Renal Hypomagnesemia 2

Mendelian MONDO:0007937 Pathograph 16 Show in embeddings browser Primary Hypomagnesemia Renal Tubulopathy

Renal hypomagnesemia 2 (HOMG2), also called isolated dominant hypomagnesemia (IDH), is an autosomal dominant renal magnesium-wasting disorder caused by a heterozygous missense variant in FXYD2, the gene for the gamma subunit of the Na,K-ATPase. Every genetically confirmed patient carries the same variant, p.Gly41Arg, which places a charged arginine in the single transmembrane helix of the subunit. The mutant subunit is misrouted and retained inside the cell, and it binds wild-type FXYD2 and impairs its routing as well, which explains why one mutant allele is enough to cause disease while loss of one FXYD2 copy is not. FXYD2 normally sits with the Na,K-ATPase at the basolateral membrane of the distal convoluted tubule (DCT), the segment that sets final urinary magnesium. How its loss produces magnesium wasting is not settled: one model holds that the pump is destabilized and the apical driving force for magnesium entry falls, another that FXYD2 itself carries basolateral magnesium exit. Patients have low serum magnesium with inappropriately high urinary magnesium and low urinary calcium. Many carriers are asymptomatic; others have muscle cramps, tetany, seizures and, in adults, chondrocalcinosis. All known patients belong to three Dutch and Belgian families that share a founder haplotype.

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Classifications

Harrison's Part
KIDNEY URINARY TRACT
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous p.Gly41Arg carriers are affected across several generations of the reported families. Low serum magnesium is found in carriers without symptoms, so the biochemical trait is consistent while clinical expressivity varies.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (3 references)
PMID:3298795 SUPPORT Human clinical
"Hypomagnesemia due to isolated renal magnesium loss was demonstrated in two unrelated families with autosomal dominant mode of inheritance."
The original clinical description of the dominant families.
PMID:12763862 SUPPORT Human clinical
"After candidate screening, we identified a heterozygous mutation in the FXYD2 gene, encoding the Na(+),K(+)-ATPase gamma-subunit, cosegregating with the patients of this family, which was not found in 132 control chromosomes."
A heterozygous variant cosegregating with disease supports dominant inheritance.
PMID:9915957 SUPPORT Human clinical
"Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic."
Affected family members can be asymptomatic, supporting variable expressivity.
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Mechanistic Hypotheses

2
Na,K-ATPase destabilization reduces the apical driving force for TRPM6
pump_destabilization EMERGING
Evidence balance 1 support
Loss of the FXYD2 interaction destabilizes and inactivates the DCT Na,K-ATPase over time, lowering intracellular potassium and the apical membrane potential that drives TRPM6-mediated magnesium entry.
Pathograph links
Loss of FXYD2 Regulation of the DCT Na,K-ATPase -> Reduced DCT Transcellular Magnesium Reabsorption INDIRECT KNOWN INTERMEDIATES Two mechanisms are proposed for how losing FXYD2 reduces DCT magnesium reabsorption. One holds that the pump is destabilized and inactivated, so the cell cannot sustain the intracellular potassium that sets the apical membrane potential driving TRPM6 magnesium entry. The other holds that FXYD2 itself mediates basolateral magnesium exit, which the mutant cannot do. The step is not demonstrated in patient tissue. Intermediates: Na,K-ATPase destabilization with loss of apical driving force for TRPM6; loss of FXYD2-mediated basolateral magnesium extrusion
Show evidence (1 reference)
PMID:30175537 SUPPORT REVIEW SYNTHESIS Other
"Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase."
States the destabilization hypothesis.
FXYD2 mediates basolateral magnesium extrusion
basolateral_magnesium_exit EMERGING
Evidence balance 1 support
FXYD2 itself carries or supports basolateral magnesium exit from the DCT cell, shown as a wild-type-specific transepithelial magnesium current in MDCK cells that the G41R mutant does not support.
Pathograph links
Loss of FXYD2 Regulation of the DCT Na,K-ATPase -> Reduced DCT Transcellular Magnesium Reabsorption INDIRECT KNOWN INTERMEDIATES Two mechanisms are proposed for how losing FXYD2 reduces DCT magnesium reabsorption. One holds that the pump is destabilized and inactivated, so the cell cannot sustain the intracellular potassium that sets the apical membrane potential driving TRPM6 magnesium entry. The other holds that FXYD2 itself mediates basolateral magnesium exit, which the mutant cannot do. The step is not demonstrated in patient tissue. Intermediates: Na,K-ATPase destabilization with loss of apical driving force for TRPM6; loss of FXYD2-mediated basolateral magnesium extrusion
Show evidence (1 reference)
PMID:18448590 SUPPORT In vitro / ex vivo
"These results suggest that FXYD2 can mediate basolateral extrusion of magnesium from cultured renal epithelial cells and provide new insights into the understanding of the possible physiological roles of FXYD2 wild-type and mutant proteins."
Supports a direct basolateral magnesium-exit role for FXYD2.
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Discussions and Knowledge Gaps

2
How does loss of functional FXYD2 at the DCT basolateral membrane reduce transcellular magnesium reabsorption?
INTERPRETATION OPEN fxyd2_mg_wasting_mechanism_unsettled
Attached to
pathophysiology#Loss of FXYD2 Regulation of the DCT Na,K-ATPase pathophysiology#Reduced DCT Transcellular Magnesium Reabsorption
Two mechanisms are proposed and curated as the hypothesis groups on the edge into Reduced DCT Transcellular Magnesium Reabsorption. One holds that without FXYD2 the Na,K-ATPase is destabilized and inactivated, lowering the intracellular potassium and the apical membrane potential that drive TRPM6 magnesium entry (PMID:30175537). The other holds that FXYD2 itself mediates basolateral magnesium exit, shown as a wild-type-specific magnesium current in MDCK cells that G41R lacks (PMID:18448590). Neither is demonstrated in patient tissue, and FXYD2 both inhibits and stabilizes the pump, so the net effect on pump activity is itself debated. The hypocalciuria is separately described as not easily explained.
The two hypotheses are not mutually exclusive; both would reduce DCT magnesium reabsorption.
Does a whole-animal FXYD2 defect reproduce the renal magnesium wasting of human HOMG2?
HUMAN MODEL MISMATCH OPEN no_in_vivo_model_of_fxyd2_g41r
Attached to
pathophysiology#Reduced DCT Transcellular Magnesium Reabsorption
There is no reported G41R knock-in animal. The available model is the Fxyd2-null mouse, which is a loss-of-one-function model rather than the human dominant-negative one, and it does not show overt hypomagnesemia: FXYD2-deficient mice kept urine electrolytes in the normal range (PMID:25472608). A later reanalysis of the same data argues that urinary magnesium was in fact moderately but significantly raised (PMID:30175537), so whether the mouse is even a partial model is disputed. Because the human disease is dominant-negative and the mouse is a null, the mouse may not test the human mechanism at all.
Proposed experiments
Fxyd2 p.Gly41Arg knock-in mouse
fxyd2_g41r_knockin_mouse
Knock the patient variant into mouse Fxyd2 and measure serum magnesium, fractional magnesium excretion and DCT magnesium transport, alongside an Fxyd2-null line, to separate the dominant-negative mechanism from simple loss of the subunit.
Would support
pathophysiology#Reduced DCT Transcellular Magnesium Reabsorption
Supporting outcome
  • Knock-in mice waste magnesium in the urine and become hypomagnesemic while null mice do not.
Refuting outcome
  • Knock-in mice keep normal serum magnesium and fractional magnesium excretion.
Show evidence (2 references)
PMID:25472608 SUPPORT Model organism
"no obvious renal phenotype was detected in mice with global deletion of FXYD2"
The Fxyd2-null mouse shows no overt renal phenotype.
PMID:30175537 SUPPORT REVIEW SYNTHESIS Other
"Urinary Mg was also measured and although pronounced hypermagnesuria was not observed, the published data appear to show a moderate but significantly increased urinary Mg secretion in the FXYD2−/− mice"
A reanalysis argues the null mouse does show modestly raised urinary magnesium.
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Pathophysiology

