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Heng Wang - One of the best experts on this subject based on the ideXlab platform.
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multiple sequence variations in slc5a1 gene are associated with glucose galactose Malabsorption in a large cohort of old order amish
Clinical Genetics, 2011Co-Authors: Heng WangAbstract:Xin B, Wang H. Multiple sequence variations in SLC5A1 gene are associated with glucose–galactose Malabsorption in a large cohort of Old Order Amish. Glucose-Galactose Malabsorption (GGM) is an autosomal recessive disease with life-threatening newborn diarrhea caused by mutations in the Na+/glucose cotransporter gene SLC5A1. Because of its rarity, the clinical course of the disease has not been well studied. Here, we report 33 patients with GGM from a large Old Order Amish pedigree and the associated mutations in SLC5A1 gene. Clinically, all affected individuals presented with classic watery diarrhea and dehydration. The increased bowel sounds, distended abdomen, vigorous nursing regardless of their illness, and irritability and apathy were also noted as part of the initial presentation. Patients underwent a dramatic turnaround with an immediate cease of the diarrhea and a quick rehydration if they were correctly diagnosed and adequately managed, followed by a normal growth and development pattern afterwards; whereas a prolonged clinical course would follow if the disease was not recognized. Sequence analysis of the 15 protein-coding exons and the corresponding exon–intron boundaries of SLC5A1 gene revealed four homozygous missense mutations, c.152A>G (p.N51S), c.1231G>A (p.A411T), c.1673G>A (p.R558H), and c.1845C>G (p.H615Q), that co-segregate with the GGM phenotype in all of the affected individuals. These findings suggest that founder effect of the SLC5A1 mutations associated with the disease in Amish and a population specific genetic testing is in need to pursue an early diagnosis which is critical for a favorable outcome.
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multiple sequence variations in slc5a1 gene are associated with glucose galactose Malabsorption in a large cohort of old order amish
Clinical Genetics, 2011Co-Authors: B Xin, Heng WangAbstract:Glucose-Galactose Malabsorption (GGM) is an autosomal recessive disease with life-threatening newborn diarrhea caused by mutations in the Na(+) /glucose cotransporter gene SLC5A1. Because of its rarity, the clinical course of the disease has not been well studied. Here, we report 33 patients with GGM from a large Old Order Amish pedigree and the associated mutations in SLC5A1 gene. Clinically, all affected individuals presented with classic watery diarrhea and dehydration. The increased bowel sounds, distended abdomen, vigorous nursing regardless of their illness, and irritability and apathy were also noted as part of the initial presentation. Patients underwent a dramatic turnaround with an immediate cease of the diarrhea and a quick rehydration if they were correctly diagnosed and adequately managed, followed by a normal growth and development pattern afterwards; whereas a prolonged clinical course would follow if the disease was not recognized. Sequence analysis of the 15 protein-coding exons and the corresponding exon-intron boundaries of SLC5A1 gene revealed four homozygous missense mutations, c.152A>G (p.N51S), c.1231G>A (p.A411T), c.1673G>A (p.R558H), and c.1845C>G (p.H615Q), that co-segregate with the GGM phenotype in all of the affected individuals. These findings suggest that founder effect of the SLC5A1 mutations associated with the disease in Amish and a population specific genetic testing is in need to pursue an early diagnosis which is critical for a favorable outcome.
Martin G Martin - One of the best experts on this subject based on the ideXlab platform.
