Alternative titles; symbols
HGNC Approved Gene Symbol: FXYD2
SNOMEDCT: 725393000;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38) : 11:117,820,057-117,828,089 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Hypomagnesemia 2, renal | 154020 | Autosomal dominant | 3 |
The gene family FXYD (pronounced fix-id) consists of small membrane proteins containing a core motif of 35 invariant and conserved amino acids centered on a single transmembrane span.
Kim et al. (1997) cloned a cDNA encoding the sodium-potassium-ATPase gamma-subunit polypeptide from a human fetal liver cDNA library. The deduced amino acid sequence of the protein comprises 58 amino acids with a calculated molecular weight of 6,400 Da and shows about 86% homology when compared with those of the bovine, rat, and mouse gamma subunits. Northern blot analysis showed that the cDNA hybridizes to a 0.7-kb mRNA that is expressed in human kidney, pancreas, and fetal liver. See ATP1A1 (182310).
By EST database searching and in silico analysis, Sweadner and Rael (2000) identified genes and protein sequences for 7 FXYD molecules in rodents and humans. The deduced FXYD2 protein, the smallest of the 7, has 2 variants. The gamma-b isoform contains 66 amino acids and has no signal peptide. Sweadner and Rael (2000) noted that ESTs for FXYD2 are found in muscle, blood, and transport tissues, particularly kidney, but not in nervous system tissues, suggesting wide but not ubiquitous expression.
Sweadner et al. (2000) purified Na,K-ATPase-enriched membranes from rat and human kidneys. By Western blot analysis, they confirmed that both rat and human FXYD2 proteins migrate as doublets, with apparent molecular masses of 7.9 and 6.9 kD.
Sweadner et al. (2000) determined that the FXYD2 gene contains 7 exons and spans 9.2 kb. They identified 2 alternatively spliced exons encoding different N termini as well as 2 candidate promoters with consensus sites for transcription factors SP1, AP1 and AP2, consistent with independent transcription of the splice variants. The gene has a high concentration of repeat elements.
Annabi et al. (1998) mapped the gene for glycogen storage disease Ib (232220) to a 3-cM region on 11q23, between markers D11S939 and D11S4129. They found that the IL10R (146933), ATP1G1, and ALL1 (159555) genes were present in the same interval, in that order from centromere to telomere.
Crystal Structure
Morth et al. (2007) presented the x-ray crystal structure at 3.5-angstrom resolution of the pig renal sodium-potassium-ATPase (Na+,K(+)-ATPase) with 2 rubidium ions bound (as potassium congeners) in an occluded state in the transmembrane part of the alpha-subunit. Several of the residues forming the cavity for rubidium/potassium occlusion in the Na+,K(+)-ATPase are homologous to those binding calcium in the calcium-ion ATPase of sarcoendoplasmic reticulum (SERCA1; 108730). The beta and gamma subunits specific to the Na+,K(+)-ATPase are associated with transmembrane helices alpha-M7/alpha-M10, and alpha-M9, respectively. The gamma subunit corresponds to a fragment of the V-type ATPase c subunit. The carboxy terminus of the alpha subunit is contained within a pocket between transmembrane helices and seems to be a novel regulatory element controlling sodium affinity, possibly influenced by the membrane potential.
Autosomal dominant isolated renal magnesium loss (154020) is due to loss of magnesium in the kidney. It is usually associated with lowered urinary excretion of calcium, presumably as a consequence of increased reabsorption of calcium in the loop of Henle. By a candidate gene approach in a large Dutch kindred with hypomagnesemia, following mapping of the disorder to 11q23, Meij et al. (2000) identified a putative dominant-negative mutation in the gene encoding the Na+,K(+)-ATPase gamma subunit (601814.0001), leading to defective routing of the protein, which failed to find its way to the plasma membrane. This is a small, type I membrane protein localized on basolateral membranes of nephron epithelial cells and expressed in the distal convoluted tubule, the main site of active renal Mg(2+) reabsorption. This was said to be the first time that mutations in a gene encoding an Na+,K(+)-ATPase subunit had been implicated in human disease.