7
Heterozygous FXYD2 p.Gly41Arg Variant
The c.121G>A variant replaces glycine 41, a conserved residue in the single transmembrane helix of the 65-residue gamma subunit, with arginine and so introduces a positive charge into the membrane span.
FXYD2 hgnc:4026 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FXYD2 (hgnc:4026). hgnc:4026 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Downstream
Misrouting and Intracellular Retention of G41R FXYD2 The mutant subunit does not reach the cell surface and accumulates in perinuclear structures.
Show evidence (3 references)
PMID:12763862 SUPPORT Human clinical
"The mutation leads to a G41R substitution, introducing a charged amino acid residue in the predicted transmembrane region of the gamma-subunit protein."
Identifies the variant and its position in the transmembrane region.
PMID:25765846 SUPPORT Human clinical
"We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria."
The same variant in two further families.
PMID:12225751 SUPPORT BACKGROUND Human clinical
"This 65 amino acid residues protein has been linked to a form of dominant renal hypomagnesaemia resulting from substitution of a highly conserved glycine residue (Gly41) to arginine residue."
States that the substituted glycine is highly conserved.
Misrouting and Intracellular Retention of G41R FXYD2
In transfected cells the G41R subunit is retained in perinuclear compartments and lacks a posttranslational modification carried by the wild-type protein. The alpha and beta subunits of the pump still reach the surface, but without a functional gamma subunit.
kidney distal convoluted tubule epithelial cell CL:1000849 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney distal convoluted tubule epithelial cell (CL:1000849). CL:1000849 is a cell type from the Cell Ontology.
protein localization to basolateral plasma membrane GO:1903361 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to basolateral plasma membrane (GO:1903361). GO:1903361 is a biological process from the Gene Ontology.
Downstream
Dominant-Negative Retention of Wild-Type FXYD2 The mutant oligomerizes with wild-type FXYD2 and reduces its routing, so the wild-type product of the normal allele is also lost from the surface.
Loss of FXYD2 Regulation of the DCT Na,K-ATPase Mutant gamma that does not reach the surface cannot regulate the alpha and beta subunits that do.
Show evidence (3 references)
PMID:12763862 SUPPORT In vitro / ex vivo
"Expression studies in insect Sf9 and COS-1 cells showed that the mutant gamma-subunit protein was incorrectly routed and accumulated in perinuclear structures."
The mutant protein is retained intracellularly.
PMID:12763862 SUPPORT In vitro / ex vivo
"In addition to disturbed routing of the G41R mutant, Western blot analysis of Xenopus oocytes expressing wild-type or mutant gamma-subunit showed mutant gamma-subunit lacking a posttranslational modification."
The retained mutant also lacks normal posttranslational processing.
PMID:11929868 SUPPORT In vitro / ex vivo
"The results show that Gly-41 --> Arg prevents trafficking of gamma but not alphabeta pumps to the cell surface and abrogates functional effects of gamma on alphabeta pumps."
In alpha1-transfected HeLa cells, G41R gamma fails to reach the surface while the alpha-beta pump does.
Dominant-Negative Retention of Wild-Type FXYD2
FXYD2 forms oligomers, and G41R FXYD2 oligomerizes with itself and with wild-type FXYD2. When the two are co-expressed, processing of the wild-type protein (read out as artificial glycosylation) is reduced, which suggests the mutant holds wild-type subunits back from the plasma membrane. Haploinsufficiency is unlikely to explain the disease, because people lacking one FXYD2 copy have normal serum magnesium. A study of isolated transmembrane peptides found the opposite result for oligomerization, so the physical basis of the interference is not fully settled.
kidney distal convoluted tubule epithelial cell CL:1000849 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney distal convoluted tubule epithelial cell (CL:1000849). CL:1000849 is a cell type from the Cell Ontology.
protein homooligomerization GO:0051260 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein homooligomerization (GO:0051260). GO:0051260 is a biological process from the Gene Ontology.
Downstream
Loss of FXYD2 Regulation of the DCT Na,K-ATPase Retention of wild-type subunits further depletes functional gamma at the basolateral membrane.
Show evidence (5 references)
PMID:17980699 SUPPORT In vitro / ex vivo
"Moreover, FXYD2-G41R also shows oligomerisation with itself and with the wild type protein."
Co-immunoprecipitation shows mutant-wild-type oligomers.
PMID:17980699 SUPPORT In vitro / ex vivo
"Finally, we demonstrated that artificial glycosylation of the wild type FXYD2 is reduced when co-expressed with FXYD2-G41R."
Co-expressed mutant impairs processing of the wild-type protein.
PMID:12763862 SUPPORT INDIRECT Human clinical
"Finally, we investigated two individuals lacking one copy of the FXYD2 gene and found their serum Mg(2+) levels to be within the normal range."
Loss of one FXYD2 copy does not cause hypomagnesemia, which argues against haploinsufficiency and so, by exclusion, for a dominant-negative effect of the mutant.
+ 2 more references
Loss of FXYD2 Regulation of the DCT Na,K-ATPase
The gamma subunit is a regulatory subunit of the basolateral Na,K-ATPase in the DCT and other nephron segments. In the disease the pump loses its normal FXYD2 partner. Proximal tubular cells cultured from a patient's urine express less FXYD2 and raise FXYD2 and Na,K-ATPase less than control cells under hypertonic stress. Whether pump activity in the DCT ends up lower or higher is debated, because FXYD2 both inhibits the pump kinetically and stabilizes it.
FXYD2 mediates basolateral magnesium extrusion Na,K-ATPase destabilization reduces the apical driving force for TRPM6
kidney distal convoluted tubule epithelial cell CL:1000849 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney distal convoluted tubule epithelial cell (CL:1000849). CL:1000849 is a cell type from the Cell Ontology.
FXYD2 hgnc:4026 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FXYD2 (hgnc:4026). hgnc:4026 is a gene from the HUGO Gene Nomenclature Committee.
P-type sodium:potassium-exchanging transporter activity GO:0005391 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated P-type sodium:potassium-exchanging transporter activity (GO:0005391). GO:0005391 is a molecular function from the Gene Ontology.
distal convoluted tubule UBERON:0001292 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in distal convoluted tubule (UBERON:0001292). UBERON:0001292 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Xenopus oocytes and MDCK cells expressing wild-type or G41R FXYD2 CELL LINE The oocyte and MDCK assays show that G41R changes FXYD2 ion-handling and abolishes a basolateral magnesium current carried by wild-type FXYD2.
Downstream
Reduced DCT Transcellular Magnesium Reabsorption Two mechanisms are proposed for how losing FXYD2 reduces DCT magnesium reabsorption. One holds that the pump is destabilized and inactivated, so the cell cannot sustain the intracellular potassium that sets the apical membrane potential driving TRPM6 magnesium entry. The other holds that FXYD2 itself mediates basolateral magnesium exit, which the mutant cannot do. The step is not demonstrated in patient tissue. Na,K-ATPase destabilization reduces the apical driving force for TRPM6 FXYD2 mediates basolateral magnesium extrusion
Show evidence (3 references)
PMID:21130072 SUPPORT Model organism
"By immunohistochemistry, it was shown that the γa- and γb-subunits colocalize at the basolateral membrane of the DCT segment of mouse kidney."
Places both FXYD2 isoforms at the basolateral membrane of the DCT.
PMID:30175537 SUPPORT REVIEW SYNTHESIS Other
"Mutations in FXYD2 (G41R), and transcription factors (HNF-1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K-ATPase."
A review naming impaired FXYD2-pump interaction as the shared lesion.
PMID:19865785 SUPPORT In vitro / ex vivo
"FXYD2 protein expression was lower in patient cells and could be increased in both cell lines upon culturing in hyperosmotic medium but to a lesser extent in patient cells."
Immortalized proximal tubular cells from a G41R patient carry less FXYD2 protein than control cells; these are proximal, not DCT, cells, from one patient and one control.
Reduced DCT Transcellular Magnesium Reabsorption
The distal convoluted tubule sets final urinary magnesium, and its transcellular reabsorption falls. Because more distal segments are largely impermeable to magnesium, the DCT defect is not compensated and magnesium is lost in the urine. Urinary calcium is low, which distinguishes this disorder from the hypercalciuric forms of renal magnesium wasting.
magnesium ion transmembrane transport GO:1903830 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased magnesium ion transmembrane transport (GO:1903830). GO:1903830 is a biological process from the Gene Ontology.
distal convoluted tubule UBERON:0001292 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in distal convoluted tubule (UBERON:0001292). UBERON:0001292 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Renal magnesium wasting The tubular defect is measured clinically as inappropriate urinary magnesium loss.
Hypomagnesemia Continuing urinary magnesium loss lowers serum magnesium.
Show evidence (2 references)
PMID:19812536 SUPPORT REVIEW SYNTHESIS Other
"The DCT is the final determinant of plasma Mg(2+) levels, as the more distal nephron segments are largely impermeable to Mg(2+)."
Establishes the DCT as the segment that sets final urinary magnesium.
PMID:3298795 SUPPORT Human clinical
"Magnesium infusions performed in two patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium."
Magnesium infusion studies demonstrate a tubular reabsorption defect in patients.
Hypomagnesemia
Chronic low serum magnesium, below about 0.7 mmol/L, is the defining biochemical feature and is present in symptomatic and asymptomatic carriers.
magnesium ion homeostasis GO:0010960 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal magnesium ion homeostasis (GO:0010960). GO:0010960 is a biological process from the Gene Ontology.
Downstream
Neuromuscular Hyperexcitability Low extracellular magnesium raises neuromuscular excitability.
Chondrocalcinosis Chronic magnesium deficiency reduces the activity of magnesium-dependent alkaline phosphatase, so inorganic pyrophosphate accumulates and calcium pyrophosphate crystals deposit in cartilage.
Show evidence (1 reference)
PMID:25765846 SUPPORT Human clinical
"In 2000, mutations in FXYD2, encoding the γ-subunit of the Na(+)-K(+)-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis."
Hypomagnesemia is the central feature of the disease.
Neuromuscular Hyperexcitability
Reduced extracellular magnesium increases neuromuscular excitability, the basis of the cramps, tetany and seizures reported in symptomatic patients.
Downstream
Muscle cramps Neuromuscular hyperexcitability presents as muscle cramps.
Tetany Severe neuromuscular hyperexcitability presents as tetany.
Seizure Neuromuscular hyperexcitability can present as epileptic seizures.
Show evidence (1 reference)
PMID:27234911 SUPPORT REVIEW SYNTHESIS Human clinical
"Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias."
Neuromuscular irritability and seizures follow from magnesium deficiency.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Renal Hypomagnesemia 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Genitourinary 2
Renal magnesium wasting HP:0005567 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal magnesium wasting (HP:0005567). HP:0005567 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3298795 SUPPORT Human clinical
"Magnesium infusions performed in two patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium."
The renal magnesium-handling defect in patients.
Hypocalciuria HP:0003127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalciuria (HP:0003127). HP:0003127 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3298795 SUPPORT Human clinical
"All members of both families who presented with hypomagnesemia had also a lowered excretion of calcium in the urine, presumably as a consequence of increased reabsorption in Henle's loop."
Low urinary calcium in all affected family members.
PMID:30175537 SUPPORT REVIEW SYNTHESIS Other
"Note that hypocalciuria associated with the FXYD2 G41R mutation is not easily explained and reveals complexity of the mechanism."
Records that the hypocalciuria mechanism is unexplained.
Metabolism 3
Hypomagnesemia HP:0002917 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomagnesemia (HP:0002917), qualified as temporality chronic. HP:0002917 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:25765846 SUPPORT Human clinical
"In 2000, mutations in FXYD2, encoding the γ-subunit of the Na(+)-K(+)-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis."
Hypomagnesemia in the reported families.
Hypokalemia HP:0002900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokalemia (HP:0002900). HP:0002900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35894287 SUPPORT REVIEW SYNTHESIS Human clinical
"Later, a careful biochemical workup in members of two additional families with the identical mutation also revealed a tendency towards hypokalemia and metabolic alkalosis."
A tendency to hypokalemia in two of the families.
Metabolic alkalosis HP:0200114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic alkalosis (HP:0200114). HP:0200114 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35894287 SUPPORT REVIEW SYNTHESIS Human clinical
"Later, a careful biochemical workup in members of two additional families with the identical mutation also revealed a tendency towards hypokalemia and metabolic alkalosis."
A tendency to metabolic alkalosis in two of the families.
Musculoskeletal 4
Muscle cramps Muscle spasm HP:0003394 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle cramps, annotated with Muscle spasm (HP:0003394). HP:0003394 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25765846 SUPPORT Human clinical
"As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
Muscle cramps in affected patients.
Tetany HP:0001281 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetany (HP:0001281). HP:0001281 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9915957 SUPPORT Human clinical
"Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic."
Tetany in symptomatic patients.
Chondrocalcinosis HP:0000934 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chondrocalcinosis (HP:0000934). HP:0000934 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25765846 SUPPORT Human clinical
"As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
Chondrocalcinosis in affected patients.
Generalized muscle weakness HP:0003324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized muscle weakness (HP:0003324). HP:0003324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29344503 SUPPORT REVIEW SYNTHESIS Human clinical
"All of the affected individuals complained of muscle cramps and generalized weakness."
Generalized weakness in the affected individuals of the three families.
Nervous System 1
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25765846 SUPPORT Human clinical
"As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
Epilepsy in affected patients.
PMID:35894287 SUPPORT REVIEW SYNTHESIS Human clinical
"The index patients presented with seizures during childhood and profound hypomagnesemia [55,56]."
Childhood seizures in the originally reported patients.
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Genetic Associations

1
FXYD2 (Causative)
Gene: FXYD2 hgnc:4026 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FXYD2 (hgnc:4026). hgnc:4026 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (1 reference)
PMID:11062458 SUPPORT Human clinical
"We identified a putative dominant-negative mutation in the gene encoding the Na(+), K(+)-ATPase gamma-subunit (FXYD2), leading to defective routing of the protein in a family with dominant renal hypomagnesaemia."
The original identification of FXYD2 as the causal gene.
Variants (1)
NM_001680.5:c.121G>A (p.Gly41Arg) Pathogenic
MISSENSE
The only reported disease allele, heterozygous in all genetically confirmed patients across three families with a shared founder haplotype, and absent from 132 control chromosomes in the original study. A review numbers the same change c.115G>A on another transcript.
Identifiers: ClinVar:VCV000007684
Show evidence (2 references)
PMID:12763862 SUPPORT Human clinical
"The mutation leads to a G41R substitution, introducing a charged amino acid residue in the predicted transmembrane region of the gamma-subunit protein."
Reports the variant and the resulting substitution.
PMID:25765846 SUPPORT Human clinical
"Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect."
The shared haplotype across all reported families is a founder effect.
💊

Medical Actions

1
Magnesium supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: magnesium ion CHEBI:39128 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses magnesium ion (CHEBI:39128). CHEBI:39128 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral magnesium is the standard management of renal magnesium wasting. Serum magnesium is hard to normalize because supplementation drives further renal loss. No treatment study specific to FXYD2 disease was found, so this is curated from reviews of genetic hypomagnesemias that include FXYD2.
Target Phenotypes: Hypomagnesemia HP:0002917 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypomagnesemia (HP:0002917). HP:0002917 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30175537 SUPPORT REVIEW SYNTHESIS Other
"Hypomagnesemia (Mg < 0.7 mmol/L) is the most frequent manifestation associated with Mg imbalance and must be treated with dietary Mg supplements"
General management of hypomagnesemia is dietary magnesium supplementation.
PMID:27234911 SUPPORT REVIEW SYNTHESIS Human clinical
"Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function."
Magnesium supplementation remains the treatment for the genetic hypomagnesemias including FXYD2.
📊

