Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma-aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney

The H+-Activated Ovarian Cancer G Protein-Coupled Receptor 1 (OGR1) is responsible for Renal Calcium Loss during Acidosis

ABSTRACT Hypercalciuria is a common feature during metabolic acidosis. However, the mechanisms sensing acidosis and inducing increased urinary calcium excretion during acidosis are still unknown. Here we report that mice deficient for the Ovarian cancer G-protein coupled receptor 1 (OGR1 or Gpr68) did not excrete more calcium during chronic metabolic acidosis. Wild type (OGR1+/+) and OGR1-deficient mice (OGR1-/-) were subjected to standard chow (control) or 0.28 M NH4Cl in water for 1 day (acute metabolic acidosis) or 2 % NH4Cl in food for 7 days (chronic metabolic acidosis). OGR1 mRNA is ubiquitously expressed, including kidneys, and found along the entire nephron. No differences in responding to the acid load were observed in OGR1-/- mice, except for higher plasma [HCO3-] after 1 day. Bone mineral density and resorption activity of osteoclasts were similar between OGR1+/+ and OGR1-/- mice. Plasma PTH and Vitamin D3 levels were indistinguishable. However, the expression levels of key proteins for active transepithelial Ca2+ reabsorption in the distal convoluted tubule, TRPV5 and Calbindin-D28k were increased in OGR1-/- mice under metabolic acidosis. TRPV5 abundance was downregulated in wild type mice during metabolic acidosis but maintained at the same level in the absence of OGR1. OGR1-/- also exhibited higher NHE3 abundance when compared to OGR1+/+ under metabolic acidosis. In conclusion, OGR1 is a pH sensor involved in the hypercalciuria developed during metabolic acidosis and may regulate renal calcium excretion through modulation of proximal tubular NHE3 activity and regulation of the distal tubule TRPV5 calcium channel

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma-aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG

Genome-wide Association Study Identifies Five New Susceptibility Loci For Primary Angle Closure Glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 x 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 x 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 x 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 x 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 x 10(-12)). We also confirmed significant association at three previously described loci (P < 5 x 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18)(1), providing new insights into the biology of PACG.485556+Singapore Ministry of Health's National Medical Research Council under its Translational and Clinical Research (TCR) Flagship Programme Grant Stratified Medicine for Primary Angle Closure Glaucoma [NMRC/TCR/008-SERI/2013]Singapore Translational Research (STaR) Investigator Award Singapore Angle Closure Glaucoma Program Characterization, Prevention, and Management [NMRC/STAR/0023/2014]Biomedical Research CouncilAgency for Science, Technology and Research (A-STAR), SingaporeUniversiti Sains Malaysia [RUI 1001/PPSP/812101, RUI 1001/PPSP/812152]Program of Beijing ScholarsLeading Talents-High-Level Talents of the Health System of Beijing [2009-1-05]National Major Scientific and Technological Special Project for 'Significant New Drugs Development' [2011ZX09302-007-05]National Natural Science Foundation of China [81570837

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG

Genetic Association Study Of Exfoliation Syndrome Identifies A Protective Rare Variant At Loxl1 And Five New Susceptibility Loci

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.Wo