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long term dietary changes in subjects with glucose galactose Malabsorption secondary to biallelic mutations of slc5a1
Digestive Diseases and Sciences, 2021Co-Authors: Alvin P Chan, Shweta S Namjoshi, Patricia Jardack, Lisa Maloney, Atrin Ardjmand, Nicholas N Jackson, Martin G MartinAbstract:Glucose galactose Malabsorption (GGM) is a congenital diarrheal disorder of intestinal Na+/glucose cotransport (SGLT1/SLC5A1). The required glucose and galactose-restricted diet has been well described in infancy, but long-term nutrition follow-up is limited. To perform a comprehensive nutritional assessment on a cohort of patients with GGM to gain insights into the consumption patterns within the population. A cross-sectional study examining dietary intake of a GGM cohort using prospective food records. The calories and nutrients of all foods, beverages, and condiments were analyzed with descriptive statistics and compared to intake patterns of age- and sex-matched NHANES groups. The six patients were 0.7–26 years old. Whole foods and vegetable fats were major parts of the diet, while dairy and added sweeteners were restricted. Compared to typical US intakes, mean macronutrient distribution was 88th percentile from fat, 18th percentile from carbohydrates, and 78th percentile from protein. Fructose consumption, as a proportion of total sugar intake, decreased with age, from 86.1 to 50.4%. Meanwhile, glucose consumption increased with age, from 13.8 to 48.6% of sugar intake. However, the actual amount of glucose consumed remained low, equivalent to 4th percentile of US consumption level. Galactose intake was marginal throughout life. A GGM diet is a high-fat and high-protein/low-carbohydrate diet that is rich in fruits and vegetables but limited in dairy and added sugar. Relatively less fructose but more glucose is incorporated into the diet with age. Future studies should investigate the effects of the GGM diet on gut microbiome and long-term health.
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intestinal absorption in health and disease sugars
Best Practice & Research in Clinical Gastroenterology, 2003Co-Authors: Ernest M Wright, Martin G Martin, Eric TurkAbstract:Carbohydrates are mostly digested to glucose, fructose and galactose before absorption by the small intestine. Absorption across the brush border and basolateral membranes of enterocytes is mediated by sodium-dependent and -independent membrane proteins. Glucose and galactose transport across the brush border occurs by a Na(+)/glucose (galactose) co-transporter (SGLT1), whereas passive fructose transport is mediated by a uniporter (GLUT5). The passive exit of all three sugars out of the cell across the basolateral membrane occurs through two uniporters (GLUT2 and GLUT5). Mutations in SGLT1 cause a major defect in glucose and galactose absorption (Glucose-Galactose Malabsorption), but mutations in GLUT2 do not appear to disrupt glucose and galactose absorption. Studies on GLUT1 null mice and Fanconi-Bickel patients suggest that there is another exit pathway for glucose and galactose that may involve exocytosis. There are no known defects of fructose absorption.
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molecular basis for glucose galactose Malabsorption
Cell Biochemistry and Biophysics, 2002Co-Authors: Ernest M Wright, Eric Turk, Martin G MartinAbstract:Glucose-Galactose Malabsorption (GGM) is an autosomal recessive disease that presents in newborn infants as a life-threatening diarrhea. The diarrhea ceases within 1 h of removing oral intake of lactose, glucose, and galactose, but promptly returns with the introduction of one or more of the offending sugars into the diet. Our goal is to determine whether or not mutations in the sodium-glucose cotransporter gene (SGLT1) are responsible for GGM. We first isolated the human cDNA (hSGLT1), mapped the gene, and identified its chromosomal location (22q13.1). Our approach was then to screen GGM patients for mutations in hSGLT1 and then determine if these caused defects in sugar transport using the Xenopus laevis oocyte expression system. In 46 patients we have identified the mutations responsible for GGM. These included missense, nonsense, frame shift, splice site, and promoter mutations. In 30 patients, the same mutations were on both alleles, and the remaining 16 had different mutations on each allele (compound heterozygotes). Several mutations (e.g., C355S) were found in unrelated patients. The nonsense, frame shift, and splice site mutations all produce nonfunctional truncated proteins. In 22 out of the 23 missense mutations tested in the oocyte expression system, the proteins were translated and were stable in the cell, but did not reach the plasma membrane. In four of these mutants, an alanine residue was replaced by a valine, and in two, the trafficking defect was rescued by changing the valine to cysteine. One mutant protein (Q457R) did reach the plasma membrane, but it was unable to transport the sugar across the cell membrane. We conclude that mutations in the SGLT1 gene are the cause of Glucose-Galactose Malabsorption, and sugar transport is impaired mainly because the mutant proteins are either truncated or are not targeted properly to the cell membrane.