Prevalence

2
Worldwide
Point prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class below 1 per 1,000,000.
Show evidence (1 reference)
ORPHA:34528 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25765846"
Orphanet epidemiology table.
Worldwide reported literature
Cases/families reported in the literature Ultra-rare
Three families, two Dutch and one Belgian, with 29 reported patients who share a founder haplotype. ClinGen counts them as 18 probands from one family.
Show evidence (2 references)
PMID:40428357 SUPPORT BACKGROUND Human clinical
"So far, only three families (29 patients, all descendants of a common founder) have been reported."
Counts the reported families and patients.
CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2025-12-03T050000.000Z SUPPORT Other
"One variant (the missense variant Gly41Arg) has been reported in 18 probands from one family in 2 publications (PMIDs: 25765846, 11062458) included in this curation."
ClinGen scores the reported patients as one extended family.
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Experimental Models

1
Xenopus oocytes and MDCK cells expressing wild-type or G41R FXYD2 CELL_LINE
Xenopus oocytes injected with wild-type or G41R FXYD2 cRNA, and MDCK renal epithelial monolayers expressing either construct, used to measure ion currents and a basolateral magnesium current.
Publication
PMID:18448590
Pathograph links
Loss of FXYD2 Regulation of the DCT Na,K-ATPase partially recapitulates fidelity: low observes: molecular The oocyte and MDCK assays show that G41R changes FXYD2 ion-handling and abolishes a basolateral magnesium current carried by wild-type FXYD2.
Limitations: Xenopus oocytes and canine MDCK cells are heterologous systems, not DCT cells, and the G41R gain-of-function cation current they report is one of two competing mechanisms and is not shown in patients.
Divergences from the human mechanism
species mismatch qualifying
The systems are amphibian oocyte and canine kidney epithelium, not human DCT, so the magnesium-handling context of the human segment is not reproduced.
boundary omission qualifying
The assays observe a single transfected protein's currents and do not contain the intact DCT pump, the apical TRPM6 channel, or the tubular magnesium gradient that set reabsorption in the patient.
Show evidence (1 reference)
PMID:18448590 SUPPORT In vitro / ex vivo
"in contrast to the wild-type FXYD2 currents, inward rectifying cation currents were induced by hyperpolarization pulses in oocytes expressing the G41R mutant."
The mutant has distinct electrophysiological behaviour in oocytes.
{ }

Source YAML

click to show 
name: Renal Hypomagnesemia 2
creation_date: "2026-10-31T14:00:00Z"
category: Mendelian
description: >-
  Renal hypomagnesemia 2 (HOMG2), also called isolated dominant hypomagnesemia
  (IDH), is an autosomal dominant renal magnesium-wasting disorder caused by a
  heterozygous missense variant in FXYD2, the gene for the gamma subunit of the
  Na,K-ATPase. Every genetically confirmed patient carries the same variant,
  p.Gly41Arg, which places a charged arginine in the single transmembrane helix
  of the subunit. The mutant subunit is misrouted and retained inside the cell,
  and it binds wild-type FXYD2 and impairs its routing as well, which explains
  why one mutant allele is enough to cause disease while loss of one FXYD2 copy
  is not. FXYD2 normally sits with the Na,K-ATPase at the basolateral membrane
  of the distal convoluted tubule (DCT), the segment that sets final urinary
  magnesium. How its loss produces magnesium wasting is not settled: one model
  holds that the pump is destabilized and the apical driving force for magnesium
  entry falls, another that FXYD2 itself carries basolateral magnesium exit.
  Patients have low serum magnesium with inappropriately high urinary magnesium
  and low urinary calcium. Many carriers are asymptomatic; others have muscle
  cramps, tetany, seizures and, in adults, chondrocalcinosis. All known patients
  belong to three Dutch and Belgian families that share a founder haplotype.
notes: >-
  The entry is anchored on MONDO:0007937 (OMIM 154020, ORPHA:34528) and FXYD2
  (hgnc:4026). The human data come from three families with one founder
  haplotype, all carrying FXYD2 p.Gly41Arg; ClinGen scored them as 18 probands
  from one family. No other FXYD2 variant has been reported with this phenotype.
  A second heterozygous FXYD2 missense variant, p.Arg27His, has been reported
  with a proximal tubulopathy with hexose wasting and hypercalciuria
  (PMID:40428357); that phenotype is not this disease and is not curated here.

  ClinGen (Tubulopathy GCEP) classifies FXYD2 for this disease as Moderate and
  describes the mechanism as loss of function. The human and cell data curated
  here point more specifically to a dominant-negative effect, because two people
  lacking one FXYD2 copy had normal serum magnesium (PMID:12763862).

  Hypocalciuria, hypokalemia, metabolic alkalosis and generalized weakness are
  curated as phenotypes without an incoming causal edge. The mechanism of
  hypocalciuria in this disease is described as unexplained (PMID:30175537), and
  no cited source links the potassium, acid-base or weakness findings to a
  specific step of the FXYD2 mechanism.

  Not curated: polyuria, reported in some patients, and kidney failure, reported
  in one proband, both only in a review (PMID:29344503) that also calls the
  patients hypocalcemic where the primary reports describe hypocalciuria; the
  ClinGen summary also mentions renal failure.

  No treatment study in this disease was found. Magnesium supplementation is
  curated from reviews of genetic hypomagnesemias that include FXYD2.