In affected members of a Dutch family and a Belgian family segregating autosomal dominant isolated hypomagnesemia, de Baaij et al. (2015) identified heterozygosity for the G41R mutation in the FXYD2 gene.
In affected individuals from a large Dutch kindred with autosomal dominant isolated renal magnesium loss (HOMG2; 154020), originally described by Geven et al. (1987), Meij et al. (2000) identified a heterozygous mutation, 121G-A, in the FXYD2 gene that cosegregated with the disorder. The mutation caused a substitution of the conserved glycine-41 within the putative transmembrane domain by arginine (G41R).
In affected members of a Dutch family and a Belgian family segregating autosomal dominant isolated hypomagnesemia, de Baaij et al. (2015) identified heterozygosity for the G41R mutation in the FXYD2 gene, which they designated as resulting from a c.115G-A change (c.115G-A, NM_001680.4). Patients from both families as well as the original Dutch kindred (Geven et al., 1987) shared the same haplotype, suggesting that all 3 families are related through a common ancestor.
Annabi, B., Hiraiwa, H., Mansfield, B. C., Lei, K.-J., Ubagai, T., Polymeropoulos, M. H., Moses, S. W., Parvari, R., Hershkovitz, E., Mandel, H., Fryman, M., Chou, J. Y. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am. J. Hum. Genet. 62: 400-405, 1998. [PubMed: 9463334] [Full Text: https://doi.org/10.1086/301727]
de Baaij, J. H. F., Dorresteijn, E. M., Hennekam, E. A. M., Kamsteeg, E.-J., Meijer, R., Dahan, K., Muller, M., van den Dorpel, M. A., Bindels, R. J. M., Hoenderop, J. G. J., Devuyst, O., Knoers, N. V. A. M. Recurrent FXYD2 p.gly41arg mutation in patients with isolated dominant hypomagnesaemia. Nephrol. Dial. Transplant. 30: 952-957, 2015. [PubMed: 25765846] [Full Text: https://doi.org/10.1093/ndt/gfv014]
Geven, W. B., Monnens, L. A., Willems, H. L., Buijs, W. C., ter Haar, B. G. Renal magnesium wasting in two families with autosomal dominant inheritance. Kidney Int. 31: 1140-1144, 1987. [PubMed: 3298795] [Full Text: https://doi.org/10.1038/ki.1987.120]
Kim, J. W., Lee, Y., Lee, I. A., Kang, H. B., Choe, Y. K., Choe, I. S. Cloning and expression of human cDNA encoding Na(+),K(+)-ATPase gamma-subunit. Biochim. Biophys. Acta 1350: 133-135, 1997. [PubMed: 9048881] [Full Text: https://doi.org/10.1016/s0167-4781(96)00219-9]
Meij, I. C., Koenderink, J. B., van Bokhoven, H., Assink, K. F. H., Groenestege, W. T., de Pont, J. J. H. H. M., Bindels, R. J. M., Monnens, L. A. H., van den Heuvel, L. P. W. J., Knoers, N. V. A. M. Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K(+)-ATPase gamma-subunit. Nature Genet. 26: 265-266, 2000. Note: Erratum. Nature Genet. 27: 125 only, 2001. [PubMed: 11062458] [Full Text: https://doi.org/10.1038/81543]
Morth, J. P., Pedersen, B. P., Toustrup-Jensen, M. S., Sorensen, T. L.-M., Petersen, J., Andersen, J. P., Vilsen, B., Nissen, P. Crystal structure of the sodium-potassium pump. Nature 450: 1043-1049, 2007. [PubMed: 18075585] [Full Text: https://doi.org/10.1038/nature06419]
Sweadner, K. J., Rael, E. The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics 68: 41-56, 2000. [PubMed: 10950925] [Full Text: https://doi.org/10.1006/geno.2000.6274]
Sweadner, K. J., Wetzel, R. K., Arystarkhova, E. Genomic organization of the human FXYD2 gene encoding the gamma subunit of the Na,K-ATPase. Biochem. Biophys. Res. Commun. 279: 196-201, 2000. [PubMed: 11112438] [Full Text: https://doi.org/10.1006/bbrc.2000.3907]