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defects in na glucose cotransporter sglt1 trafficking and function cause glucose galactose Malabsorption
Nature Genetics, 1996Co-Authors: Martin G Martin, M P Lostao, Eric Turk, Cynthia Kerner, Ernest M WrightAbstract:Cotransporters harness ion gradients to drive ‘active’ transport of substrates into cells, for example, the Na+/glucose cotransporter (SGLT1) couples sugar transport to Na+ gradients across the intestinal brush border1. Glucose-Galactose Malabsorption (GGM) is caused by a defect in SGLT1. The phenotype is neonatal onset of diarrhea that results in death unless these sugars are removed from the diet2–4. Previously we showed that two sisters with GGM had a missense mutation in the SGLT1 gene5. The gene has now been screened in 30 new patients, and a heterologous expression system has been used to link the mutations to the phenotype.
Ernest M Wright - One of the best experts on this subject based on the ideXlab platform.
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active sugar transport in health and disease
Journal of Internal Medicine, 2007Co-Authors: Ernest M Wright, Bruce A HirayamaAbstract:Secondary active glucose transport occurs by at least four members of the SLC5 gene family. This review considers the structure and function of two premier members, SGLT1 and SGLT2, and their role in intestinal glucose absorption and renal glucose reabsorption. Genetics disorders of SGLTs include Glucose-Galactose Malabsorption, and Familial Renal Glucosuria. SGLT1 plays a central role in Oral Rehydration Therapy used so effectively to treat secretory diarrhoea such as cholera. Increasing attention is being focused on SGLTs as drug targets for the therapy of diabetes.
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intestinal absorption in health and disease sugars
Best Practice & Research in Clinical Gastroenterology, 2003Co-Authors: Ernest M Wright, Martin G Martin, Eric TurkAbstract:Carbohydrates are mostly digested to glucose, fructose and galactose before absorption by the small intestine. Absorption across the brush border and basolateral membranes of enterocytes is mediated by sodium-dependent and -independent membrane proteins. Glucose and galactose transport across the brush border occurs by a Na(+)/glucose (galactose) co-transporter (SGLT1), whereas passive fructose transport is mediated by a uniporter (GLUT5). The passive exit of all three sugars out of the cell across the basolateral membrane occurs through two uniporters (GLUT2 and GLUT5). Mutations in SGLT1 cause a major defect in glucose and galactose absorption (Glucose-Galactose Malabsorption), but mutations in GLUT2 do not appear to disrupt glucose and galactose absorption. Studies on GLUT1 null mice and Fanconi-Bickel patients suggest that there is another exit pathway for glucose and galactose that may involve exocytosis. There are no known defects of fructose absorption.
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molecular basis for glucose galactose Malabsorption
Cell Biochemistry and Biophysics, 2002Co-Authors: Ernest M Wright, Eric Turk, Martin G MartinAbstract:Glucose-Galactose Malabsorption (GGM) is an autosomal recessive disease that presents in newborn infants as a life-threatening diarrhea. The diarrhea ceases within 1 h of removing oral intake of lactose, glucose, and galactose, but promptly returns with the introduction of one or more of the offending sugars into the diet. Our goal is to determine whether or not mutations in the sodium-glucose cotransporter gene (SGLT1) are responsible for GGM. We first isolated the human cDNA (hSGLT1), mapped the gene, and identified its chromosomal location (22q13.1). Our approach was then to screen GGM patients for mutations in hSGLT1 and then determine if these caused defects in sugar transport using the Xenopus laevis oocyte expression system. In 46 patients we have identified the mutations responsible for GGM. These included missense, nonsense, frame shift, splice site, and promoter mutations. In 30 patients, the same mutations were on both alleles, and the remaining 16 had different mutations on each allele (compound heterozygotes). Several mutations (e.g., C355S) were found in unrelated patients. The nonsense, frame shift, and splice site mutations all produce nonfunctional truncated proteins. In 22 out of the 23 missense mutations tested in the oocyte expression system, the proteins were translated and were stable in the cell, but did not reach the plasma membrane. In four of these mutants, an alanine residue was replaced by a valine, and in two, the trafficking defect was rescued by changing the valine to cysteine. One mutant protein (Q457R) did reach the plasma membrane, but it was unable to transport the sugar across the cell membrane. We conclude that mutations in the SGLT1 gene are the cause of Glucose-Galactose Malabsorption, and sugar transport is impaired mainly because the mutant proteins are either truncated or are not targeted properly to the cell membrane.