  No GeneReviews chapter covers this disease; just check-genereviews reports
  NO_CHAPTER against the committed Bookshelf index.
disease_term:
  preferred_term: renal hypomagnesemia 2
  term:
    id: MONDO:0007937
    label: renal hypomagnesemia 2
synonyms:
- HOMG2
- renal hypomagnesemia type 2
- isolated dominant hypomagnesemia
- isolated autosomal dominant hypomagnesemia
- isolated renal magnesium wasting
- autosomal dominant primary hypomagnesemia with hypocalciuria
- FXYD2 familial primary hypomagnesemia
- FXYD2 primary hypomagnesemia
- familial primary hypomagnesemia caused by mutation in FXYD2
- primary hypomagnesemia caused by mutation in FXYD2
parents:
- Primary Hypomagnesemia
- Renal Tubulopathy
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
    evidence:
    - reference: PMID:3298795
      reference_title: "Renal magnesium wasting in two families with autosomal dominant inheritance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypomagnesemia due to isolated renal magnesium loss was demonstrated in two unrelated families with autosomal dominant mode of inheritance."
      explanation: The disorder is a primary renal tubular magnesium-wasting disease.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    Heterozygous p.Gly41Arg carriers are affected across several generations of
    the reported families. Low serum magnesium is found in carriers without
    symptoms, so the biochemical trait is consistent while clinical expressivity
    varies.
  evidence:
  - reference: PMID:3298795
    reference_title: "Renal magnesium wasting in two families with autosomal dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypomagnesemia due to isolated renal magnesium loss was demonstrated in two unrelated families with autosomal dominant mode of inheritance."
    explanation: The original clinical description of the dominant families.
  - reference: PMID:12763862
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After candidate screening, we identified a heterozygous mutation in the FXYD2 gene, encoding the Na(+),K(+)-ATPase gamma-subunit, cosegregating with the patients of this family, which was not found in 132 control chromosomes."
    explanation: A heterozygous variant cosegregating with disease supports dominant inheritance.
  - reference: PMID:9915957
    reference_title: "Hereditary isolated renal magnesium loss maps to chromosome 11q23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic."
    explanation: Affected family members can be asymptomatic, supporting variable expressivity.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class below 1 per 1,000,000.
  evidence:
  - reference: ORPHA:34528
    reference_title: "Autosomal dominant primary hypomagnesemia with hypocalciuria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25765846"
    explanation: Orphanet epidemiology table.
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three families, two Dutch and one Belgian, with 29 reported patients who
    share a founder haplotype. ClinGen counts them as 18 probands from one
    family.
  evidence:
  - reference: PMID:40428357
    reference_title: "The Metabolic Consequences of Pathogenic Variant in FXYD2 Gene Encoding the Gamma Subunit of Sodium/Potassium-Transporting ATPase in Two Siblings with Sodium-Dependent Defect of Fructose, Galactose and Glucose Renal Reabsorption."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, only three families (29 patients, all descendants of a common founder) have been reported."
    explanation: Counts the reported families and patients.
  - reference: CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2025-12-03T050000.000Z
    reference_title: "FXYD2 / renal hypomagnesemia 2 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One variant (the missense variant Gly41Arg) has been reported in 18 probands from one family in 2 publications (PMIDs: 25765846, 11062458) included in this curation."
    explanation: ClinGen scores the reported patients as one extended family.
pathophysiology:
- name: Heterozygous FXYD2 p.Gly41Arg Variant
  biological_scale: MOLECULAR
  description: >-
    The c.121G>A variant replaces glycine 41, a conserved residue in the single
    transmembrane helix of the 65-residue gamma subunit, with arginine and so
    introduces a positive charge into the membrane span.
  genes:
  - preferred_term: FXYD2
    term:
      id: hgnc:4026
      label: FXYD2
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
  evidence:
  - reference: PMID:12763862
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation leads to a G41R substitution, introducing a charged amino acid residue in the predicted transmembrane region of the gamma-subunit protein."
    explanation: Identifies the variant and its position in the transmembrane region.
  - reference: PMID:25765846
    reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria."
    explanation: The same variant in two further families.
  - reference: PMID:12225751
    reference_title: "Oligomerization of a peptide derived from the transmembrane region of the sodium pump gamma subunit: effect of the pathological mutation G41R."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "This 65 amino acid residues protein has been linked to a form of dominant renal hypomagnesaemia resulting from substitution of a highly conserved glycine residue (Gly41) to arginine residue."
    explanation: States that the substituted glycine is highly conserved.
  downstream:
  - target: Misrouting and Intracellular Retention of G41R FXYD2
    causal_link_type: DIRECT
    description: >-
      The mutant subunit does not reach the cell surface and accumulates in
      perinuclear structures.
    evidence:
    - reference: PMID:12763862
      reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression studies in insect Sf9 and COS-1 cells showed that the mutant gamma-subunit protein was incorrectly routed and accumulated in perinuclear structures."
      explanation: Heterologous expression shows the variant causes misrouting.
- name: Misrouting and Intracellular Retention of G41R FXYD2
  biological_scale: CELLULAR
  description: >-
    In transfected cells the G41R subunit is retained in perinuclear
    compartments and lacks a posttranslational modification carried by the
    wild-type protein. The alpha and beta subunits of the pump still reach the
    surface, but without a functional gamma subunit.
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  biological_processes:
  - preferred_term: protein localization to basolateral plasma membrane
    term:
      id: GO:1903361
      label: protein localization to basolateral plasma membrane
    modifier: DECREASED
  evidence:
  - reference: PMID:12763862
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression studies in insect Sf9 and COS-1 cells showed that the mutant gamma-subunit protein was incorrectly routed and accumulated in perinuclear structures."
    explanation: The mutant protein is retained intracellularly.
  - reference: PMID:12763862
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In addition to disturbed routing of the G41R mutant, Western blot analysis of Xenopus oocytes expressing wild-type or mutant gamma-subunit showed mutant gamma-subunit lacking a posttranslational modification."
    explanation: The retained mutant also lacks normal posttranslational processing.
  - reference: PMID:11929868
    reference_title: "Distinct regulatory effects of the Na,K-ATPase gamma subunit."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results show that Gly-41 --> Arg prevents trafficking of gamma but not alphabeta pumps to the cell surface and abrogates functional effects of gamma on alphabeta pumps."
    explanation: >-
      In alpha1-transfected HeLa cells, G41R gamma fails to reach the surface
      while the alpha-beta pump does.
  downstream:
  - target: Dominant-Negative Retention of Wild-Type FXYD2
    causal_link_type: DIRECT
    description: >-
      The mutant oligomerizes with wild-type FXYD2 and reduces its routing, so
      the wild-type product of the normal allele is also lost from the surface.
    evidence:
    - reference: PMID:17980699
      reference_title: "Impaired routing of wild type FXYD2 after oligomerisation with FXYD2-G41R might explain the dominant nature of renal hypomagnesemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data indicate that binding of FXYD2-G41R to wild type FXYD2 subunit might abrogate the routing of wild type FXYD2 to the plasma membrane thus causing the dominant nature of this mutation."
      explanation: The authors' conclusion linking mutant binding to loss of wild-type routing.
  - target: Loss of FXYD2 Regulation of the DCT Na,K-ATPase
    causal_link_type: DIRECT
    description: >-
      Mutant gamma that does not reach the surface cannot regulate the alpha and
      beta subunits that do.
    evidence:
    - reference: PMID:11929868
      reference_title: "Distinct regulatory effects of the Na,K-ATPase gamma subunit."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The results show that Gly-41 --> Arg prevents trafficking of gamma but not alphabeta pumps to the cell surface and abrogates functional effects of gamma on alphabeta pumps."
      explanation: The pumps that reach the surface lack the regulatory effect of gamma.
- name: Dominant-Negative Retention of Wild-Type FXYD2
  biological_scale: CELLULAR
  description: >-
    FXYD2 forms oligomers, and G41R FXYD2 oligomerizes with itself and with
    wild-type FXYD2. When the two are co-expressed, processing of the wild-type
    protein (read out as artificial glycosylation) is reduced, which suggests
    the mutant holds wild-type subunits back from the plasma membrane.
    Haploinsufficiency is unlikely to explain the disease, because people
    lacking one FXYD2 copy have normal serum magnesium. A study of isolated
    transmembrane peptides found the opposite result for oligomerization, so the
    physical basis of the interference is not fully settled.
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  biological_processes:
  - preferred_term: protein homooligomerization
    term:
      id: GO:0051260
      label: protein homooligomerization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17980699
    reference_title: "Impaired routing of wild type FXYD2 after oligomerisation with FXYD2-G41R might explain the dominant nature of renal hypomagnesemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, FXYD2-G41R also shows oligomerisation with itself and with the wild type protein."
    explanation: Co-immunoprecipitation shows mutant-wild-type oligomers.
  - reference: PMID:17980699
    reference_title: "Impaired routing of wild type FXYD2 after oligomerisation with FXYD2-G41R might explain the dominant nature of renal hypomagnesemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, we demonstrated that artificial glycosylation of the wild type FXYD2 is reduced when co-expressed with FXYD2-G41R."
    explanation: Co-expressed mutant impairs processing of the wild-type protein.
  - reference: PMID:12763862
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, we investigated two individuals lacking one copy of the FXYD2 gene and found their serum Mg(2+) levels to be within the normal range."
    explanation: >-
      Loss of one FXYD2 copy does not cause hypomagnesemia, which argues against
      haploinsufficiency and so, by exclusion, for a dominant-negative effect of
      the mutant.
  - reference: PMID:12763862
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that the arrest of mutant gamma-subunit in distinct intracellular structures is associated with aberrant posttranslational processing and that the G41R mutation causes dominant renal hypomagnesemia associated with hypocalciuria through a dominant negative mechanism."
    explanation: The original authors' conclusion of a dominant-negative mechanism.
  - reference: PMID:12225751
    reference_title: "Oligomerization of a peptide derived from the transmembrane region of the sodium pump gamma subunit: effect of the pathological mutation G41R."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Importantly, oligomerization of gamma-TM is abrogated in a peptide that contains either the disease-causing mutation G41R, or the more conservative mutation G41L."
    explanation: >-
      In detergent micelles a synthetic G41R transmembrane peptide fails to
      oligomerize, which conflicts with the co-immunoprecipitation finding that
      full-length G41R FXYD2 oligomerizes with itself and with wild type. The
      peptide lacks the rest of the protein and the pump, so the conflict is
      indirect.
  downstream:
  - target: Loss of FXYD2 Regulation of the DCT Na,K-ATPase
    causal_link_type: DIRECT
    description: >-
      Retention of wild-type subunits further depletes functional gamma at the
      basolateral membrane.
    evidence:
    - reference: PMID:35894287
      reference_title: "The genetic spectrum of Gitelman(-like) syndromes."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: IN_VITRO
      snippet: "Expression studies of mutant p.G41R-FXYD2 revealed a dominant-negative effect leading to a retention of the γ-subunit in the Golgi complex [60]."
      explanation: A review summarizing the expression studies of the dominant-negative effect.
- name: Loss of FXYD2 Regulation of the DCT Na,K-ATPase
  biological_scale: CELLULAR
  description: >-
    The gamma subunit is a regulatory subunit of the basolateral Na,K-ATPase in
    the DCT and other nephron segments. In the disease the pump loses its normal
    FXYD2 partner. Proximal tubular cells cultured from a patient's urine
    express less FXYD2 and raise FXYD2 and Na,K-ATPase less than control cells
    under hypertonic stress. Whether pump activity in the DCT ends up lower or
    higher is debated, because FXYD2 both inhibits the pump kinetically and
    stabilizes it.
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  genes:
  - preferred_term: FXYD2
    term:
      id: hgnc:4026
      label: FXYD2
  molecular_functions:
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DYSREGULATED
  locations:
  - preferred_term: distal convoluted tubule
    term:
      id: UBERON:0001292
      label: distal convoluted tubule
  evidence:
  - reference: PMID:21130072
    reference_title: "HNF-1B specifically regulates the transcription of the γa-subunit of the Na+/K+-ATPase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By immunohistochemistry, it was shown that the γa- and γb-subunits colocalize at the basolateral membrane of the DCT segment of mouse kidney."
    explanation: Places both FXYD2 isoforms at the basolateral membrane of the DCT.
  - reference: PMID:30175537
    reference_title: "Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Mutations in FXYD2 (G41R), and transcription factors (HNF-1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K-ATPase."
    explanation: A review naming impaired FXYD2-pump interaction as the shared lesion.
  - reference: PMID:19865785
    reference_title: "FXYD2 and Na,K-ATPase expression in isolated human proximal tubular cells: disturbed upregulation on renal hypomagnesemia?"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FXYD2 protein expression was lower in patient cells and could be increased in both cell lines upon culturing in hyperosmotic medium but to a lesser extent in patient cells."
    explanation: >-
      Immortalized proximal tubular cells from a G41R patient carry less FXYD2
      protein than control cells; these are proximal, not DCT, cells, from one
      patient and one control.
  downstream:
  - target: Reduced DCT Transcellular Magnesium Reabsorption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - pump_destabilization
    - basolateral_magnesium_exit
    description: >-
      Two mechanisms are proposed for how losing FXYD2 reduces DCT magnesium
      reabsorption. One holds that the pump is destabilized and inactivated, so
      the cell cannot sustain the intracellular potassium that sets the apical
      membrane potential driving TRPM6 magnesium entry. The other holds that
      FXYD2 itself mediates basolateral magnesium exit, which the mutant cannot
      do. The step is not demonstrated in patient tissue.
    intermediate_mechanisms:
    - Na,K-ATPase destabilization with loss of apical driving force for TRPM6
    - loss of FXYD2-mediated basolateral magnesium extrusion
    evidence:
    - reference: PMID:30175537
      reference_title: "Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: OTHER
      snippet: "Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase."
      explanation: The pump-destabilization hypothesis, stated in a review.
    - reference: PMID:18448590
      reference_title: "Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "These results suggest that FXYD2 can mediate basolateral extrusion of magnesium from cultured renal epithelial cells and provide new insights into the understanding of the possible physiological roles of FXYD2 wild-type and mutant proteins."
      explanation: >-
        In MDCK cells wild-type FXYD2, but not G41R, carried a basolateral
        magnesium current, supporting the magnesium-exit hypothesis. It is a
        cell-culture result, not patient data.
- name: Reduced DCT Transcellular Magnesium Reabsorption
  biological_scale: TISSUE
  description: >-
    The distal convoluted tubule sets final urinary magnesium, and its
    transcellular reabsorption falls. Because more distal segments are largely
    impermeable to magnesium, the DCT defect is not compensated and magnesium is
    lost in the urine. Urinary calcium is low, which distinguishes this disorder
    from the hypercalciuric forms of renal magnesium wasting.
  locations:
  - preferred_term: distal convoluted tubule
    term:
      id: UBERON:0001292
      label: distal convoluted tubule
  biological_processes:
  - preferred_term: magnesium ion transmembrane transport
    term:
      id: GO:1903830
      label: magnesium ion transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:19812536
    reference_title: "New molecular players facilitating Mg(2+) reabsorption in the distal convoluted tubule."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "The DCT is the final determinant of plasma Mg(2+) levels, as the more distal nephron segments are largely impermeable to Mg(2+)."
    explanation: Establishes the DCT as the segment that sets final urinary magnesium.
  - reference: PMID:3298795
    reference_title: "Renal magnesium wasting in two families with autosomal dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnesium infusions performed in two patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium."
    explanation: Magnesium infusion studies demonstrate a tubular reabsorption defect in patients.
  downstream:
  - target: Renal magnesium wasting
    causal_link_type: DIRECT
    description: The tubular defect is measured clinically as inappropriate urinary magnesium loss.
    evidence:
    - reference: PMID:3298795
      reference_title: "Renal magnesium wasting in two families with autosomal dominant inheritance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Magnesium infusions performed in two patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium."
      explanation: The renal handling defect measured in patients.
  - target: Hypomagnesemia
    causal_link_type: DIRECT
    description: Continuing urinary magnesium loss lowers serum magnesium.
    evidence:
    - reference: PMID:25765846
      reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Blood Mg(2+) levels <0.7 mmol/L may cause a heterogeneous clinical phenotype, including muscle cramps and epilepsy and disturbances in K(+) and Ca(2+) homeostasis."
      explanation: Low serum magnesium is the defining consequence of the renal loss.
- name: Hypomagnesemia
  biological_scale: ORGANISM
  description: >-
    Chronic low serum magnesium, below about 0.7 mmol/L, is the defining
    biochemical feature and is present in symptomatic and asymptomatic carriers.
  biological_processes:
  - preferred_term: magnesium ion homeostasis
    term:
      id: GO:0010960
      label: magnesium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25765846
    reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2000, mutations in FXYD2, encoding the γ-subunit of the Na(+)-K(+)-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis."
    explanation: Hypomagnesemia is the central feature of the disease.
  downstream:
  - target: Neuromuscular Hyperexcitability
    causal_link_type: DIRECT
    description: Low extracellular magnesium raises neuromuscular excitability.
    evidence:
    - reference: PMID:27234911
      reference_title: "Genetic causes of hypomagnesemia, a clinical overview."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias."
      explanation: Links hypomagnesemia to neuromuscular irritability and seizures.
  - target: Chondrocalcinosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic magnesium deficiency reduces the activity of magnesium-dependent
      alkaline phosphatase, so inorganic pyrophosphate accumulates and calcium
      pyrophosphate crystals deposit in cartilage.
    intermediate_mechanisms:
    - reduced magnesium-dependent alkaline phosphatase activity
    - accumulation of inorganic pyrophosphate
    evidence:
    - reference: PMID:29657876
      reference_title: "Magnesium disorders can cause calcium pyrophosphate deposition disease: A case report and literature review."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Mg acts as a cofactor for ALP enzyme, and its deficiency results in excess accumulation of inorganic pyrophosphatase."
      explanation: >-
        Gives the proposed biochemical link from magnesium deficiency to
        pyrophosphate accumulation behind calcium pyrophosphate deposition.
- name: Neuromuscular Hyperexcitability
  biological_scale: ORGANISM
  description: >-
    Reduced extracellular magnesium increases neuromuscular excitability, the
    basis of the cramps, tetany and seizures reported in symptomatic patients.
  evidence:
  - reference: PMID:27234911
    reference_title: "Genetic causes of hypomagnesemia, a clinical overview."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias."
    explanation: Neuromuscular irritability and seizures follow from magnesium deficiency.
  downstream:
  - target: Muscle cramps
    causal_link_type: DIRECT
    description: Neuromuscular hyperexcitability presents as muscle cramps.
    evidence:
    - reference: PMID:25765846
      reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
      explanation: Muscle cramps in affected patients.
  - target: Tetany
    causal_link_type: DIRECT
    description: Severe neuromuscular hyperexcitability presents as tetany.
    evidence:
    - reference: PMID:9915957
      reference_title: "Hereditary isolated renal magnesium loss maps to chromosome 11q23."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic."
      explanation: Tetany in symptomatic patients of the reported families.
  - target: Seizure
    causal_link_type: DIRECT
    description: Neuromuscular hyperexcitability can present as epileptic seizures.
    evidence:
    - reference: PMID:25765846
      reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
      explanation: Epilepsy in affected patients.
phenotypes:
- category: Metabolic
  name: Hypomagnesemia
  description: Chronic low serum magnesium, below about 0.7 mmol/L.
  phenotype_term:
    preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
    temporality: CHRONIC
  diagnostic: true
  evidence:
  - reference: PMID:25765846
    reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2000, mutations in FXYD2, encoding the γ-subunit of the Na(+)-K(+)-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis."
    explanation: Hypomagnesemia in the reported families.
- category: Renal
  name: Renal magnesium wasting
  description: >-
    Urinary magnesium excretion is inappropriately high for the low serum level,
    shown by magnesium infusion studies as a lowered renal threshold and tubular
    maximum.
  phenotype_term:
    preferred_term: Renal magnesium wasting
    term:
      id: HP:0005567
      label: Renal magnesium wasting
  diagnostic: true
  evidence:
  - reference: PMID:3298795
    reference_title: "Renal magnesium wasting in two families with autosomal dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnesium infusions performed in two patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium."
    explanation: The renal magnesium-handling defect in patients.
- category: Renal
  name: Hypocalciuria
  description: >-
    Urinary calcium excretion is low. It distinguishes this disorder from the
    hypercalciuric forms of renal magnesium wasting but its mechanism in FXYD2
    disease is not understood, so no mechanism node points to it.
  phenotype_term:
    preferred_term: Hypocalciuria
    term:
      id: HP:0003127
      label: Hypocalciuria
  diagnostic: true
  evidence:
  - reference: PMID:3298795
    reference_title: "Renal magnesium wasting in two families with autosomal dominant inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All members of both families who presented with hypomagnesemia had also a lowered excretion of calcium in the urine, presumably as a consequence of increased reabsorption in Henle's loop."
    explanation: Low urinary calcium in all affected family members.
  - reference: PMID:30175537
    reference_title: "Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Note that hypocalciuria associated with the FXYD2 G41R mutation is not easily explained and reveals complexity of the mechanism."
    explanation: Records that the hypocalciuria mechanism is unexplained.
- category: Musculoskeletal
  name: Muscle cramps
  description: Muscle cramps reported in several affected patients.
  phenotype_term:
    preferred_term: Muscle cramps
    term:
      id: HP:0003394
      label: Muscle spasm
  evidence:
  - reference: PMID:25765846
    reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
    explanation: Muscle cramps in affected patients.
- category: Musculoskeletal
  name: Tetany
  description: Tetany reported as a manifestation of magnesium deficiency in patients.
  phenotype_term:
    preferred_term: Tetany
    term:
      id: HP:0001281
      label: Tetany
  evidence:
  - reference: PMID:9915957
    reference_title: "Hereditary isolated renal magnesium loss maps to chromosome 11q23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic."
    explanation: Tetany in symptomatic patients.
- category: Neurological
  name: Seizure
  description: >-
    Epilepsy or convulsions in a subset of patients; many carriers are
    asymptomatic.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:25765846
    reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
    explanation: Epilepsy in affected patients.
  - reference: PMID:35894287
    reference_title: "The genetic spectrum of Gitelman(-like) syndromes."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The index patients presented with seizures during childhood and profound hypomagnesemia [55,56]."
    explanation: Childhood seizures in the originally reported patients.
- category: Musculoskeletal
  name: Chondrocalcinosis
  description: >-
    Calcium pyrophosphate deposition in cartilage, reported in adults with
    long-standing disease.
  phenotype_term:
    preferred_term: Chondrocalcinosis
    term:
      id: HP:0000934
      label: Chondrocalcinosis
  evidence:
  - reference: PMID:25765846
    reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy."
    explanation: Chondrocalcinosis in affected patients.
- category: Musculoskeletal
  name: Generalized muscle weakness
  description: >-
    Generalized weakness reported across the FXYD2 families; not linked to a
    specific step of the mechanism here.
  phenotype_term:
    preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  evidence:
  - reference: PMID:29344503
    reference_title: "Genetics of Magnesium Disorders."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the affected individuals complained of muscle cramps and generalized weakness."
    explanation: Generalized weakness in the affected individuals of the three families.
- category: Metabolic
  name: Hypokalemia
  description: >-
    A tendency to low serum potassium was found on careful workup of two of the
    families; it is not a constant feature and is not linked here to a mechanism
    node.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:35894287
    reference_title: "The genetic spectrum of Gitelman(-like) syndromes."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Later, a careful biochemical workup in members of two additional families with the identical mutation also revealed a tendency towards hypokalemia and metabolic alkalosis."
    explanation: A tendency to hypokalemia in two of the families.
- category: Metabolic
  name: Metabolic alkalosis
  description: >-
    A tendency to metabolic alkalosis was found in two of the families on
    careful workup; it is not a constant feature.
  phenotype_term:
    preferred_term: Metabolic alkalosis
    term:
      id: HP:0200114
      label: Metabolic alkalosis
  evidence:
  - reference: PMID:35894287
    reference_title: "The genetic spectrum of Gitelman(-like) syndromes."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Later, a careful biochemical workup in members of two additional families with the identical mutation also revealed a tendency towards hypokalemia and metabolic alkalosis."
    explanation: A tendency to metabolic alkalosis in two of the families.
genetic:
- name: FXYD2
  gene_term:
    preferred_term: FXYD2
    term:
      id: hgnc:4026
      label: FXYD2
  association: Causative
  variant_origin: GERMLINE
  features: >-
    FXYD2 (11q23) encodes the gamma subunit of the Na,K-ATPase, a 65-residue
    single-span regulatory subunit with two splice variants, gamma-a and
    gamma-b, that modulate the pump's cation and ATP affinities at the
    basolateral membrane of the DCT. One recurrent disease allele, p.Gly41Arg,
    is known.
  notes: >-
    relationship_type is deliberately left unset. The schema defines CAUSATIVE
    as corresponding to ClinGen Definitive or Strong, and ClinGen (Tubulopathy
    GCEP) classifies FXYD2 for renal hypomagnesemia 2 as Moderate (autosomal
    dominant), recorded under gene_disease_validity. No other
    GeneDiseaseRelationshipEnum value describes a disease-defining gene with
    moderate validity: RISK_FACTOR, MODIFIER and SUSCEPTIBILITY describe a
    different kind of relationship, and UNKNOWN and DISPUTED do not fit a
    classified, uncontested pair. FXYD2 is nonetheless the sole gene for this
    Mendelian disorder. See dismech#16102.
  gene_disease_validity:
  - validity_classification: MODERATE
    classified_by: CLINGEN
    external_id: CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2025-12-03T050000.000Z
    evidence:
    - reference: CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2025-12-03T050000.000Z
      reference_title: "FXYD2 / renal hypomagnesemia 2 (Moderate)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "FXYD2 | HGNC:4026 | renal hypomagnesemia 2 | MONDO:0007937 | AD | Moderate"
      explanation: ClinGen Tubulopathy GCEP classification of the FXYD2-HOMG2 relationship.
  evidence:
  - reference: PMID:11062458
    reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a putative dominant-negative mutation in the gene encoding the Na(+), K(+)-ATPase gamma-subunit (FXYD2), leading to defective routing of the protein in a family with dominant renal hypomagnesaemia."
    explanation: The original identification of FXYD2 as the causal gene.
  variants:
  - name: NM_001680.5:c.121G>A (p.Gly41Arg)
    type: MISSENSE
    clinical_significance: PATHOGENIC
    identifiers:
    - ClinVar:VCV000007684
    description: >-
      The only reported disease allele, heterozygous in all genetically
      confirmed patients across three families with a shared founder haplotype,
      and absent from 132 control chromosomes in the original study. A review
      numbers the same change c.115G>A on another transcript.
    evidence:
    - reference: PMID:12763862
      reference_title: "Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation leads to a G41R substitution, introducing a charged amino acid residue in the predicted transmembrane region of the gamma-subunit protein."
      explanation: Reports the variant and the resulting substitution.
    - reference: PMID:25765846
      reference_title: "Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect."
      explanation: The shared haplotype across all reported families is a founder effect.
treatments:
- name: Magnesium supplementation
  description: >-
    Oral magnesium is the standard management of renal magnesium wasting.
    Serum magnesium is hard to normalize because supplementation drives further
    renal loss. No treatment study specific to FXYD2 disease was found, so this
    is curated from reviews of genetic hypomagnesemias that include FXYD2.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: magnesium ion
      term:
        id: CHEBI:39128
        label: magnesium ion
  target_phenotypes:
  - preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  evidence:
  - reference: PMID:30175537
    reference_title: "Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Hypomagnesemia (Mg < 0.7 mmol/L) is the most frequent manifestation associated with Mg imbalance and must be treated with dietary Mg supplements"
    explanation: General management of hypomagnesemia is dietary magnesium supplementation.
  - reference: PMID:27234911
    reference_title: "Genetic causes of hypomagnesemia, a clinical overview."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function."
    explanation: Magnesium supplementation remains the treatment for the genetic hypomagnesemias including FXYD2.
experimental_models:
- name: Xenopus oocytes and MDCK cells expressing wild-type or G41R FXYD2
  experimental_model_type: CELL_LINE
  description: >-
    Xenopus oocytes injected with wild-type or G41R FXYD2 cRNA, and MDCK renal
    epithelial monolayers expressing either construct, used to measure ion
    currents and a basolateral magnesium current.
  publication: PMID:18448590
  modeled_mechanisms:
  - target: Loss of FXYD2 Regulation of the DCT Na,K-ATPase
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      The oocyte and MDCK assays show that G41R changes FXYD2 ion-handling and
      abolishes a basolateral magnesium current carried by wild-type FXYD2.
    limitations: >-
      Xenopus oocytes and canine MDCK cells are heterologous systems, not DCT
      cells, and the G41R gain-of-function cation current they report is one of
      two competing mechanisms and is not shown in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The systems are amphibian oocyte and canine kidney epithelium, not human
        DCT, so the magnesium-handling context of the human segment is not
        reproduced.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The assays observe a single transfected protein's currents and do not
        contain the intact DCT pump, the apical TRPM6 channel, or the tubular
        magnesium gradient that set reabsorption in the patient.
    evidence:
    - reference: PMID:18448590
      reference_title: "Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "in contrast to the wild-type FXYD2 currents, inward rectifying cation currents were induced by hyperpolarization pulses in oocytes expressing the G41R mutant."
      explanation: The mutant has distinct electrophysiological behaviour in oocytes.
discussions:
- discussion_id: fxyd2_mg_wasting_mechanism_unsettled
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of FXYD2 Regulation of the DCT Na,K-ATPase
  - pathophysiology#Reduced DCT Transcellular Magnesium Reabsorption
  prompt: >-
    How does loss of functional FXYD2 at the DCT basolateral membrane reduce
    transcellular magnesium reabsorption?
  rationale: >-
    Two mechanisms are proposed and curated as the hypothesis groups on the edge
    into Reduced DCT Transcellular Magnesium Reabsorption. One holds that without
    FXYD2 the Na,K-ATPase is destabilized and inactivated, lowering the
    intracellular potassium and the apical membrane potential that drive TRPM6
    magnesium entry (PMID:30175537). The other holds that FXYD2 itself mediates
    basolateral magnesium exit, shown as a wild-type-specific magnesium current
    in MDCK cells that G41R lacks (PMID:18448590). Neither is demonstrated in
    patient tissue, and FXYD2 both inhibits and stabilizes the pump, so the net
    effect on pump activity is itself debated. The hypocalciuria is separately
    described as not easily explained.
  notes: >-
    The two hypotheses are not mutually exclusive; both would reduce DCT
    magnesium reabsorption.
- discussion_id: no_in_vivo_model_of_fxyd2_g41r
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced DCT Transcellular Magnesium Reabsorption
  prompt: >-
    Does a whole-animal FXYD2 defect reproduce the renal magnesium wasting of
    human HOMG2?
  rationale: >-
    There is no reported G41R knock-in animal. The available model is the
    Fxyd2-null mouse, which is a loss-of-one-function model rather than the human
    dominant-negative one, and it does not show overt hypomagnesemia:
    FXYD2-deficient mice kept urine electrolytes in the normal range
    (PMID:25472608). A later reanalysis of the same data argues that urinary
    magnesium was in fact moderately but significantly raised (PMID:30175537), so
    whether the mouse is even a partial model is disputed. Because the human
    disease is dominant-negative and the mouse is a null, the mouse may not test
    the human mechanism at all.
  proposed_experiments:
  - experiment_id: fxyd2_g41r_knockin_mouse
    experiment_design: TARGETED_PERTURBATION
    name: Fxyd2 p.Gly41Arg knock-in mouse
    description: >-
      Knock the patient variant into mouse Fxyd2 and measure serum magnesium,
      fractional magnesium excretion and DCT magnesium transport, alongside an
      Fxyd2-null line, to separate the dominant-negative mechanism from simple
      loss of the subunit.
    would_support:
    - pathophysiology#Reduced DCT Transcellular Magnesium Reabsorption
    supporting_outcome:
    - Knock-in mice waste magnesium in the urine and become hypomagnesemic while null mice do not.
    refuting_outcome:
    - Knock-in mice keep normal serum magnesium and fractional magnesium excretion.
  evidence:
  - reference: PMID:25472608
    reference_title: "Paradoxical activation of the sodium chloride cotransporter (NCC) without hypertension in kidney deficient in a regulatory subunit of Na,K-ATPase, FXYD2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "no obvious renal phenotype was detected in mice with global deletion of FXYD2"
    explanation: The Fxyd2-null mouse shows no overt renal phenotype.
  - reference: PMID:30175537
    reference_title: "Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Urinary Mg was also measured and although pronounced hypermagnesuria was not observed, the published data appear to show a moderate but significantly increased urinary Mg secretion in the FXYD2−/− mice"
    explanation: A reanalysis argues the null mouse does show modestly raised urinary magnesium.
mechanistic_hypotheses:
- hypothesis_group_id: pump_destabilization
  hypothesis_label: Na,K-ATPase destabilization reduces the apical driving force for TRPM6
  status: EMERGING
  description: >-
    Loss of the FXYD2 interaction destabilizes and inactivates the DCT
    Na,K-ATPase over time, lowering intracellular potassium and the apical
    membrane potential that drives TRPM6-mediated magnesium entry.
  evidence:
  - reference: PMID:30175537
    reference_title: "Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase."
    explanation: States the destabilization hypothesis.
- hypothesis_group_id: basolateral_magnesium_exit
  hypothesis_label: FXYD2 mediates basolateral magnesium extrusion
  status: EMERGING
  description: >-
    FXYD2 itself carries or supports basolateral magnesium exit from the DCT
    cell, shown as a wild-type-specific transepithelial magnesium current in
    MDCK cells that the G41R mutant does not support.
  evidence:
  - reference: PMID:18448590
    reference_title: "Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that FXYD2 can mediate basolateral extrusion of magnesium from cultured renal epithelial cells and provide new insights into the understanding of the possible physiological roles of FXYD2 wild-type and mutant proteins."
    explanation: Supports a direct basolateral magnesium-exit role for FXYD2.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Renal Hypomagnesemia 2 · 2026-11-01T21:07:00Z · View source

