Alternative titles; symbols
HGNC Approved Gene Symbol: ATP1A1
SNOMEDCT: 1187620007;
Cytogenetic location: 1p13.1 Genomic coordinates (GRCh38) : 1:116,373,244-116,404,774 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.1 | Charcot-Marie-Tooth disease, axonal, type 2DD | 618036 | Autosomal dominant | 3 |
| Hypomagnesemia, seizures, and impaired intellectual development 2 | 618314 | Autosomal dominant | 3 |
The ATP1A1 gene encodes the alpha-1 isoform of the Na(+),K(+)-ATPase (EC 3.6.1.9), an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. As these gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle, the enzyme plays an essential role in cellular physiology. It is composed of at least 2 subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta) (ATP1B1; 182330). ATP1A1 and ATP1A2 (182340) are isoforms of the catalytic subunit. Kidney contains predominantly ATP1A1, whereas both subunits are found in brain, adipose tissue, and skeletal muscle (summary by Shull and Lingrel, 1987).
Shull and Lingrel (1987) identified separate genes encoding the alpha (ATP1A1) and alpha(+) (ATP1A2; 182340) isoforms. In addition, they isolated 2 other genes, termed alpha-C (ATP1A3; 182350) and alpha-D (ATP1A4; 607321), one of which is physically linked to the ATP1A2 gene; these genes showed nucleotide and deduced amino acid homology to the catalytic subunit cDNA sequences but did not correspond to any previously identified isoforms.
Chehab et al. (1987) cloned from human placenta a 2.2-kb clone comprising a major portion of the coding sequence of the alpha subunit. They found that its sequence was identical to that encoding the alpha subunit of the human kidney and HeLa cells. Southern blot analysis revealed a RFLP.
By immunostaining of peripheral rat sciatic nerve, Lassuthova et al. (2018) found that Atp1a1 localized to the axolemma of myelinated sensory and motor axons, to Schwann cells, and to Schmidt-Lanterman incisures of myelin sheaths, which are regions of noncompact myelin. Atp1a1 was the predominant ATP1A paralog present in most of the motor and sensory axons of the ventral and dorsal roots in the spinal cord; it was also found in the large motor neurons in the ventral horn.
Kent et al. (1987) used a panel of mouse-hamster somatic cell hybrids and restriction fragment length polymorphisms between 2 mouse species (Mus musculus and Mus spretus) to determine the chromosomal localization of genes encoding the alpha and beta subunits of Na,K-ATPase. Three isoforms of the alpha subunit mapped to 3 different chromosomes: alpha-1 to mouse chromosome 3; alpha-2 to mouse chromosome 7; and alpha-3 to mouse chromosome 1. The beta-subunit gene mapped to the same region of chromosome 1 but was not tightly linked to the alpha-3 gene.
Sverdlov et al. (1987) demonstrated intra-individual RFLPs in DNA isolated from different tissues of mouse, rabbit, and humans. They suggested that these tissue-specific RFLPs could be the result of rearrangements in the gene loci for the alpha and beta subunits of ATPase.
By hybridization to flow-sorted chromosomes and by in situ hybridization, Chehab et al. (1987) showed that the gene for the alpha subunit is on chromosome 1p13-p11. Yang-Feng et al. (1988) assigned the ATP1A1 gene to 1p21-cen by Southern analysis of DNA from panels of rodent/human somatic cell hybrid lines. The gene for this type of alpha chain appears to be expressed in most tissues.
Fan et al. (2018) found that overexpression of ATP1A1AS1, a long noncoding RNA produced from a gene antisense to ATP1A1, in cultured HK2 cells reduced ATP1A1 mRNA and protein expression, thereby inhibiting ATP1A1-related signaling and cell proliferation. The authors concluded that ATP1A1AS1 is negative regulator of ATP1A1.
