Alternative titles; symbols
HGNC Approved Gene Symbol: ATP1A2
SNOMEDCT: 1260330000;
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38): 1:160,115,759-160,143,591 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.2 | Alternating hemiplegia of childhood 1 | 104290 | Autosomal dominant | 3 |
| Developmental and epileptic encephalopathy 98 | 619605 | Autosomal dominant | 3 | |
| Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies | 619602 | Autosomal recessive | 3 | |
| Migraine, familial basilar | 602481 | Autosomal dominant | 3 | |
| Migraine, familial hemiplegic, 2 | 602481 | Autosomal dominant | 3 |
The ATP1A2 gene encodes the alpha-2 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. The pump is composed of 2 subunits, a large catalytic subunit (alpha), encoded by several genes (see, e.g., ATP1A1, 182310), and a smaller glycoprotein subunit (beta) (see ATP1B1, 182330) (summary by Shull and Lingrel, 1987).
Shull and Lingrel (1987) identified separate genes encoding the alpha and alpha(+) isoforms of the catalytic subunit of the Na(+),K(+)-ATPase. These genes were called alpha-A (ATP1A1) and alpha-B (ATP1A2), respectively. 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 alpha-B 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.
Shull et al. (1989) cloned the ATP1A2 gene. The amino acid sequence deduced from the genomic sequence exhibited 99% identity to the rat alpha-2 isoform. Several transcription factor binding sites are located in the 5-prime end of the gene.
The alpha-2 subunit consists of 10 transmembrane helices M1-M10, harboring the Na(+) and K(+)-binding sites, and a cytoplasmic head made up of 3 subdomains: A (actuator), N (nucleotide binding), and P (phosphorylation) (summary by Schack et al., 2012).
ATP1A2 is expressed in skeletal muscle, heart, vascular smooth muscle, and brain (summary by Monteiro et al., 2020).
Shull et al. (1989) determined that the ATP1A2 gene contains 23 exons and spans approximately 25 kb.
Katzmarzyk et al. (1999) examined the relationship between the ATP1A2 (exon 1 and exon 21-22 with BglII) and ATP1B1 (182330) (MspI and PvuII) genes and resting metabolic rate (RMR) and respiratory quotient (RQ). RMR and RQ were adjusted for age, sex, fat mass, and fat-free mass. Sib-pair analyses indicated a significant linkage between RQ and the ATP1A2 exon 1 and exon 21-22 markers (P of 0.03 and 0.02, respectively). No linkage was detected between the ATP1B1 markers and either RMR or RQ, and RMR was not linked with the ATP1A2 markers. There was a significant interaction (p less than 0.0003) between ATP1A2 exon 1 carrier status and age group (younger adults (those less than 45 years old) vs older adults (those 45 or more years old)) for RQ. The association between carrier status and RQ was significant in younger adults (RQ of 0.76 in carriers vs 0.80 in noncarriers; p less than 0.0001) but was not in older adults (RQ of 0.81 in carriers vs 0.80 in noncarriers). The ATP1A2 exon 1 gene accounted for approximately 9.1% and 0.3% of the variance in RQ in younger and older adults, respectively. The results suggested that the ATP1A2 gene may play a role in fuel oxidation, particularly in younger individuals.
To determine the functional roles of the ATP1A1 and ATP1A2 proteins, James et al. (1999) generated mice with a targeted disruption of either the Atp1a1 or the 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.
By Southern analysis of DNA from panels of rodent/human somatic cell hybrid lines, Yang-Feng et al. (1988) mapped the ATP1A2 gene to 1cen-q32. Furthermore, they detected a common Pst1 RFLP with the ATP1A2 probe. In the course of creating a physical map of human 1q21-q23, Oakey et al. (1992) confirmed this assignment.
Stumpf (2021) mapped the ATP1A2 gene to chromosome 1q23.2 based on an alignment of the ATP1A2 sequence (GenBank BC052271) with the genomic sequence (GRCh38).
