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Yoshinori Moriyama - One of the best experts on this subject based on the ideXlab platform.
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type 1 sodium dependent phosphate transporter SLC17A1 protein is a cl dependent urate exporter
Journal of Biological Chemistry, 2010Co-Authors: Masafumi Iharada, Takaaki Miyaji, Hiroshi Omote, Takahiro Fujimoto, Miki Hiasa, Yoshinori MoriyamaAbstract:Abstract SLC17A1 protein (NPT1) is the first identified member of the SLC17 phosphate transporter family and mediates the transmembrane cotransport of Na+/Pi in oocytes. Although this protein is believed to be a renal polyspecific anion exporter, its transport properties are not well characterized. Here, we show that proteoliposomes containing purified SLC17A1 transport various organic anions such as p-aminohippuric acid and acetylsalicylic acid (aspirin) in an inside positive membrane potential (Δψ)-dependent manner. We found that NPT1 also transported urate. The uptake characteristics were similar to that of SLC17 members in its Cl− dependence and inhibitor sensitivity. When arginine 138, an essential amino acid residue for members of the SLC17 family such as the vesicular glutamate transporter, was specifically mutated to alanine, the resulting mutant protein was inactive in Δψ-dependent anion transport. Heterologously expressed and purified human NPT1 carrying the single nucleotide polymorphism mutation that is associated with increased risk of gout in humans exhibited 32% lower urate transport activity compared with the wild type protein. These results strongly suggested that NPT1 is a Cl−-dependent polyspecific anion exporter involved in urate excretion under physiological conditions.
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type 1 sodium dependent phosphate transporter SLC17A1 protein is a cl dependent urate exporter
Journal of Biological Chemistry, 2010Co-Authors: Masafumi Iharada, Takaaki Miyaji, Hiroshi Omote, Takahiro Fujimoto, Miki Hiasa, Yoshinori MoriyamaAbstract:SLC17A1 protein (NPT1) is the first identified member of the SLC17 phosphate transporter family and mediates the transmembrane cotransport of Na(+)/P(i) in oocytes. Although this protein is believed to be a renal polyspecific anion exporter, its transport properties are not well characterized. Here, we show that proteoliposomes containing purified SLC17A1 transport various organic anions such as p-aminohippuric acid and acetylsalicylic acid (aspirin) in an inside positive membrane potential (Deltapsi)-dependent manner. We found that NPT1 also transported urate. The uptake characteristics were similar to that of SLC17 members in its Cl(-) dependence and inhibitor sensitivity. When arginine 138, an essential amino acid residue for members of the SLC17 family such as the vesicular glutamate transporter, was specifically mutated to alanine, the resulting mutant protein was inactive in Deltapsi-dependent anion transport. Heterologously expressed and purified human NPT1 carrying the single nucleotide polymorphism mutation that is associated with increased risk of gout in humans exhibited 32% lower urate transport activity compared with the wild type protein. These results strongly suggested that NPT1 is a Cl(-)-dependent polyspecific anion exporter involved in urate excretion under physiological conditions.
Jeremy Veenstravanderweele - One of the best experts on this subject based on the ideXlab platform.
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association testing of the positional and functional candidate gene slc1a1 eaac1 in early onset obsessive compulsive disorder
Archives of General Psychiatry, 2006Co-Authors: Diane E. Dickel, Bennett L. Leventhal, Edwin H. Cook, Nancy J. Cox, Daniel Fischer, Joseph A. Himle, Jeremy Veenstravanderweele, Michelle Van Ettenlee, Gregory L. HannaAbstract:Context The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 ( SLC1A1 ) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. Objective To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. Design Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. Setting Anxiety disorders program in an academic medical center. Participants Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. Methods Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. Results Significant association was detected at rs3780412 ( P = .04) and rs301430 ( P = .03), 2 common adjacent single nucleotide polymorphisms in the 3′ region of SLC1A1 . Analysis by sex revealed that association at rs3780412 was limited to male probands ( P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 ( P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands ( P = .003). A deletion in the 3′ flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. Conclusions The 3′ region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.
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genomic organization of the slc1a1 eaac1 gene and mutation screening in early onset obsessive compulsive disorder
Molecular Psychiatry, 2001Co-Authors: Jeremy Veenstravanderweele, Gregory L. Hanna, Bennett L. Leventhal, Soo Jeong Kim, D. Gonen, Edwin H. CookAbstract:The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium.
Edwin H. Cook - One of the best experts on this subject based on the ideXlab platform.
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association testing of the positional and functional candidate gene slc1a1 eaac1 in early onset obsessive compulsive disorder
Archives of General Psychiatry, 2006Co-Authors: Diane E. Dickel, Bennett L. Leventhal, Edwin H. Cook, Nancy J. Cox, Daniel Fischer, Joseph A. Himle, Jeremy Veenstravanderweele, Michelle Van Ettenlee, Gregory L. HannaAbstract:Context The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 ( SLC1A1 ) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. Objective To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. Design Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. Setting Anxiety disorders program in an academic medical center. Participants Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. Methods Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. Results Significant association was detected at rs3780412 ( P = .04) and rs301430 ( P = .03), 2 common adjacent single nucleotide polymorphisms in the 3′ region of SLC1A1 . Analysis by sex revealed that association at rs3780412 was limited to male probands ( P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 ( P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands ( P = .003). A deletion in the 3′ flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. Conclusions The 3′ region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.