Autosomal Dominant Axonal Charcot-Marie-Tooth Disease Type 2DD
In affected members of 7 unrelated families with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified 7 different missense heterozygous mutations in the ATP1A1 gene (see, e.g., 182310.0001-182310.0005). Five of the mutations occurred in a hotspot within the helical linker region (residues 592 to 608) that couples the N and P domains involved in ATP hydrolysis and phosphorylation. These mutations were predicted to cause decoupling of ATP hydrolysis and phosphorylation, which is essential for ion selectivity and driving the 2 major alternating conformations of the pump. In vitro electrophysiologic functional expression studies in Xenopus oocytes showed that 2 of the mutations (P600A, 182310.0002 and D811A, 182310.0005) resulted in significantly fewer Na(+)-dependent currents compared to wildtype. Additional functional studies using a ouabain survival assay in U2OS cells with ouabain-insensitive ATP1A1 mutants showed that several of the CMT2DD-associated mutations caused a significant decrease in cell survival, supporting a detrimental functional effect of the mutations. Lassuthova et al. (2018) suggested that ATP1A1 mutations cause a reduction in Na+/K(+)-ATPase activity, thus reducing the Na+ gradient across the axonal membrane and potentially causing increased intracellular axonal Ca(2+) levels, which would be toxic to the cell and cause axonal degeneration. The findings indicated a loss-of-function effect and indicated haploinsufficiency. The patients were ascertained from multiple large international data cohorts.
Hypomagnesemia, Seizures, and Impaired Intellectual Development 2
In 3 children with hypomagnesemia and intractable seizures associated with severely impaired intellectual development (HOMGSMR2; 618314), Schlingmann et al. (2018) identified heterozygosity for de novo missense mutations in the ATP1A1 gene (182310.0006-182310.0008). Functional analysis demonstrated loss of Na(+)/K(+)-ATPase activity with the mutant subunits, as well as abnormal cation permeabilities causing membrane depolarization. The authors noted that clinical evaluation of the 3 affected children at ages 4 years, 6 years, and 10 years, respectively, did not reveal any signs of peripheral neuropathy.
Salt Homeostasis and Possible Role in Hypertension
Based on observations that the ATP1A1 and NKCC2 (SLC12A1; 600839) genes interactively increase susceptibility to hypertension in the Dahl salt-sensitive hypertensive rat model, Glorioso et al. (2001) genotyped a relatively genetically homogeneous cohort in northern Sardinia to find whether parallel molecular genetic mechanisms exist in human essential hypertension. Their data indicated that ATP1A1 and NKCC2 are candidate interacting hypertension susceptibility loci in human essential hypertension.
Somatic Mutations
Beuschlein et al. (2013) performed exome sequencing of aldosterone-producing adenomas and identified somatic hotspot mutations in the ATP1A1 gene, encoding a sodium/potassium ATPase alpha subunit, and the ATP2B3 (300014) gene, encoding a calcium ATPase, in 3 and 2 of the 9 aldosterone-producing adenomas, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium, and calcium ion homeostasis. Functional in vitro studies of the ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiologic ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 aldosterone-producing adenomas, Beuschlein et al. (2013) found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations, and lower potassium concentrations compared with mutation-negative cases.
Azizan et al. (2013) performed exome sequencing of 10 zona glomerulosa-like aldosterone-producing adenomas and identified 9 with somatic mutations in either ATP1A1, encoding the Na+/K+ ATPase alpha-1 subunit, or CACNA1D (114206). The ATP1A1 mutations all caused inward leak currents under physiologic conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation, or increased currents. Many APAs with these mutations were less than 1 cm in diameter and had been overlooked on conventional adrenal imaging. Azizan et al. (2013) concluded that recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
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.
In a search for an essential hypertension (145500) gene, Herrera and Ruiz-Opazo (1990) used an approach that integrated molecular, transgenic, and genetic analysis to study the Dahl salt-sensitive (S) and Dahl salt-resistant (R) rat (Dahl et al. (1962, 1974)). Because alpha-1-Na,K-ATPase is the sole active Na+ transporter in the renal basolateral epithelia throughout the nephron, it was a logical candidate gene to be considered in the assessment of the abnormal renal sodium handling in the Dahl S rat. Herrera and Ruiz-Opazo (1990) and Ruiz-Opazo et al. (1994) purportedly demonstrated a gln276-to-leu (Q276L) substitution in the Atp1a gene in Dahl S rats. To determine the role of the Dahl-sensitive Q276L gene variant, Herrera et al. (1998) developed transgenic Dahl S rats bearing the Dahl R wildtype Atp1a1 cDNA directed by the cognate wildtype promoter region. Transgenic Dahl S rats exhibited less rat salt-sensitive hypertension, less hypertensive renal disease, and longer life span when compared with nontransgenic Dahl S controls. Chromosome 2 linkage analysis of F2(SxR) male rats detected cosegregation of the Atp1a1 locus with salt-sensitive hypertension. These data supported the view that the Atp1a1 gene is a susceptibility gene for salt-sensitive hypertension in the Dahl S rat model, and provided the basis for the study of the same locus in human hypertension.