Created the HOMG2 entry (MONDO:0007937, FXYD2 hgnc:4026, autosomal dominant). One OpenScientist deep-research report was used (research/Renal_Hypomagnesemia_2-deep-research-openscientist.md): reference_validation 13/13 resolved (1 flagged off-topic, PMID:11278761, which was read and not cited), term_validation 19/20 resolved with needs_review for mislabelled bucket tags that are an artifact of the report format, not wrong CURIEs; preflight-dr returned WARN, correctly flagging that the report writes HGNC:4028 (FXYD4) beside FXYD2 in three places, so FXYD2=hgnc:4026 was taken from HGNC and the structured ClinGen/Orphanet caches, not the report. The report's citations were used as leads and every snippet was verified against the cached reference abstract or full text. Causal chain runs from the heterozygous FXYD2 p.Gly41Arg variant through intracellular misrouting, dominant-negative retention of wild-type FXYD2, loss of DCT Na,K-ATPase regulation, reduced DCT magnesium reabsorption, renal magnesium wasting and hypomagnesemia, to neuromuscular hyperexcitability (cramps, tetany, seizures) and chondrocalcinosis. The unsettled Mg-wasting mechanism is recorded as two EMERGING mechanistic_hypotheses (pump destabilization vs basolateral Mg exit) and an INTERPRETATION discussion; the Fxyd2-null mouse is a HUMAN_MODEL_MISMATCH discussion. gene_disease_validity records the ClinGen Moderate (AD, Tubulopathy GCEP) tier copied from CGGV:assertion_aef2e6fc; relationship_type left unset to avoid an overstated finding per dismech#16102. Validated: just validate (61/61 snippets), validate-terms, validate-disorders, check-gene-validity (overstated 0), entity-refs, causal-targets, coarse-phenotypes, qualifier-terms, enum-values, duplicate-keys, block-scalar-comments, logical-rules, snippet-length, title-snippets, reference-titles, folded-hyphens, snippet-grading, retired-support-prose, shared-disease-terms, gene-term-mismatches all clean. No GeneReviews chapter (NO_CHAPTER).