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 (ATP2A1 (SERCA1); 108730). The beta (see ATP1B1, 182330) and gamma (see ATP1G1, 601814) 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.
Crystal structures of the potassium-bound form of the sodium potassium ATPase pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain (e.g., Morth et al., 2007). Poulsen et al. (2010) showed that this element is a key regulator of a theretofore unrecognized ion pathway. Models of P-type ATPases operated with a single ion conduit through the pump, but the data of Poulsen et al. (2010) suggested an additional pathway in the Na+/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least 8 mutations in the region that cause severe neurologic diseases. This novel model for ion transport by the Na+/K(+)-ATPase was established by electrophysiologic studies of C-terminal mutations in familial hemiplegic migraine (602481) and was further substantiated by molecular dynamics simulations. Poulsen et al. (2010) considered a similar ion regulation likely to apply to the H+/K(+)-ATPase and the Ca(2+)-ATPase.
Familial Hemiplegic Migraine 2
In affected members of a large Italian family segregating familial hemiplegic migraine-2 (FHM2; 602481), De Fusco et al. (2003) identified heterozygosity for mutations in the ATP1A2 gene (182340.0001-182340.0002).
Jurkat-Rott et al. (2004) identified 6 different mutations in the ATP1A2 gene (see, e.g., 182340.0008; 182340.0009) in affected members of 6 unrelated families with FHM2. Penetrance was mildly reduced at approximately 87%.
Vanmolkot et al. (2007) reported an affected family in which the proband with severe FHM2 was compound heterozygous for 2 mutations in the ATP1A2 gene (182340.0011; 182340.0012). Family members with milder forms of the disorder were heterozygous for 1 of the mutations, suggesting reduced penetrance. The authors stated that this was the first report of compound heterozygosity in FHM2.
In affected members of a 3-generation Korean family with FHM2, Oh et al. (2015) identified a heterozygous missense mutation (V191M; 182340.0015) in the ATP1A2 gene. All affected members of the family also had progressive hearing loss. The mutation segregated with the phenotype in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 200 Korean controls with normal audiograms. See DFNA7 (601412) and DFNA49 (608372) for 2 hearing loss loci that map to the same region as the ATP1A2 gene.
Alternating Hemiplegia of Childhood 1
In affected members of a family with alternating hemiplegia of childhood-1 (AHC1; 104290), Swoboda et al. (2004) identified a mutation in the ATP1A2 gene (182340.0005).
In a Brazilian boy with a phenotype reminiscent of AHC1, Sampedro Castaneda et al. (2018) identified a de novo heterozygous missense mutation in the ATP1A2 gene (S779N; 182340.0023). The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis. The patient developed episodic tetraparesis at age 2 years. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. The symptoms improved with potassium, but worsened with acetazolamide. Sampedro Castaneda et al. (2018) noted the phenotypic similarities to hypokalemic periodic paralysis (see 170400) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations.
Fetal Akinesia, Respiratory Insufficiency, Microcephaly, Polymicrogyria, and Dysmorphic Facies
In 3 infants from 2 unrelated families with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Monteiro et al. (2020) identified homozygous frameshift mutations in the ATP1A2 gene (182340.0016 and 182340.0017). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither were present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but both were predicted to result in a complete loss of ATP1A2 function. All 3 patients died in the perinatal period.
In 3 sibs, conceived of consanguineous Algerian parents, and an unrelated infant, born of consanguineous Pakistani parents, with FARIMPD, Chatron et al. (2019) identified a homozygous frameshift and nonsense mutation, respectively, in the ATP1A2 gene (182340.0018 and 182340.0019). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Both were absent from the gnomAD database. No ATP1A2 immunostaining was detected in brain samples from 2 patients, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed. All patients either died in infancy or the pregnancies were terminated.
