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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, Jahrgang 25, Nr. 3, 03.2023, S. 100351.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › Kurzpublikation › Forschung › Begutachtung

Harvard

Majmundar, AJ, Widmeier, E, Heneghan, JF, Daga, A, Wu, C-HW, Buerger, F, Hugo, H, Ullah, I, Amar, A, Ottlewski, I, Braun, DA, Jobst-Schwan, T, Lawson, JA, Zahoor, MY, Rodig, NM, Tasic, V, Nelson, CP, Khaliq, S, Schönauer, R, Halbritter, J, Sayer, JA, Fathy, HM, Baum, MA, Shril, S, Mane, S, Alper, SL & Hildebrandt, F 2023, 'OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis', GENET MED, Jg. 25, Nr. 3, S. 100351. https://doi.org/10.1016/j.gim.2022.11.019

APA

Majmundar, A. J., Widmeier, E., Heneghan, J. F., Daga, A., Wu, C-H. W., Buerger, F., Hugo, H., Ullah, I., Amar, A., Ottlewski, I., Braun, D. A., Jobst-Schwan, T., Lawson, J. A., Zahoor, M. Y., Rodig, N. M., Tasic, V., Nelson, C. P., Khaliq, S., Schönauer, R., ... Hildebrandt, F. (2023). OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis. GENET MED, 25(3), 100351. https://doi.org/10.1016/j.gim.2022.11.019

Vancouver

Majmundar AJ, Widmeier E, Heneghan JF, Daga A, Wu C-HW, Buerger F et al. OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis. GENET MED. 2023 Mär;25(3):100351. https://doi.org/10.1016/j.gim.2022.11.019

Bibtex

@article{1a1c2cae3f26467daf62539370416281,
title = "OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis",
abstract = "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.",
keywords = "Humans, Calcium Oxalate, Nephrolithiasis/genetics, Mutation, Missense/genetics, Sulfate Transporters/genetics, Receptors, Purinergic P2/genetics",
author = "Majmundar, {Amar J} and Eugen Widmeier and Heneghan, {John F} and Ankana Daga and Wu, {Chen-Han Wilfred} and Florian Buerger and Hannah Hugo and Ihsan Ullah and Ali Amar and Isabel Ottlewski and Braun, {Daniela A} and Tilman Jobst-Schwan and Lawson, {Jennifer A} and Zahoor, {Muhammad Yasir} and Rodig, {Nancy M} and Velibor Tasic and Nelson, {Caleb P} and Shagufta Khaliq and Ria Sch{\"o}nauer and Jan Halbritter and Sayer, {John A} and Fathy, {Hanan M} and Baum, {Michelle A} and Shirlee Shril and Shrikant Mane and Alper, {Seth L} and Friedhelm Hildebrandt",
note = "Copyright {\textcopyright} 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.",
year = "2023",
month = mar,
doi = "10.1016/j.gim.2022.11.019",
language = "English",
volume = "25",
pages = "100351",
journal = "GENET MED",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

RIS

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 -