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Key Findings
openscientist-autonomous 13 citations 2026-10-31T14:20:03.478700

Key Findings

Finding 1 — HOMG2 is caused by the recurrent FXYD2 p.Gly41Arg mutation

Linkage analysis in a large Dutch family mapped the disease trait to chromosome 11q23 within a ~5.6-cM region. Within this interval, a heterozygous mutation c.121G>A in FXYD2 — producing the amino acid substitution p.Gly41Arg — cosegregated with all affected family members and was absent from 132 control chromosomes (PMID: 12763862; PMID: 11062458). The same mutation was subsequently found to recur in two additional families with isolated dominant hypomagnesemia and hypocalciuria, with haplotype analysis revealing an overlapping haplotype indicating a founder effect (PMID: 25765846).

"we identified a heterozygous mutation in the FXYD2 gene, encoding the Na(+),K(+)-ATPase gamma-subunit, cosegregating with the patients of this family, which was not found in 132 control chromosomes. The mutation leads to a G41R substitution" — PMID: 12763862

"We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria. Interestingly, this is the same mutation as was described in the original study" — PMID: 25765846

Glycine 41 is a highly conserved residue within the single transmembrane span of the 65-residue γ-subunit; its substitution by the bulky, positively charged arginine is the molecular lesion underlying the disease.

Finding 2 — The dominant-negative mechanism: mutant G41R misroutes and traps wild-type γ-subunit

Heterologous expression of the mutant γ-subunit in Sf9 and COS-1 cells demonstrated that the mutant protein is incorrectly routed and accumulates in perinuclear structures, lacking a post-translational modification (glycosylation) that marks correctly trafficked protein. Critically, haploinsufficiency was excluded: individuals carrying only a single functional FXYD2 copy have normal serum Mg²⁺, meaning simple loss of one allele is not sufficient to cause disease — the mutant must actively interfere with the wild-type product (PMID: 12763862).

The physical basis of this interference was established by co-immunoprecipitation showing that FXYD2 oligomerizes, and that G41R hetero-oligomerizes with wild-type γ-subunit, reducing its glycosylation and plasma-membrane routing (PMID: 17980699). Biophysical work on synthetic transmembrane peptides confirmed that the G41R substitution abrogates normal γ-TM oligomerization (as does the conservative G41L substitution), whereas an arginine substitution on a different helical face (position 35) retains oligomerization — directly linking the disease to disrupted γ-subunit quaternary assembly (PMID: 12225751).

"binding of FXYD2-G41R to wild type FXYD2 subunit might abrogate the routing of wild type FXYD2 to the plasma membrane thus causing the dominant nature of this mutation" — PMID: 17980699

"the mutant gamma-subunit protein was incorrectly routed and accumulated in perinuclear structures" — PMID: 12763862

Finding 3 — Clinical phenotype: isolated renal Mg²⁺ wasting with hypocalciuria and neuromuscular features

Affected individuals show serum Mg²⁺ below ~0.7 mmol/L due to inappropriate renal magnesium wasting, together with hypocalciuria (low urinary calcium). The clinical spectrum includes muscle cramps/tetany, chondrocalcinosis, and epilepsy/convulsions (PMID: 25765846; PMID: 12763862). The phenotype is "isolated" in that it is not accompanied by the broader electrolyte derangements (hypokalemia, metabolic alkalosis) seen in Gitelman/Bartter syndromes, nor the secondary hypocalcemia of TRPM6 disease.

"several patients suffered from muscle cramps, chondrocalcinosis and epilepsy" — PMID: 25765846

"These disorders share the general symptoms of hypomagnesemia, tetany and epileptiformic convulsions, and often include secondary or associated disturbances in calcium excretion" — PMID: 12763862

Suggested HPO terms: Hypomagnesemia (HP:0002917); Hypocalciuria (HP:0003127); Chondrocalcinosis (HP:0000934); Seizure (HP:0001250); Muscle cramps (HP:0003394); Tetany (HP:0001281); Renal magnesium wasting (HP:0012605).

Finding 4 — Normal γ-subunit function: tuning Na,K-ATPase ATP/cation affinity; γa vs γb isoforms

Under normal conditions, the FXYD2 γ-subunit is a type-2 single-pass transmembrane regulator of the Na,K-ATPase. Rat kidney expresses two splice variants, γa and γb, differing only at the extracellular N-terminus. Functionally, the γ-subunit produces (i) an increase in apparent affinity for ATP (secondary to a left shift in the E1↔E2 conformational equilibrium) and (ii) an increase in K⁺ antagonism of cytoplasmic Na⁺ activation. The subunit localizes to the basolateral membrane of several tubule segments, most strongly in the medullary thick ascending limb and also in the DCT (PMID: 11278761).

This normal function is woven into the broader DCT magnesium-handling network: the transcription factor HNF1B specifically activates the γa isoform, and HNF1B mutations impair γa through a dominant-negative effect, linking the HNF1B-associated hypomagnesemia syndrome to the same FXYD2 pathway (PMID: 21130072).

"an increase in apparent affinity for ATP, probably secondary to a left shift in E(1) <--> E(2) conformational equilibrium and (ii) an increase in K(+) antagonism of cytoplasmic Na(+) activation" — PMID: 11278761

"HNF-1B specifically acts as an activator of the γa-subunit" — PMID: 21130072

Finding 5 — Gain-of-function branch: membrane-reaching G41R acts as an inward-rectifying cation channel

Electrophysiology in Xenopus oocytes showed that both wild-type and G41R FXYD2 generate large nonselective ion currents, but only G41R produces inward-rectifying cation currents upon hyperpolarization. The rectification depended on the presence of a positive charge at residue 41, was blocked by extracellular divalent/trivalent cations (Ca²⁺, Ba²⁺, La³⁺), and was removed by intracellular EDTA (PMID: 18448590). In MDCK renal epithelial cells, wild-type FXYD2 (but not G41R) supported a Mg²⁺-gradient-driven transepithelial current that was inhibited by basolateral Ba²⁺, supporting a physiological role for FXYD2 in basolateral Mg²⁺ extrusion.

"in contrast to the wild-type FXYD2 currents, inward rectifying cation currents were induced by hyperpolarization pulses in oocytes expressing the G41R mutant" — PMID: 18448590

"FXYD2 can mediate basolateral extrusion of magnesium from cultured renal epithelial cells" — PMID: 18448590

This establishes a dual pathological mechanism: dominant-negative misrouting (the dominant contributor, since most mutant protein never reaches the membrane) plus aberrant channel behavior in the residual membrane-resident fraction.