Developmental and Epileptic Encephalopathy 98
In 6 unrelated patients with developmental and epileptic encephalopathy-98 (DEE98; 619605), Vetro et al. (2021) identified 5 de novo heterozygous missense mutations in the ATP1A2 gene (see, e.g., 182340.0020-182340.0022). The mutations, which occurred at conserved residues, were not present in the gnomAD database. In vitro functional expression studies showed that all of the mutations caused variable functional defects in the Na+/(K+)ATPase. Variants with more severe functional deficits were associated with a more severe phenotype. The findings were consistent with a loss-of-function effect. Vetro et al. (2021) estimated that about 5% of ATP1A2 mutations may be associated with DEE. Polymicrogyria was estimated to occur in about 1% of patients with ATP1A2 mutations.
Variant Functional Studies
Schack et al. (2012) reported functional analysis of 9 different pathogenic mutations in the ATP1A2 gene, including 4 in the P domain (M731T (182340.0003), R593W, V628M, and E700K), 2 in the A domain (R202Q and T263M), 1 in the transmembrane domain M2 (V138A), 1 in transmembrane M4 domain near the P domain (T345A; 182340.0007), and 1 between M6 and M7 close to the P domain (R834Q). Expression of the mutations in COS-1 cells showed that all had reductions in the catalytic turnover rate of Na+ and K+. The decrease was most severe for R593W, V628M, M731T, and R834Q (less than one-third of wildtype), about 50% for T263M, T345A, E700K, and V138A, and less than 20% of control for R202Q. All mutants showed essentially normal affinity for K+ and Na+, but rapid kinetic studies of the phosphorylation from ATP showed reduced Vmax of phosphorylation as a major factor contributing to the reduction of the catalytic turnover rate of mutants V138A, T345A, R593W, V628M, M731T, and R834Q (2- to 6-fold decrease). The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. E700K, R202Q, and T263M phosphorylation rates were similar to wildtype, but E700K showed impaired rates of dephosphorylation, and R202Q and T263M were predicted to affect the turnover rate of the E1P/E2P pump conformations. Overall, the findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+.
In Drosophila, Kaneko et al. (2014) identified a dominant missense mutation (A617T) in the calcium ATPase Serca gene (see SERCA2 (ATP2A2); 108740) that conferred temperature-sensitive motor uncoordination in a gain-of-function manner. The homologous residue is conserved by different type II P-type ATPases, including ATP1A2. Introduction of an R751Q mutation in the Drosophila Serca gene also caused a temperature-sensitive uncoordination phenotype. The corresponding residue in human SERCA2, ATP1A2, and ATP1A3 (182350) is mutated in the human diseases Darier disease (124200), FHM2, and dystonia-12 (DYT12; 128235), respectively. Cellular expression of Drosophila A617T resulted in temperature-induced decreased levels of stored calcium compared to wildtype, whereas cellular expression of R751Q elicited depletion of stored calcium even without heating. These calcium changes were due to leakage through the mutant channel pores that overwhelmed the pumping capacity of the cell. Similar results occurred after transfection of these mutations, as well as other disease-causing mutations that affected different parts of the protein, into mouse cells. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases.
Ikeda et al. (2004) found that homozygous knockout of the Atp1a2 gene in mice was embryonic lethal due to severe motor deficits that also abolished respiration by the medullary respiratory center neurons. Analysis of spinal cord motoneurons in mutant mice showed absence of normal spontaneous rhythmic discharges. This was associated with increased inhibitory GABA levels in the extracellular spaces throughout the brain, as well as increased chloride (Cl-) levels within neurons. Ikeda et al. (2004) hypothesized that Atp1a2 normally generates a K+ gradient that fuels extrusion of cytosolic Cl- by KCC2 (SLC12A5; 606726) in respiratory center neurons in the perinatal period. In the absence of this, due to loss of Atp1a2, neurons thus become persistently depolarized and cannot produce action potentials due to the inactivation of fast sodium channels.