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defects in na glucose cotransporter sglt1 trafficking and function cause glucose galactose Malabsorption
Nature Genetics, 1996Co-Authors: Martin G Martin, M P Lostao, Eric Turk, Cynthia Kerner, Ernest M WrightAbstract:Cotransporters harness ion gradients to drive ‘active’ transport of substrates into cells, for example, the Na+/glucose cotransporter (SGLT1) couples sugar transport to Na+ gradients across the intestinal brush border1. Glucose-Galactose Malabsorption (GGM) is caused by a defect in SGLT1. The phenotype is neonatal onset of diarrhea that results in death unless these sugars are removed from the diet2–4. Previously we showed that two sisters with GGM had a missense mutation in the SGLT1 gene5. The gene has now been screened in 30 new patients, and a heterologous expression system has been used to link the mutations to the phenotype.
Eric Turk - One of the best experts on this subject based on the ideXlab platform.
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intestinal absorption in health and disease sugars
Best Practice & Research in Clinical Gastroenterology, 2003Co-Authors: Ernest M Wright, Martin G Martin, Eric TurkAbstract:Carbohydrates are mostly digested to glucose, fructose and galactose before absorption by the small intestine. Absorption across the brush border and basolateral membranes of enterocytes is mediated by sodium-dependent and -independent membrane proteins. Glucose and galactose transport across the brush border occurs by a Na(+)/glucose (galactose) co-transporter (SGLT1), whereas passive fructose transport is mediated by a uniporter (GLUT5). The passive exit of all three sugars out of the cell across the basolateral membrane occurs through two uniporters (GLUT2 and GLUT5). Mutations in SGLT1 cause a major defect in glucose and galactose absorption (Glucose-Galactose Malabsorption), but mutations in GLUT2 do not appear to disrupt glucose and galactose absorption. Studies on GLUT1 null mice and Fanconi-Bickel patients suggest that there is another exit pathway for glucose and galactose that may involve exocytosis. There are no known defects of fructose absorption.
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molecular basis for glucose galactose Malabsorption
Cell Biochemistry and Biophysics, 2002Co-Authors: Ernest M Wright, Eric Turk, Martin G MartinAbstract:Glucose-Galactose Malabsorption (GGM) is an autosomal recessive disease that presents in newborn infants as a life-threatening diarrhea. The diarrhea ceases within 1 h of removing oral intake of lactose, glucose, and galactose, but promptly returns with the introduction of one or more of the offending sugars into the diet. Our goal is to determine whether or not mutations in the sodium-glucose cotransporter gene (SGLT1) are responsible for GGM. We first isolated the human cDNA (hSGLT1), mapped the gene, and identified its chromosomal location (22q13.1). Our approach was then to screen GGM patients for mutations in hSGLT1 and then determine if these caused defects in sugar transport using the Xenopus laevis oocyte expression system. In 46 patients we have identified the mutations responsible for GGM. These included missense, nonsense, frame shift, splice site, and promoter mutations. In 30 patients, the same mutations were on both alleles, and the remaining 16 had different mutations on each allele (compound heterozygotes). Several mutations (e.g., C355S) were found in unrelated patients. The nonsense, frame shift, and splice site mutations all produce nonfunctional truncated proteins. In 22 out of the 23 missense mutations tested in the oocyte expression system, the proteins were translated and were stable in the cell, but did not reach the plasma membrane. In four of these mutants, an alanine residue was replaced by a valine, and in two, the trafficking defect was rescued by changing the valine to cysteine. One mutant protein (Q457R) did reach the plasma membrane, but it was unable to transport the sugar across the cell membrane. We conclude that mutations in the SGLT1 gene are the cause of Glucose-Galactose Malabsorption, and sugar transport is impaired mainly because the mutant proteins are either truncated or are not targeted properly to the cell membrane.
