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Coen C. Paulusma - One of the best experts on this subject based on the ideXlab platform.
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extended abstract deficiency of sodium taurocholate cotransporting polypeptide SLC10A1 a new inborn error of metabolism with an attenuated phenotype
Digestive Diseases, 2017Co-Authors: Frederic M Vaz, Hidde H Huidekoper, Coen C. PaulusmaAbstract:We present the first patient with a defect in the Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP), which plays a key role in the enterohepatic circulation of bile salts. The clinical presentation of the child was mild and the child showed no signs of liver dysfunction or pruritus despite extremely elevated plasma bile salt levels (>100-fold upper-limit of normal). A homozygous point mutation was found in the SLC10A1 gene (resulting in amino acid change R252H) and functional studies confirmed the pathogenicity of the mutation. This confirms the role of NTCP as the major transporter of conjugated bile salts into the liver as part of the enterohepatic circulation and shows that other transporters partly can take over its function, resulting in a relatively mild phenotype. This work was published previously in [Vaz et al.: Hepatology 2015;61:260-267] and supplemented with some follow-up information of the patient.
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the lipid flippase heterodimer atp8b1 cdc50a is essential for surface expression of the apical sodium dependent bile acid transporter slc10a2 asbt in intestinal caco 2 cells
Biochimica et Biophysica Acta, 2014Co-Authors: Vincent A Van Der Mark, Kam S Homok, Rudi D De Waart, Heleen W Voogt, Ronald Oude P J Elferink, Merit M Tabbers, A S Knisely, Coen C. PaulusmaAbstract:Abstract Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.
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The lipid flippase heterodimer ATP8B1–CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells
Biochimica et Biophysica Acta, 2014Co-Authors: Vincent A Van Der Mark, Heleen W Voogt, Dirk R. De Waart, Merit M Tabbers, A S Knisely, Coen C. PaulusmaAbstract:Abstract Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.
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.
Vincent A Van Der Mark - One of the best experts on this subject based on the ideXlab platform.
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the lipid flippase heterodimer atp8b1 cdc50a is essential for surface expression of the apical sodium dependent bile acid transporter slc10a2 asbt in intestinal caco 2 cells
Biochimica et Biophysica Acta, 2014Co-Authors: Vincent A Van Der Mark, Kam S Homok, Rudi D De Waart, Heleen W Voogt, Ronald Oude P J Elferink, Merit M Tabbers, A S Knisely, Coen C. PaulusmaAbstract:Abstract Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.
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The lipid flippase heterodimer ATP8B1–CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells
Biochimica et Biophysica Acta, 2014Co-Authors: Vincent A Van Der Mark, Heleen W Voogt, Dirk R. De Waart, Merit M Tabbers, A S Knisely, Coen C. PaulusmaAbstract:Abstract Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.