Ashmore et al. (2009) identified 6 different EMS-induced missense mutations in the Atp1a2 and Atp1a3 (182350) genes in Drosophila. All mutations resulted in reduced respiration activity consistent with a loss of ATPase function and a hypomorphic effect. Different mutant strains exhibited some abnormalities, including progressive temperature-dependent paralysis, progressive stress-sensitive paralysis, and decreased locomotor activity in response to startle, suggesting a decrease in maximal locomotion capacity. Neuromuscular studies showed allele-specific pathology, including brain vacuoles and myopathology, and biochemical studies showed decreased metabolic rates. An unexpected finding was the some mutant strains had increased longevity, which was not related to caloric restriction. Low doses of ouabain showed a similar effect on longevity in control groups. Ashmore et al. (2009) suggested that these findings may be relevant for studying the pathogenesis of FHM2 and DYT12 (128235).
In a large Italian family with familial hemiplegic migraine-2 (602481), De Fusco et al. (2003) identified a heterozygous 2395T-C mutation in the ATP1A2 gene, resulting in a leu764-to-pro (L764P) substitution. The mutation segregated with the disorder in all 22 affected members who were tested and was not present in 400 control chromosomes. Functional studies in HeLa cells showed that the L764P and W887R (182340.0002) mutations inhibited Na+/K+ pump activity, but did not affect assembly or translocation to the cell membrane. Resultant abnormalities in intra- and extracellular ion concentrations may contribute to the pathophysiology of the disorder.
In a family with familial hemiplegic migraine-2 (602481), De Fusco et al. (2003) identified a heterozygous 2763T-C mutation in the ATP1A2 gene, resulting in a trp887-to-arg (W887R) substitution. The mutation segregated with the disorder in all 7 affected members and was not present in 400 control chromosomes. Also see 182340.0001.
In affected members of a family with familial hemiplegic migraine-2 (602481), Vanmolkot et al. (2003) identified a heterozygous 2296T-C transition in exon 16 of the ATP1A2 gene, resulting in a met731-to-thr (M731T) substitution.
Segall et al. (2005) found that the mutant M731T and R689Q (182340.0004) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. In addition, M731T showed an increased apparent affinity for ATP. Segall et al. (2005) suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling.
Castro et al. (2007) identified the M731T mutation in 3 affected members of a Portuguese family with FHM2. A fourth mutation carrier had only migraine with aura.
Schack et al. (2012) noted that the M731T mutation occurs in the P domain. Expression of the mutation in COS-1 cells showed a severe reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+.
In affected members of a family with familial hemiplegic migraine-2 (FHM2; 602481), previously reported by Terwindt et al. (1997), Vanmolkot et al. (2003) identified a 2170G-A transition in exon 15 of the ATP1A2 gene, resulting in an arg689-to-gln (R689Q) substitution. Three individuals with the mutation and FHM also had benign familial infantile convulsions (BFIC), 1 member had the mutation and only BFIC, and 2 members had the mutation and only migraine with or without aura. Pelzer et al. (2014) found that 4 affected members of the family reported by Vanmolkot et al. (2003) who had BFIC carried a heterozygous truncating mutation in the PRRT2 gene (614386.0016), consistent with benign familial infantile convulsions-2 (BFIC2; 605751). Thus, 2 different neurologic disorders segregated in this family; the diagnosis was more complex as both disorders showed incomplete penetrance.
Segall et al. (2005) found that the mutant R689Q and M731T (182340.0003) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. Segall et al. (2005) suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling.
In affected members of a family with alternating hemiplegia of childhood-1 (AHC1; 104290) originally reported by Kanavakis et al. (2003), Swoboda et al. (2004) identified a 1237C-A transversion in exon 9 of the ATP1A2 gene, resulting in a thr378-to-asn (T378N) substitution. The mutation affects a highly conserved residue in the second cytoplasmic loop of the protein and was not identified in 382 control chromosomes.
