OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis
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OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis. / Majmundar, Amar J; Widmeier, Eugen; Heneghan, John F; Daga, Ankana; Wu, Chen-Han Wilfred; Buerger, Florian; Hugo, Hannah; Ullah, Ihsan; Amar, Ali; Ottlewski, Isabel; Braun, Daniela A; Jobst-Schwan, Tilman; Lawson, Jennifer A; Zahoor, Muhammad Yasir; Rodig, Nancy M; Tasic, Velibor; Nelson, Caleb P; Khaliq, Shagufta; Schönauer, Ria; Halbritter, Jan; Sayer, John A; Fathy, Hanan M; Baum, Michelle A; Shril, Shirlee; Mane, Shrikant; Alper, Seth L; Hildebrandt, Friedhelm.
In: GENET MED, Vol. 25, No. 3, 03.2023, p. 100351.Research output: SCORING: Contribution to journal › Short publication › Research › peer-review
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TY - JOUR
T1 - OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis
AU - Majmundar, Amar J
AU - Widmeier, Eugen
AU - Heneghan, John F
AU - Daga, Ankana
AU - Wu, Chen-Han Wilfred
AU - Buerger, Florian
AU - Hugo, Hannah
AU - Ullah, Ihsan
AU - Amar, Ali
AU - Ottlewski, Isabel
AU - Braun, Daniela A
AU - Jobst-Schwan, Tilman
AU - Lawson, Jennifer A
AU - Zahoor, Muhammad Yasir
AU - Rodig, Nancy M
AU - Tasic, Velibor
AU - Nelson, Caleb P
AU - Khaliq, Shagufta
AU - Schönauer, Ria
AU - Halbritter, Jan
AU - Sayer, John A
AU - Fathy, Hanan M
AU - Baum, Michelle A
AU - Shril, Shirlee
AU - Mane, Shrikant
AU - Alper, Seth L
AU - Hildebrandt, Friedhelm
N1 - Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
PY - 2023/3
Y1 - 2023/3
N2 - PURPOSE: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.METHODS: Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.RESULTS: Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ2 = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca2+ uptake, demonstrating loss of function.CONCLUSION: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.
AB - PURPOSE: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.METHODS: Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.RESULTS: Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ2 = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca2+ uptake, demonstrating loss of function.CONCLUSION: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.
KW - Humans
KW - Calcium Oxalate
KW - Nephrolithiasis/genetics
KW - Mutation, Missense/genetics
KW - Sulfate Transporters/genetics
KW - Receptors, Purinergic P2/genetics
U2 - 10.1016/j.gim.2022.11.019
DO - 10.1016/j.gim.2022.11.019
M3 - Short publication
C2 - 36571463
VL - 25
SP - 100351
JO - GENET MED
JF - GENET MED
SN - 1098-3600
IS - 3
ER -