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defects in na glucose cotransporter sglt1 trafficking and function cause glucose galactose Malabsorption
Nature Genetics, 1996Co-Authors: Martin G Martin, M P Lostao, Eric Turk, Cynthia Kerner, Ernest M WrightAbstract:Cotransporters harness ion gradients to drive ‘active’ transport of substrates into cells, for example, the Na+/glucose cotransporter (SGLT1) couples sugar transport to Na+ gradients across the intestinal brush border1. Glucose-Galactose Malabsorption (GGM) is caused by a defect in SGLT1. The phenotype is neonatal onset of diarrhea that results in death unless these sugars are removed from the diet2–4. Previously we showed that two sisters with GGM had a missense mutation in the SGLT1 gene5. The gene has now been screened in 30 new patients, and a heterologous expression system has been used to link the mutations to the phenotype.
Annette Schürmann - One of the best experts on this subject based on the ideXlab platform.
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na d glucose cotransporter sglt1 is pivotal for intestinal glucose absorption and glucose dependent incretin secretion
Diabetes, 2012Co-Authors: Valentin Gorboulev, Annette Schürmann, Volker Vallon, Helmut Kipp, Alexander Jaschke, Dirk Klessen, Alexandra Friedrich, Stephan Scherneck, Timo Rieg, Robyn CunardAbstract:To clarify the physiological role of Na+-d-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1−/− mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1−/− mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1−/− mice developed a Glucose-Galactose Malabsorption syndrome but thrive normally when fed a Glucose-Galactose–free diet. In wild-type mice, passage of d-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1−/− mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed ∼3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of d-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2.
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the glucose transporter families sglt and glut molecular basis of normal and aberrant function
Journal of Parenteral and Enteral Nutrition, 2004Co-Authors: Andrea Scheepers, Hansgeorg Joost, Annette SchürmannAbstract:Glucose enters eucaryotic cells via 2 different types of membrane associated carrier proteins, the Na+-coupled glucose transporters (SGLT) and glucose transporter facilitators (GLUT). Three members of the SGLT family function as sugar transporters (SGLT1 and SGLT2) or sensors (SGLT3). The human GLUT family consists of 14 members, of which 11 have been shown to catalyze sugar transport. The individual isotypes exhibit different substrate specificity, kinetic characteristics, and expression profiles, thereby allowing a tissue-specific adaptation of glucose uptake through regulation of their gene expression. Furthermore, some transporters (eg, GLUT4 and GLUT8) are regulated by their subcellular distribution. In addition to catalyzing glucose entry into cells, some isotypes (eg, GLUT2) seem to be involved in the mechanisms of glucosensing of pancreatic beta-cells, neuronal, or other cells, thereby playing a major role in the hormonal and neural control. Targeted disruption in mice has helped to elucidate the physiologic function of some isotypes (GLUT1, GLUT2, GLUT4). Furthermore, several congenital defects of sugar metabolism are caused by aberrant transporter genes (eg, the Glucose-Galactose Malabsorption syndrome, SGLT1; the glucose transporter 1 deficiency syndrome; and the Fanconi-Bickel syndrome, GLUT2). In addition, a malfunction of glucose transporter expression or regulation (GLUT4) appears to contribute to the insulin resistance syndrome.