In 4 affected members of a Greek family with alternating hemiplegia of childhood, Bassi et al. (2004) identified the T378N mutation. The mutation was not present in unaffected members of the family or in 250 control chromosomes.
In affected members of an Italian family with severe familial hemiplegic migraine-2 (FHM2; 602481), Spadaro et al. (2004) identified a 901G-A transition in the ATP1A2 gene, resulting in a gly301-to-arg (G301R) substitution. The mutation occurs in a highly conserved residue within transmembrane segment M3 of the protein that is important for the dephosphorylation of homologous ATPases. The mutation was not identified in 179 controls.
In affected members of a Finnish family with familial hemiplegic migraine-2 (FHM2; 602481) with associated symptoms such as coma and showing linkage to 1q23, Kaunisto et al. (2004) identified a 1033A-G transition in exon 9 of the ATP1A2 gene, resulting in a thr345-to-ala (T345A) substitution. All 11 affected members in this family showed hemisensoric aura with mild to moderate hemiparesis affecting mostly the arm. Interictal neurologic examinations were normal. Migraine attacks usually started with gradually spreading hemisensoric aura which was always accompanied by hemiparesthesias, dysarthria, or dysphagia, and often by visual symptoms. Of the 11 affected family members, 10 reported onset before the age of 15 years. The frequency of attacks varied from 2 per month to once a year, and 2 individuals reported cessation of attacks during their teens. Minor head trauma triggered attacks in 5 of the 11 patients and severe vomiting could last for days in 4 patients. Confusion and mild anxiety were common features during attacks in 5 subjects. In 4 of these patients a mild head trauma had triggered coma accompanied by fever that lasted 2 days to 2 weeks. Hemiparetic symptoms could persist for as long as 2 weeks in some individuals. None of the patients had seizures.
In functional expression studies, Segall et al. (2004) found that cells transduced with the T345A mutant protein showed growth comparable to wildtype cells and no reduction in catalytic turnover of the subunit protein; however, kinetic studies showed that the T345A mutant protein had an approximately 2-fold decrease in apparent affinity for extracellular potassium. The authors concluded that the slow removal of potassium from the extracellular space slowed the recovery phase of nerve impulse transmission.
Schack et al. (2012) noted that the T345A mutation occurs in the M4 transmembrane domain near the P domain. Expression of the mutation in COS-1 cells showed about a 50% reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+.
In 6 affected members spanning 4 generations of a family with familial hemiplegic migraine-2 (FHM2; 602481), Jurkat-Rott et al. (2004) identified a heterozygous 2152G-A transition in the ATP1A2 gene, resulting in an asp718-to-asn (D718N) substitution. Age at onset ranged from 3 to 12 years, and hemiplegic episodes were long, lasting from 6 to 336 hours. In most patients, the frequency of attacks ranged from 1 to 2 episodes per month. Aural features included dysarthria, diplopia, and impaired hearing. One patient was mentally retarded and had epileptic seizures, and another had low IQ. The D718N mutation affects a magnesium-interaction site and is predicted to result in complete loss of ATPase function due to lack of catalytic activity.
In 5 affected members of a family with familial hemiplegic migraine-2 (FHM2; 602481), Jurkat-Rott et al. (2004) identified a heterozygous 2936C-T transition in the ATP1A2 gene, resulting in a pro979-to-leu (P979L) substitution. Age at onset ranged from 3 to 23 years, and hemiplegic attacks occurred several times per year. One patient had mental retardation, and another had epileptic seizures.
In a father and son (proband) with basilar migraine (see 602481), Ambrosini et al. (2005) identified a heterozygous 1643G-A transition in exon 12 of the ATP1A2 gene, resulting in an arg548-to-his (R548H) substitution in a highly conserved region of the protein. Residue 548 occurs in the major alpha-2 subunit cytoplasmic loop, which plays a key role in pump function. The mutation was not identified in 400 control chromosomes. The R548H mutation was also identified in the proband's paternal uncle who had basilar migraines in his youth, but at the time of the report had migraine without aura, and in the proband's first cousin, who had migraine without aura. Ambrosini et al. (2005) concluded that basilar migraine is allelic to FHM2.