A putative 1079A-T mutation in the Atp1a1 gene was also proposed in the New Zealand genetically hypertensive strain of rat, known to have a blood pressure quantitative trait locus on chromosome 2. Barnard et al. (2001) appeared to have excluded the existence of this mutation which would predict a Q276L amino acid substitution in the protein. They suggested that alternative candidate genes in the region defined by the rat chromosome 2 hypertension quantitative trait locus should be examined.
To determine the functional roles of the ATP1A1 and ATP1A2 proteins, James et al. (1999) generated mice with targeted disruption of either the Atp1a1 or Atp1a2 gene. Hearts from heterozygous Atp1a2 mice were hypercontractile as a result of increased calcium transients during the contractile cycle. In contrast, hearts from heterozygous Atp1a1 mice were hypocontractile. The different functional roles of these 2 proteins were further demonstrated since inhibition of the Atp1a2 protein with ouabain increased the contractility of heterozygous Atp1a1 hearts. These results illustrated a specific role for the ATP1A2 protein in calcium signaling during cardiac contraction.
In 12 affected members of a multigenerational Czech family (family 1) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified a heterozygous c.143T-G transversion (c.143T-G, NM_000701) in exon 5 of the ATP1A1 gene, resulting in a leu48-to-arg (L48R) substitution at a highly conserved residue adjacent to a phosphorylation site in the actuator domain in the N-terminal region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. In vitro electrophysiologic functional expression studies in Xenopus oocytes showed that the L48R variant did not alter Na(+)-dependent currents compared to wildtype, suggesting that it may cause functional defects that are not detected in this assay or may affect other functions, such as intracellular trafficking of the pump to the plasma membrane.
In 5 affected members of a multigenerational Southern Italian family (family 2) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified a heterozygous c.1798C-G transversion (c.1798C-G, NM_000701) in exon 13 of the ATP1A1 gene, resulting in a pro600-to-ala (P600A) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. The substitution occurred in the intracellular loop between transmembrane domains M4 and M5 where ATP binding and hydrolysis occur. In vitro electrophysiologic functional expression studies in Xenopus oocytes showed that the mutation resulted in significantly fewer Na(+)-dependent currents compared to wildtype, consistent with a loss of function and haploinsufficiency.
In 4 affected members of a U.S. family (family 4) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified a heterozygous c.1798C-A transversion in exon 13 of the ATP1A1 gene, resulting in a pro600-to-thr (P600T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. The substitution occurred in the intracellular loop between transmembrane domains M4 and M5 where ATP binding and hydrolysis occur.
In 4 affected members of a U.S. family (family 3) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified a heterozygous c.1775T-C transition (c.1775T-C, NM_000701) in exon 13 of the ATP1A1 gene, resulting in an ile592-to-thr (I592T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. The substitution occurred in the intracellular loop between transmembrane domains M4 and M5 where ATP binding and hydrolysis occur.
In a 33-year-old Korean man (family 7) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified a heterozygous c.2432A-C transversion (c.2432A-C, NM_000701) in exon 19 of the ATP1A1 gene, resulting in an asp811-to-ala (D811A) substitution at a highly conserved residue in the fifth transmembrane domain where Na+ binding occurs. The mutation was found through the analysis of 513 whole exomes from 399 unrelated Korean families with CMT. The patient's unaffected mother did not carry the mutation, but DNA from the deceased father was unavailable; he reportedly had no symptoms of the disorder in his sixth decade. In vitro electrophysiologic functional expression studies in Xenopus oocytes showed that the mutation resulted in significantly fewer Na(+)-dependent currents compared to wildtype, consistent with a loss of function and haploinsufficiency.
