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Genet Med
2023 Mar 01;253:100351. doi: 10.1016/j.gim.2022.11.019.
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OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis.
Majmundar AJ
,
Widmeier E
,
Heneghan JF
,
Daga A
,
Wu CW
,
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
.
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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 distalnephron. 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.
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36571463
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Amlal,
Deletion of the anion exchanger Slc26a4 (pendrin) decreases apical Cl(-)/HCO3(-) exchanger activity and impairs bicarbonate secretion in kidney collecting duct.
2010, Pubmed
Amlal,
Deletion of the anion exchanger Slc26a4 (pendrin) decreases apical Cl(-)/HCO3(-) exchanger activity and impairs bicarbonate secretion in kidney collecting duct.
2010,
Pubmed
Barone,
Deletion of the Cl-/HCO3- exchanger pendrin downregulates calcium-absorbing proteins in the kidney and causes calcium wasting.
2012,
Pubmed
Braun,
Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis.
2016,
Pubmed
Coe,
Idiopathic hypercalciuria and formation of calcium renal stones.
2016,
Pubmed
Connaughton,
Monogenic causes of chronic kidney disease in adults.
2019,
Pubmed
Daga,
Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.
2018,
Pubmed
Dhyani,
GPCR mediated control of calcium dynamics: A systems perspective.
2020,
Pubmed
Halbritter,
Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis.
2015,
Pubmed
Halbritter,
High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing.
2012,
Pubmed
Halbritter,
Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.
2013,
Pubmed
He,
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors.
2004,
Pubmed
Hildebrandt,
A systematic approach to mapping recessive disease genes in individuals from outbred populations.
2009,
Pubmed
Krebs,
The formation of citric and alpha-ketoglutaric acids in the mammalian body.
1938,
Pubmed
Lazo-Fernandez,
α-Ketoglutarate stimulates pendrin-dependent Cl- absorption in the mouse CCD through protein kinase C.
2018,
Pubmed
Okada,
Successful formation of calcium oxalate crystal deposition in mouse kidney by intraabdominal glyoxylate injection.
2007,
Pubmed
Park,
Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease.
2018,
Pubmed
Rule,
Kidney stones and the risk for chronic kidney disease.
2009,
Pubmed
Sayer,
The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.
2006,
Pubmed
Scales,
Prevalence of kidney stones in the United States.
2012,
Pubmed
Seelow,
HomozygosityMapper--an interactive approach to homozygosity mapping.
2009,
Pubmed
Shavit,
What is nephrocalcinosis?
2015,
Pubmed
Tokonami,
α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism.
2013,
Pubmed