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genomic organization of the slc1a1 eaac1 gene and mutation screening in early onset obsessive compulsive disorder
Molecular Psychiatry, 2001Co-Authors: Jeremy Veenstravanderweele, Gregory L. Hanna, Bennett L. Leventhal, Soo Jeong Kim, D. Gonen, Edwin H. CookAbstract:The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium.
Gregory L. Hanna - One of the best experts on this subject based on the ideXlab platform.
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association testing of the positional and functional candidate gene slc1a1 eaac1 in early onset obsessive compulsive disorder
Archives of General Psychiatry, 2006Co-Authors: Diane E. Dickel, Bennett L. Leventhal, Edwin H. Cook, Nancy J. Cox, Daniel Fischer, Joseph A. Himle, Jeremy Veenstravanderweele, Michelle Van Ettenlee, Gregory L. HannaAbstract:Context The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 ( SLC1A1 ) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. Objective To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. Design Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. Setting Anxiety disorders program in an academic medical center. Participants Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. Methods Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. Results Significant association was detected at rs3780412 ( P = .04) and rs301430 ( P = .03), 2 common adjacent single nucleotide polymorphisms in the 3′ region of SLC1A1 . Analysis by sex revealed that association at rs3780412 was limited to male probands ( P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 ( P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands ( P = .003). A deletion in the 3′ flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. Conclusions The 3′ region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.
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genomic organization of the slc1a1 eaac1 gene and mutation screening in early onset obsessive compulsive disorder
Molecular Psychiatry, 2001Co-Authors: Jeremy Veenstravanderweele, Gregory L. Hanna, Bennett L. Leventhal, Soo Jeong Kim, D. Gonen, Edwin H. CookAbstract:The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium.
Masafumi Iharada - One of the best experts on this subject based on the ideXlab platform.
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type 1 sodium dependent phosphate transporter SLC17A1 protein is a cl dependent urate exporter
Journal of Biological Chemistry, 2010Co-Authors: Masafumi Iharada, Takaaki Miyaji, Hiroshi Omote, Takahiro Fujimoto, Miki Hiasa, Yoshinori MoriyamaAbstract:Abstract SLC17A1 protein (NPT1) is the first identified member of the SLC17 phosphate transporter family and mediates the transmembrane cotransport of Na+/Pi in oocytes. Although this protein is believed to be a renal polyspecific anion exporter, its transport properties are not well characterized. Here, we show that proteoliposomes containing purified SLC17A1 transport various organic anions such as p-aminohippuric acid and acetylsalicylic acid (aspirin) in an inside positive membrane potential (Δψ)-dependent manner. We found that NPT1 also transported urate. The uptake characteristics were similar to that of SLC17 members in its Cl− dependence and inhibitor sensitivity. When arginine 138, an essential amino acid residue for members of the SLC17 family such as the vesicular glutamate transporter, was specifically mutated to alanine, the resulting mutant protein was inactive in Δψ-dependent anion transport. Heterologously expressed and purified human NPT1 carrying the single nucleotide polymorphism mutation that is associated with increased risk of gout in humans exhibited 32% lower urate transport activity compared with the wild type protein. These results strongly suggested that NPT1 is a Cl−-dependent polyspecific anion exporter involved in urate excretion under physiological conditions.
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type 1 sodium dependent phosphate transporter SLC17A1 protein is a cl dependent urate exporter
Journal of Biological Chemistry, 2010Co-Authors: Masafumi Iharada, Takaaki Miyaji, Hiroshi Omote, Takahiro Fujimoto, Miki Hiasa, Yoshinori MoriyamaAbstract:SLC17A1 protein (NPT1) is the first identified member of the SLC17 phosphate transporter family and mediates the transmembrane cotransport of Na(+)/P(i) in oocytes. Although this protein is believed to be a renal polyspecific anion exporter, its transport properties are not well characterized. Here, we show that proteoliposomes containing purified SLC17A1 transport various organic anions such as p-aminohippuric acid and acetylsalicylic acid (aspirin) in an inside positive membrane potential (Deltapsi)-dependent manner. We found that NPT1 also transported urate. The uptake characteristics were similar to that of SLC17 members in its Cl(-) dependence and inhibitor sensitivity. When arginine 138, an essential amino acid residue for members of the SLC17 family such as the vesicular glutamate transporter, was specifically mutated to alanine, the resulting mutant protein was inactive in Deltapsi-dependent anion transport. Heterologously expressed and purified human NPT1 carrying the single nucleotide polymorphism mutation that is associated with increased risk of gout in humans exhibited 32% lower urate transport activity compared with the wild type protein. These results strongly suggested that NPT1 is a Cl(-)-dependent polyspecific anion exporter involved in urate excretion under physiological conditions.