In a young woman with severe hemiplegic migraine (FHM2; 602481), Vanmolkot et al. (2007) identified compound heterozygosity for 2 mutations in the ATP1A2 gene: a 961T-C transition in exon 8, resulting in an ile286-to-thr (I286T) substitution, and a 1348C-T transition in exon 10, resulting in a thr415-to-met (T415M; 182340.0012) substitution, both of which are located in the intracellular portion of the protein. The patient had onset at age 8 years of hemiplegic migraine with visual aura and subsequent dysphasia, hemiplegia, and migraine headache. Her mother and maternal aunt, both of whom were heterozygous for the I286T mutation, had aura without headache and a milder form of hemiplegic migraine, respectively. In vitro functional expression studies showed that the I286T mutant protein was expressed but caused significantly decreased cell survival that reflected a dysfunctional pump. Her unaffected daughter was heterozygous for the T415M mutation, as were her father and son, who had nonmigrainous headaches and migraine with aura, respectively. In vitro functional expression studies showed that the T415M mutant protein was expressed, but cells with the mutant protein were unable to survive, indicating complete loss of function. Vanmolkot et al. (2007) noted that this was the first reported case of compound heterozygosity for mutations in the ATP1A2 gene and concluded that the mutations showed reduced penetrance in the heterozygous state.
For discussion of the thr415-to-met (T415M) mutation in the ATP1A2 gene that was found in compound heterozygous state in a patient with familial hemiplegic migraine-2 (FHM2; 602481) by Vanmolkot et al. (2007), see 182340.0011.
In 3 affected members of a family with familial hemiplegic migraine-2 (FHM2; 602481), Tonelli et al. (2007) identified a heterozygous 193C-T transition in exon 4 of the ATP1A2 gene, resulting in an arg65-to-trp (R65W) substitution in the cytoplasmic N-terminal portion of the protein, within the actuator domain (A domain).
In affected members of a Portuguese family with pure familial hemiplegic migraine-2 (FHM2; 602481), Castro et al. (2007) identified a heterozygous 1231C-T transition in exon 9 of the ATP1A2 gene, resulting in a thr376-to-met (T376M) substitution in the M4 cytoplasmic loop. In vitro functional expression studies showed that the mutant protein had decreased function.
In affected members of a 3-generation Korean family (KNUF-47) with familial hemiplegic migraine-2 (FHM2; 602481), Oh et al. (2015) identified a heterozygous c.571G-A transition (c.571G-A, NM_00702.3) in the ATP1A2 gene, predicting a val191-to-met (V191M) substitution at a highly conserved residue in the A domain. All affected members of the family also had progressive hearing loss. The mutation segregated with the phenotype in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 200 Korean controls with normal audiograms. In silico studies suggested that the variant causes a change in hydrophobic interactions and thereby slightly destabilizes the A domain of Na(+)/K(+)-ATPase. However, Western blot analysis of recombinant ATPase proteins in insect cells revealed similar expression levels of wildtype and mutant Na(+)/K(+)-ATPase, and inhibitor binding studies showed that the ouabain-binding level for mutant and wildtype was also similar. (See DFNA7 (601412) and DFNA49 (608372) for 2 hearing loss loci that map to the same region as the ATP1A2 gene.)
In an infant (patient 2), born of Brazilian parents who were not known to be related (family 1), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Monteiro et al. (2020) identified a homozygous 2-bp deletion (c.2104_2105delTG, NM_000702), predicted to result in a frameshift and premature termination (Cys702SerfsTer12) in the cytoplasmic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of ATP1A2 function. The patient had a similarly affected sib (patient 1), but genetic analysis of the sib was not performed. Patient 2 and the affected sib both died at 2 months of age. The patients' mother reported occasional migraines without aura.