Finding 6 — Inheritance and epidemiology: autosomal dominant, ultra-rare founder allele, with locus heterogeneity

All reported genetically resolved IDH families carry the identical p.Gly41Arg mutation on an overlapping haplotype, indicating a Dutch founder effect (PMID: 25765846). The trait is autosomal dominant (OMIM #154020). Crucially, an American family with a clinically similar isolated renal Mg-wasting phenotype did not link to 11q23 (multipoint LOD = −2.97 across five 11q23 loci), demonstrating genetic locus heterogeneity — i.e., the clinical phenotype of isolated renal Mg wasting is not exclusively FXYD2-mediated (PMID: 11836293).

"Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect" — PMID: 25765846

"our data demonstrate locus heterogeneity for the phenotype of isolated renal Mg wasting with hypomagnesemia" — PMID: 11836293

Section-by-Section Report

1. Disease Information

Overview. Renal Hypomagnesemia 2 (HOMG2), also called Isolated Dominant Hypomagnesemia with hypocalciuria (IDH), is a Mendelian autosomal dominant renal tubulopathy in which the kidney inappropriately wastes magnesium, producing chronic hypomagnesemia with low urinary calcium. It is caused by mutation in FXYD2 (Na,K-ATPase γ-subunit).

Key identifiers. | Resource | Identifier | |---|---| | OMIM | #154020 | | MONDO | MONDO:0007937 | | Orphanet | Primary hypomagnesemia / isolated dominant hypomagnesemia group | | ICD-10 | E83.42 (Hypomagnesemia) | | ICD-11 | 5C64.41 (Magnesium deficiency) | | MeSH | Magnesium Deficiency / renal tubular disorders | | Gene (HGNC) | FXYD2, HGNC:4028 |

Synonyms: familial primary hypomagnesemia caused by FXYD2 mutation; FXYD2 familial primary hypomagnesemia; HOMG2; isolated autosomal dominant hypomagnesemia; isolated renal magnesium wasting; renal hypomagnesemia type 2.

Information source. Derived predominantly from aggregated disease-level resources (OMIM, Orphanet) built on a small number of individual-patient family studies — the original Dutch kindred and ≤2 additional families. There is no large EHR-derived cohort given the ultra-rarity.

2. Etiology

Primary cause — genetic. The sole established cause is the heterozygous FXYD2 c.121G>A (p.Gly41Arg) missense mutation (PMID: 12763862; PMID: 25765846).

Genetic risk factors. The causal variant is itself the risk factor (fully penetrant dominant allele in reported families). A founder haplotype underlies recurrence in Dutch families. No modifier genes have been defined for HOMG2 specifically, though the broader DCT Mg²⁺ network (HNF1B, TRPM6, CNNM2, PCBD1) provides candidate interacting loci.

Environmental risk factors. None established as causal. Acquired/environmental causes of hypomagnesemia generally (diuretics, proton pump inhibitors, EGFR inhibitors, calcineurin inhibitors, alcohol, malnutrition) are relevant to differential diagnosis and may exacerbate the genetic deficit but are not part of the Mendelian etiology (PMID: 25540137).

Protective factors. No genetic protective alleles described. Dietary magnesium adequacy mitigates severity but cannot correct the renal wasting.

Gene–environment interactions. Not formally studied for FXYD2; plausibly, concurrent Mg²⁺-wasting drugs would compound the phenotype.

3. Phenotypes

Phenotype Type HPO term Onset / Severity Frequency
Hypomagnesemia (serum Mg²⁺ <0.7 mmol/L) Lab abnormality HP:0002917 Likely childhood/early; variable Obligate (defining)
Renal magnesium wasting Lab/physiologic HP:0012605 Lifelong Obligate
Hypocalciuria Lab abnormality HP:0003127 Lifelong Characteristic
Muscle cramps Symptom HP:0003394 Variable Common
Tetany Clinical sign HP:0001281 Episodic Variable
Seizures / convulsions Clinical sign HP:0001250 Variable Reported subset
Chondrocalcinosis Physical/imaging HP:0000934 Adult/late Longstanding cases

Characteristics. Onset is typically early in life (the biochemical defect is congenital), but symptomatic presentation varies from asymptomatic hypomagnesemia detected incidentally to overt neuromuscular irritability. Severity is variable; the course is chronic and stable (non-progressive at the organ level, as this is not a nephropathy that progresses to renal failure). Chondrocalcinosis is a late complication of chronic hypomagnesemia (also seen in Gitelman syndrome).

Quality-of-life impact. Generally modest with adequate supplementation; cramps, fatigue and occasional seizures can impair daily functioning. No disease-specific QoL instrument data (EQ-5D/SF-36) exist for this ultra-rare condition.

4. Genetic / Molecular Information

  • Causal gene: FXYD2 (HGNC:4028), chromosome 11q23, encoding the Na,K-ATPase γ-subunit (UniProt P54710).
  • Pathogenic variant: c.121G>A, p.Gly41Arg (G41R) — a missense change affecting a highly conserved transmembrane glycine. Classified pathogenic (cosegregation, absence from controls, functional confirmation; ACMG criteria PS3/PP1/PM1/PM2-supporting). It is essentially the only recurrent pathogenic FXYD2 allele reported for HOMG2.
  • Variant type: Single-nucleotide missense; germline.
  • Allele frequency: Absent from population controls (not in 132 control chromosomes in the original study); effectively absent/ultra-rare in gnomAD.
  • Functional consequence: Dominant-negative (loss of wild-type function via misrouting/trapping) with an additional gain-of-function cation-channel activity in membrane-reaching protein (PMID: 12763862; PMID: 17980699; PMID: 18448590).
  • Modifier genes / epigenetics / chromosomal abnormalities: None established for HOMG2. HNF1B transcriptionally regulates the γa isoform and is a mechanistically related locus (PMID: 21130072).

5. Environmental Information

No environmental, lifestyle, or infectious agents cause HOMG2 — it is monogenic. Environmental magnesium-depleting factors (diuretics, PPIs, alcohol) are relevant only as confounders/exacerbators and to the differential diagnosis (PMID: 25540137).

6. Mechanism / Pathophysiology

Ordered causal chain (mutation → clinical manifestation):

  1. Heterozygous FXYD2 c.121G>A introduces p.Gly41Arg in the transmembrane helix of the γ-subunit → results in a misfolded/mis-assembling subunit.
  2. G41R abrogates normal γ-TM oligomerization geometry (demonstrated with TM peptides) → leads to aberrant quaternary assembly.
  3. The mutant subunit is incorrectly routed and accumulates in perinuclear (ER/Golgi) structures, lacking its normal post-translational modification → results in failure to reach the DCT basolateral membrane.
  4. Because FXYD2 oligomerizes, mutant hetero-oligomerizes with wild-type γ-subunit and traps it intracellularly (dominant-negative) → leads to depletion of functional γ-subunit at the membrane (haploinsufficiency excluded).
  5. Loss of functional basolateral γ-subunit impairs Na,K-ATPase ATP/cation-affinity tuning in the DCT → results in reduced transcellular Mg²⁺ reabsorption.
  6. Branch (gain-of-function): the residual membrane-reaching G41R behaves as an inward-rectifying nonselective cation channel, perturbing membrane potential/ion flux (inferred to contribute; demonstrated in oocytes/MDCK).
  7. Reduced DCT Mg²⁺ reabsorption → results in renal magnesium wasting and hypomagnesemia; coupling of Na⁺/Mg²⁺ handling → leads to hypocalciuria.
  8. Low extracellular Mg²⁺ increases neuromuscular excitability → results in muscle cramps, tetany, and seizures; chronic Mg²⁺ deficiency → leads to chondrocalcinosis.

Molecular/cellular detail. The DCT is the final determinant of urinary Mg²⁺, as nephron segments beyond it are largely Mg²⁺-impermeable (PMID: 19812536). Apical Mg²⁺ entry occurs via TRPM6; the basolateral Na,K-ATPase (with its γ-subunit) maintains the electrochemical gradient driving transcellular transport. The γ-subunit modulates ATP affinity and K⁺/Na⁺ kinetics of the pump (PMID: 11278761). Upstream vs downstream: the mutation and misrouting are upstream; impaired DCT transport and systemic hypomagnesemia are downstream; neuromuscular symptoms are the terminal clinical readout.

Ontology suggestions. GO:0015693 (magnesium ion transport); GO:0006883 (intracellular sodium ion homeostasis); GO:0005890 (sodium:potassium-exchanging ATPase complex, CC); GO:0016020 (membrane); GO:0034976 (response to ER stress — inferred). Cell type: CL:1000849 (kidney distal convoluted tubule epithelial cell). CHEBI: CHEBI:18420 (magnesium(2+)); CHEBI:29108 (calcium(2+)).

7. Anatomical Structures Affected

  • Primary organ: Kidney (UBERON:0002113), specifically the distal convoluted tubule (UBERON:0001292).
  • Cell type: DCT epithelial cell (CL:1000849); subcellular locus of defect = basolateral plasma membrane (normal site) and perinuclear ER/Golgi (mutant accumulation site).
  • Body systems: Renal/urinary (primary); neuromuscular and musculoskeletal (secondary, via hypomagnesemia); the γ-subunit is also expressed in medullary thick ascending limb and other segments (PMID: 11278761).
  • Subcellular GO CC: sodium:potassium-exchanging ATPase complex (GO:0005890); endoplasmic reticulum membrane (GO:0005789).
  • Lateralization: Bilateral (systemic genetic defect affecting both kidneys).

8. Temporal Development

  • Onset: Congenital biochemical defect; clinically detected from childhood through adulthood, often insidious.
  • Course: Chronic, lifelong, non-progressive at the organ level (does not typically cause renal failure). Symptoms episodic/fluctuating (cramps, seizures) depending on Mg²⁺ level.
  • Progression: Stable; chondrocalcinosis accrues over decades.
  • Remission: No spontaneous remission; biochemical improvement is treatment-induced via supplementation.
  • Critical period: Continuous supplementation; attention during periods of additional Mg²⁺ loss (illness, concurrent diuretics).

9. Inheritance and Population

  • Inheritance: Autosomal dominant (OMIM #154020).
  • Penetrance / expressivity: High penetrance for the biochemical phenotype in reported families; variable clinical expressivity.
  • Founder effect: Yes — identical G41R on overlapping haplotype in Dutch families (PMID: 25765846).
  • Epidemiology: Ultra-rare; precise prevalence/incidence not established (only a handful of families reported worldwide).
  • Locus heterogeneity: The isolated renal Mg-wasting phenotype is genetically heterogeneous — a US family did not link to 11q23 (PMID: 11836293).
  • Sex ratio: No strong sex bias reported (autosomal).
  • Consanguinity / carrier frequency: Not applicable in the usual sense (dominant); no carrier-screening framework.

10. Diagnostics

  • Laboratory tests: Serum Mg²⁺ (LOINC 19123-9) — low (<0.7 mmol/L); 24-h urinary Mg²⁺ — inappropriately high (fractional excretion of Mg elevated, confirming renal wasting); urinary calcium — low (hypocalciuria), a key discriminator; serum K⁺ and acid–base typically normal (distinguishing from Gitelman/Bartter).
  • Biomarkers: Serum/urine magnesium and calcium are the operative biomarkers; no protein/metabolite biomarker beyond electrolytes.
  • Imaging: Joint radiographs may reveal chondrocalcinosis in longstanding disease.
  • Genetic testing: Targeted single-gene FXYD2 sequencing (for the recurrent G41R) is diagnostic; hypomagnesemia gene panels (including FXYD2, TRPM6, CLDN16, CLDN19, CNNM2, HNF1B, KCNA1, SLC12A3, EGF) or WES/WGS are appropriate when the phenotype overlaps other tubulopathies. Karyotype/CMA/FISH/mtDNA testing are not indicated (point mutation, not structural/mitochondrial).
  • Clinical criteria / differential diagnosis: Diagnose by the triad of hypomagnesemia + renal Mg wasting + hypocalciuria, normal K⁺/acid–base, AD family history, and FXYD2 G41R. Differentials: Gitelman syndrome (SLC12A3; adds hypokalemia/metabolic alkalosis/hypocalciuria), Bartter syndrome, TRPM6/HSH (hypomagnesemia with secondary hypocalcemia, AR), CLDN16/19 (hypomagnesemia with hypercalciuria/nephrocalcinosis), CNNM2, HNF1B (+ cysts/MODY5), EAST/SeSAME (KCNJ10), and acquired drug-induced hypomagnesemia (PMID: 27234911; PMID: 32622651).
  • Screening: Cascade testing of at-risk first-degree relatives (serum Mg²⁺ ± FXYD2 sequencing).