In a 4-year-old girl (family A) with hypomagnesemia and intractable seizures associated with severely impaired intellectual development (HOMGSMR2; 618314), Schlingmann et al. (2018) identified heterozygosity for a de novo c.905T-C transition (c.905T-C, NM_000701) in the ATP1A1 gene, resulting in a leu302-to-arg (L302R) substitution at a highly conserved residue within the third transmembrane domain. Her unaffected parents did not carry the mutation, which was not found in the ExAC or gnomAD databases. Transfected COS1 cells failed to grow under ouabain selection, indicating that the L302R mutant was not able to carry out the Na+ and K+ transport required to support cell growth. Using siRNA to knock down endogenous Na(+)/K(+)-ATPase, the authors observed phosphorylation of the L302R mutant, indicating that it was expressed; however, the mutant showed significantly reduced Na+ and K+ affinity. Patch-clamp analysis in NCI-H295R and HEK293 cells showed abnormal Na+ permeability compared to that of wildtype cells, as well as a depolarized membrane potential in the presence of Na+ that became hyperpolarized to the level of wildtype upon removal of extracellular Na+. Ouabain inhibition of endogenous Na(+)/K(+)-ATPase in HEK293 cells produced pronounced changes in intracellular Na+ and K+ that could be attenuated by wildtype ATP1A1 but not the L302R mutant. Analysis of intracellular pH levels revealed an abnormal H+ permeability and significant changes of intracellular pH upon alteration of extracellular pH with the L302R mutant.
In a 10-year-old girl (family B) with hypomagnesemia and intractable seizures associated with severely impaired intellectual development (HOMGSMR2; 618314), Schlingmann et al. (2018) identified heterozygosity for a de novo c.907G-C transversion (c.907G-C, NM_000701) in the ATP1A1 gene, resulting in a gly303-to-arg (G303R) substitution at a highly conserved residue within the third transmembrane domain. Her unaffected parents did not carry the mutation, which was not found in the ExAC or gnomAD databases. Transfected COS1 cells failed to grow under ouabain selection, indicating that the G303R mutant was not able to carry out the Na+ and K+ transport required to support cell growth. Using siRNA to knock down endogenous Na(+)/K(+)-ATPase, the authors observed phosphorylation of the G303R mutant, indicating that it was expressed, although at a significantly reduced level. In addition, the mutant showed significantly reduced cooperativity of Na+ and K+ binding. Patch-clamp analysis in NCI-H295R and HEK293 cells showed abnormal Na+ permeability compared to that of wildtype cells, as well as a depolarized membrane potential in the presence of Na+ that became hyperpolarized to the level of wildtype upon removal of extracellular Na+. Ouabain inhibition of endogenous Na(+)/K(+)-ATPase in HEK293 cells produced pronounced changes in intracellular Na+ and K+ that could be attenuated by wildtype ATP1A1 but not the G303R mutant; instead, expression of G303R resulted in even more pronounced disturbances of intracellular Na+ and K+ content compared to nontransfected cells.
In a 6-year-old boy (family C) with hypomagnesemia and intractable seizures associated with severely impaired intellectual development (HOMGSMR2; 618314), Schlingmann et al. (2018) identified heterozygosity for a de novo c.2576T-G transversion (c.2576T-G, NM_000701) in the ATP1A1 gene, resulting in a met859-to-arg (M859R) substitution at a highly conserved residue within the seventh transmembrane helix. His unaffected parents did not carry the mutation, which was not found in the ExAc or gnomAD databases. Transfected COS1 cells failed to grow under ouabain selection, indicating that the M859R mutant was not able to carry out the Na+ and K+ transport required to support cell growth. Using siRNA to knock down endogenous Na(+)/K(+)-ATPase, the authors observed phosphorylation of the M859R mutant, indicating that it was expressed, although at a significantly reduced level. In addition, the mutant showed significantly reduced cooperativity of Na+ and K+ binding. Ouabain inhibition of endogenous Na(+)/K(+)-ATPase in HEK293 cells produced pronounced changes in intracellular Na+ and K+ that could be attenuated by wildtype ATP1A1, but not the M859R mutant.
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