateral membrane of the type 1 epithelium of the descending thin limb (DTL) of short-looped nephrons [15].
• The results of our systematic mutational, structural and functional analysis of the 5' UTR led us to conclude that a ribosome-shunting mechanism - rather than leaky scanning, ribosomal reinitiation, or internal ribosome entry site (IRES)-mediated initiation - controls the translation of regA mRNA [16].
• Analysis of the methylation status of DAP-kinase's 5' UTR in DNA extracted from fresh tumor samples, showed high incidence of hypermethylation in several human carcinomas and B cell malignancies [17].

Associations of SLC14A2 with chemical compounds

• On the basis of previous structural predictions, hUT-A6 is structurally unique in that it consists of a single hydrophobic core flanked by hydrophilic NH(2)- and COOH-terminal domains [13].
• Vasopressin also up-regulates UT-A2 mRNA/protein expression in the descending thin limb of the loops of Henle [18].
• We demonstrate that thiourea diffuses through HUT11 with a Michaelis constant (Km) of 40 mM, but not through HUT2 [14].
• Both are inhibited by phloretin, although with different half-maximal inhibitory concentrations (IC50; 75 microM, for HUT11 and 230 microM for HUT2) [14].
• Human dopamine transporter gene (DAT1) has a variable number of tandem repeats (VNTR) in its 3'-untranslated region (UTR) [19].

Other interactions of SLC14A2

• A cDNA clone (HUT2) sharing 61.1% and 89.9% sequence identity with the human erythroid (HUT11) and the rabbit (UT2) urea transporters, respectively, was isolated by homology cloning from a human kidney library [12].

Analytical, diagnostic and therapeutic context of SLC14A2

• Clones expressing the C allele RNA (UTR/C) exhibited significant suppression of growth in cell proliferation assays, inhibition of colony formation in soft agar assays, and suppression of xenograft tumor growth when implanted on nude mice, compared with either T allele expressing or empty vector clones [20].
• Reverse transcriptase-polymerase chain reaction of the 5' UTR consistently resulted, in addition to the product with the expected size of 155 base pair (bp), in a second product with an approximately 65-bp deletion from the central region of the 5' UTR, suggesting the presence of a secondary structure [21].
• This case-control study examined the prevalence of a prothrombin gene mutation in the 3'-untranslated region (UTR) first reported by Poort et al in Dutch subjects with a history of venous thrombosis and in matched control subjects without a history of thrombosis [22].
• Although Northern analysis and RT-PCR indicated that whUT-A2 was exclusively expressed in kidney, Western blotting using a polyclonal antibody to rat UT-A1/UT-A2 detected various immunoreactive proteins in kidney and other tissues [23].
• Furthermore, PCR products amplified using the 5' UTR primers were sequenced and subjected to phylogenetic analysis [24].

References