11. Outcome / Prognosis

  • Survival / life expectancy: Normal with adequate magnesium replacement; no excess mortality reported.
  • Morbidity: Driven by neuromuscular symptoms (cramps, tetany, seizures) and chronic complications (chondrocalcinosis). Generally manageable.
  • Disease course: Chronic/lifelong; does not progress to end-stage renal disease.
  • Prognostic factors: Adequacy of Mg²⁺ supplementation and avoidance of additional Mg²⁺-wasting insults (diuretics, GI losses). No molecular prognostic biomarker beyond serum Mg²⁺.

12. Treatment

  • Pharmacotherapy / supportive care: Lifelong oral magnesium supplementation (e.g., magnesium oxide, magnesium chloride, magnesium aspartate; organic salts often better tolerated with less diarrhea). Doses are titrated to symptom control; complete normalization of serum Mg²⁺ is often not achievable because supplementation drives further renal loss. Severe symptomatic episodes (seizures, tetany) require IV magnesium sulfate. By analogy to Gitelman management, potassium-sparing diuretics (e.g., amiloride) are a potential Mg²⁺-retaining adjunct in some tubulopathies, though evidence specific to FXYD2 is limited (PMID: 32622651).
  • NCIT suggestion: Magnesium supplement therapy; Magnesium Sulfate; dietary/electrolyte management.
  • Advanced/experimental therapeutics: No gene therapy, RNA therapy, cell therapy, or targeted small molecule exists or is in trials for HOMG2.
  • Pharmacogenomics: Not applicable.
  • Personalized approach: Genotype confirmation (G41R) guides counseling and family screening; management remains supportive.

13. Prevention

  • Primary prevention: Not possible (Mendelian). Genetic counseling for autosomal dominant 50% transmission risk; prenatal/preimplantation genetic testing is theoretically available given a known familial variant.
  • Secondary prevention: Early biochemical screening (serum Mg²⁺) in at-risk relatives; cascade testing.
  • Tertiary prevention: Consistent Mg²⁺ supplementation to prevent seizures/tetany and reduce chondrocalcinosis risk; avoid magnesium-wasting drugs.
  • Immunization / public health / environmental interventions: Not applicable.

14. Other Species / Natural Disease

  • Orthologous gene: Fxyd2 is conserved in mouse (NCBI Gene 11936) and rat (NCBI Gene 29639); rat studies defined the γa/γb isoforms and their renal localization (PMID: 11278761).
  • Natural disease in other species: No naturally occurring FXYD2 hypomagnesemia disease is documented in companion animals or wildlife (OMIA has no established entry for this phenotype).
  • Comparative biology: The Na,K-ATPase and its FXYD regulators are deeply evolutionarily conserved; the DCT Mg²⁺-handling mechanism is conserved across mammals, making rodents informative models of normal γ-subunit physiology.
  • Zoonotic potential: Not applicable (non-infectious Mendelian disease).

15. Model Organisms

  • In vitro / heterologous systems (principal evidence): Sf9 and COS-1 cells (mislocalization/misrouting; PMID: 12763862); co-immunoprecipitation systems for oligomerization (PMID: 17980699); synthetic transmembrane peptides with CD/FRET (PMID: 12225751); Xenopus oocytes and MDCK epithelial monolayers for electrophysiology (PMID: 18448590).
  • Mammalian models: Rat kidney for γa/γb localization and function (PMID: 11278761). No dedicated G41R knock-in mouse recapitulating HOMG2 is reported in the reviewed literature — a notable gap.
  • Phenotype recapitulation: Cellular/oocyte models faithfully reproduce the molecular lesions (misrouting, dominant-negative trapping, aberrant channel activity) but do not model the integrated renal/systemic phenotype. A conditional DCT Fxyd2^G41R knock-in would be the logical next step.

Mechanistic Model / Interpretation

 FXYD2 c.121G>A (p.Gly41Arg)   [germline, heterozygous, autosomal dominant]
    │
    ▼
 Disrupted TM-helix oligomerization geometry (G41R)          [PMID 12225751]
    │
    ▼
 Misfolding → ER/Golgi (perinuclear) retention of mutant γ    [PMID 12763862]
    │
    ├───────────────► Hetero-oligomerizes with WT γ → traps WT intracellularly
    │                  (DOMINANT-NEGATIVE; haploinsufficiency excluded)  [PMID 17980699]
    │                        │
    │                        ▼
    │             Loss of functional γ at DCT basolateral membrane
    │                        │
    │                        ▼
    │             Impaired Na,K-ATPase ATP/cation tuning            [PMID 11278761]
    │                        │
    ▼                        ▼
 Residual membrane G41R →   Reduced transcellular Mg²⁺ reabsorption in DCT   [PMID 19812536]
 aberrant inward-rectifying           │
 cation channel (GAIN-OF-FN)          ▼
 [PMID 18448590]           Renal Mg²⁺ wasting → HYPOMAGNESEMIA + HYPOCALCIURIA
                      │
                      ▼
      Neuromuscular hyperexcitability → cramps, tetany, seizures
           + chronic deficiency → chondrocalcinosis           [PMID 25765846]

The dominant-negative misrouting branch is the principal driver (quantitatively, most mutant protein never reaches the membrane and additionally sequesters wild-type protein), while the gain-of-function channel branch operates on the minority of protein that reaches the surface and may further perturb DCT ion handling. Both converge on the same clinical endpoint: a DCT unable to reclaim filtered magnesium.

Evidence Base

PMID Title (abbrev.) Evidence type Role
12763862 Misrouting of Na,K-ATPase γ-subunit Human + in vitro Establishes G41R as causal; misrouting; haploinsufficiency excluded
11062458 Dominant isolated renal Mg loss Human Original identification of dominant-negative FXYD2 mutation
25765846 Recurrent p.Gly41Arg Human Recurrence + founder effect; clinical features
17980699 Impaired routing after oligomerization In vitro Mechanism of dominant-negative trapping
12225751 TM-peptide oligomerization Biophysical G41R abrogates γ-TM oligomerization
18448590 G41R inward-rectifying channel In vitro electrophysiology Gain-of-function branch; basolateral Mg²⁺ extrusion
11278761 γa/γb function & localization Model organism (rat) Normal γ-subunit physiology
21130072 HNF-1B regulates γa In vitro Links FXYD2 to HNF1B hypomagnesemia pathway
11836293 Genetic heterogeneity Human linkage Demonstrates locus heterogeneity
19812536 DCT Mg²⁺ players (review) Review Places FXYD2 in DCT transport network
27234911 Genetic causes of hypomagnesemia Review Differential diagnosis context
25540137 Magnesium in health & disease Review Hypomagnesemia overview, acquired causes
32622651 Bartter-Gitelman syndromes Review Differential + supplementation strategy

Limitations and Knowledge Gaps

  1. Single-allele evidence base. Virtually all genetic knowledge rests on one recurrent variant (G41R) in a small number of Dutch-founder families. The allelic spectrum of FXYD2 in HOMG2 is essentially unexplored; it is unknown whether other FXYD2 variants cause disease.
  2. No precise epidemiology. Prevalence/incidence are unquantified; the condition is reported only as case/family series.
  3. No in vivo disease model. There is no published G41R knock-in mouse recapitulating the renal phenotype, limiting study of integrated pathophysiology and therapeutics.
  4. Relative weight of the two mechanisms (dominant-negative vs gain-of-function) at the whole-organ level is not quantified.
  5. Hypocalciuria mechanism in FXYD2 disease is described but not mechanistically dissected at the DCT level.
  6. Penetrance/expressivity data are limited to small families; genotype–phenotype correlation beyond G41R is nonexistent.
  7. No QoL or natural-history cohort data; long-term outcomes inferred rather than measured.

Proposed Follow-up Experiments / Actions

  1. Generate a DCT-targeted Fxyd2^G41R knock-in mouse to test in vivo recapitulation of renal Mg²⁺ wasting, hypocalciuria, and neuromuscular phenotype, and to dissect dominant-negative vs channel contributions (e.g., compare to a membrane-trafficking-rescued allele).
  2. Resequence FXYD2 in unexplained isolated renal Mg-wasting cohorts (and query gnomAD/large biobanks) to define the full allelic spectrum and whether non-G41R pathogenic variants exist.
  3. Quantitative trafficking/electrophysiology in polarized DCT-like cells (e.g., mpkDCT) to measure the fraction of G41R reaching the membrane and the magnitude of aberrant cation current under physiological gradients.
  4. Therapeutic screen for trafficking correctors (pharmacological chaperones) that could rescue wild-type γ-subunit routing from mutant trapping — a mechanism-based treatment beyond symptomatic Mg²⁺ repletion.
  5. Natural-history / registry study across known families to quantify penetrance, chondrocalcinosis/seizure risk, and QoL, informing supplementation guidelines.
  6. Test amiloride/potassium-sparing diuretics prospectively as Mg²⁺-retaining adjuncts in FXYD2 disease, by analogy to Gitelman management.

Report compiled from 6 confirmed findings across 19 reviewed papers (5 investigation iterations). Evidence types: human clinical/genetic, in vitro/heterologous expression, biophysical peptide studies, and rodent model-organism physiology.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 13
On topic 10
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:11278761 (15 mentions) - Functional role and immunocytochemical localization of the gamma a and gamma b forms of the Na,K-ATPase gamma subunit.
  • shared terms: subunit

Weighed against this report's own most characteristic terms: renal, fxyd2, hypomagnesemia, g41r, subunit, magnesium, disease, phenotype, dominant, dominant-negative, dct, mutation, wasting, hypocalciuria, clinical, isolated, normal, gene, genetic, chondrocalcinosis.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 20
Resolved 19
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 16
Terms named correctly 4
Terms named as a different term 8
Terms whose name is worth a second look 4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0007937 (2 mentions) - the report calls it "MONDO"; MONDO calls it renal hypomagnesemia 2
  • HP:0002917 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Hypomagnesemia
  • HP:0003127 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Hypocalciuria
  • HP:0000934 (2 mentions) - the report calls it "Physical/imaging"; HP calls it Chondrocalcinosis
  • HP:0001250 (2 mentions) - the report calls it "Clinical sign"; HP calls it Seizure
  • HP:0003394 (2 mentions) - the report calls it "Symptom"; HP calls it Muscle spasm
  • HP:0001281 (2 mentions) - the report calls it "Clinical sign"; HP calls it Tetany
  • HP:0012605 (2 mentions) - the report calls it "Lab/physiologic"; HP calls it Hypernatriuria

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0005890 (2 mentions) - the report calls it "sodium:potassium-exchanging ATPase complex, CC", "Subcellular GO CC: sodium:potassium-exchanging ATPase complex"; GO calls it sodium:potassium-exchanging ATPase complex**
  • GO:0034976 (1 mention) - the report calls it "response to ER stress — inferred"; GO calls it response to endoplasmic reticulum stress, and lists "response to ER stress" among its other names
  • CL:1000849 (2 mentions) - the report calls it "kidney distal convoluted tubule epithelial cell", "Cell type: DCT epithelial cell"; CL calls it kidney distal convoluted tubule epithelial cell**
  • UBERON:0002113 (1 mention) - the report calls it "Primary organ: Kidney"; UBERON calls it kidney**, and lists "reniculate kidney" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HGNC:4028 - called "FXYD2", "Causal gene:* FXYD2"
  • GO:0005890 - called "sodium:potassium-exchanging ATPase complex, CC", "Subcellular GO CC:** sodium:potassium-exchanging ATPase complex"
  • CL:1000849 - called "kidney distal convoluted tubule epithelial cell", "Cell type:** DCT epithelial cell"