In a newborn female (patient 3), born of consanguineous Hispanic parents (family 2), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Monteiro et al. (2020) identified a homozygous 1-bp deletion (c.835delC, NM_000702) in the ATP1A2 gene, predicted to result in a frameshift and premature termination (Arg279GlyfsTer4) in the cytoplasmic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of ATP1A2 function. The patient died of respiratory insufficiency soon after birth.
In 3 sibs, conceived of consanguineous Algerian parents (family A), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Chatron et al. (2019) identified a homozygous 2-bp duplication (c.295_296dupTC, NM_000702.3) in the ATP1A2 gene, resulting in a frameshift and premature termination (Ile100ProfsTer71). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was absent from the gnomAD database. No ATP1A2 immunostaining was detected in patient brain samples, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed.
In a 35-week-old fetus, born of consanguineous Pakistani parents (family B), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Chatron et al. (2019) identified a homozygous c.2869G-T transversion (c.2869G-T, NM_000702.3) in the ATP1A2 gene, resulting in a glu957-to-ter (E957X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old boy (patient 2) with developmental and epileptic encephalopathy-98 (DEE98; 619605), Vetro et al. (2021) identified a de novo heterozygous c.1022G-T transversion (c.1022G-T, NM_000702.3) in the ATP1A2 gene, resulting in a cys341-to-phe (C341F) substitution at a conserved residue. In vitro functional expression studies showed that the variant was unable to support COS1 cell survival in culture. Phosphorylation was decreased to 10 to 15% of wildtype. The patient had a severe phenotype with onset of seizures at 3 weeks of age.
In 2 unrelated patients (patients 3 and 4) with developmental and epileptic encephalopathy-98 (DEE; 619605), Vetro et al. (2021) identified a de novo heterozygous c.1097G-C transversion (c.1097G-C, NM_000702.3) in the ATP1A2 gene, resulting in a gly366-to-ala (G366A) substitution at a conserved residue. In vitro functional expression studies showed that the variant was unable to support COS1 cell survival in culture. Phosphorylation was decreased to 61% of wildtype, and there was decreased affinity for both Na+ and K+ ions, consistent with pump dysfunction. The patients had a severe phenotype with onset of seizures in the first month of life. Both died of complications of refractory status epilepticus.
In an 11-year-old boy (patient 6) with developmental and epileptic encephalopathy-98 (DEE98; 619605), Vetro et al. (2021) identified a de novo heterozygous c.2723G-A transition (c.2723G-A, NM_000702.3) in the ATP1A2 gene, resulting in an arg908-to-gln (R908Q) substitution at a conserved residue. In vitro functional expression studies showed that the variant was able to support COS1 cell survival in growth culture. However, the pump activity at the membrane was decreased to about 22% of controls due to reduced Na+/(K+)ATPase turnover rate. The patient had onset of focal seizures at 8 years of age. He had moderate developmental delay with hypotonic quadriparesis; brain imaging showed polymicrogyria with thick corpus callosum. Vetro et al. (2021) noted that a heterozygous R908Q mutation had been reported in patients with familial hemiplegic migraine-2 (FHM2; 602481) (see, e.g., De Vries et al., 2007), indicating that the same mutation may have different phenotypic consequences.
In a Brazilian boy with a phenotype reminiscent of alternating hemiplegia of childhood-1 (AHC1; 104290), Sampedro Castaneda et al. (2018) identified a de novo heterozygous c.2336G-A transition in the ATP1A2 gene, resulting in a ser779-to-asn (S779N) substitution at a conserved residue in an ion-binding site. The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis. The patient developed episodic tetraparesis at age 2 years. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. The symptoms improved with potassium, but worsened with acetazolamide. Sampedro Castaneda et al. (2018) noted the phenotypic similarities to hypokalemic periodic paralysis (see 170400) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations.
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