Temperature instability of a mutation at a multidomain junction in Na,K-ATPase isoform ATP1A3 (p.Arg756His) produces a fever-induced neurological syndrome

Arystarkhova, Elena; Toustrup-Jensen, Mads S.; Holm, Rikke; Ko, Jae‐Woong; Lee, Jun Young; Feschenko, Polina; Ozelius, Laurie J.; Brashear, Allison; Vilsen, Bente; Sweadner, Kathleen J.

doi:10.1016/j.jbc.2022.102758

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Our data also suggested that the expression of the p.R756C variant of ATP1A3 was unstable in Neuro2a cells and iPSCs exposed to heat stress. This finding is consistent with recent data showing that the p.R756H variant has temperature instability in terms of both protein expression and ATPase activity in cultured cells ( Arystarkhova et al, 2023 ). Besides the heat instability of the p.R756H protein, Snow et al (2020) reported that both iPSC-derived neurons and knock-in mice expressing the p.E815K protein recapitulated severe phenotypes of patients with an identical variant in ATP1A3 .…”

Section: Discussionsupporting

confidence: 93%

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress

Fujii,

Kanemasa,

Okuzono

et al. 2024

Disease Models &Amp; Mechanisms

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Pathogenic variants in ATP1A3, the α3 subunit of the Na+/K+-ATPase-encoding gene, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerating symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as EIF4G, PABPC1 and FMRP. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C-variant ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 and increased susceptibility to heat stress. In agreement with these findings, iPSCs from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient's iPSCs showed lower calcium influxes in responses to stimulation with ATP than controls. These data indicated that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes of patients with the p.R756C variant among a variety of ATP1A3-related disorders.

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Section: Discussionsupporting

confidence: 93%

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress

Fujii,

Kanemasa,

Okuzono

et al. 2024

Disease Models &Amp; Mechanisms

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“…The p.(Arg763Leu) variant is assumed to possibly also impair interdomain hydrogen bond networks, but some pump activity is likely to be retained. In addition, it has been reported that the p.Arg756Cys, p.Arg756His and p.Arg756Leu variants in ATP1A3 , affecting homologous arginine residue (Figure S1c), caused fever‐induced encephalopathy (Arystarkhova et al, 2023). Among these ATP1A3 mutants, functional analyses using p.Arg756His mutant have showed significant reduction of ion‐pump activity at normal temperature and increment of the temperature dependent‐inactivation rate more than 100‐fold compared to that of WT in the absence of added Na + and K + .…”

Section: Discussionmentioning

confidence: 98%

Novel compound heterozygous ATP1A2 variants in a patient with fetal akinesia/hypokinesia sequence

Furukawa,

Kato,

Nomura

et al. 2023

American J of Med Genetics Pt A

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ATP1A2 encodes a subunit of sodium/potassium‐transporting adenosine triphosphatase (Na+/K+‐ATPase). Heterozygous pathogenic variants of ATP1A2 cause familial hemiplegic migraine, alternating hemiplegia of childhood, and developmental and epileptic encephalopathy. Biallelic loss‐of‐function variants in ATP1A2 lead to fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, resulting in fetal death. Here, we describe a patient with compound heterozygous ATP1A2 variants consisting of missense and nonsense variants. He survived after birth with brain malformations and the fetal akinesia/hypokinesia sequence. We report a novel type of compound heterozygous variant that might extend the disease spectrum of ATP1A2.

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“…The p.R756H variant enzyme functions at about half the wildtype enzymatic turnover rate at 37°C, but disappears from the cell surface and loses enzymatic activity at 39°C. 13 …”

Section: Discussionmentioning

confidence: 99%

“…Because episodes can involve symmetric weakness and/or ataxia, this has been referred to as relapsing encephalopathy with cerebellar ataxia (RECA) or fever-induced paroxysmal weakness and encephalopathy (FIPWE). 13 , 14 This phenotype can overlap with other ATP1A3 -related conditions such as AHC and CAPOS in which febrile illness or temperature changes can also trigger encephalopathy. However, patients with those conditions typically have other, more prominent features, such as more frequent episodes of asymmetric movement disorders and greater nonparoxysmal neurologic impairment in AHC, or the titular features of CAPOS syndrome.…”

Section: Introductionmentioning

confidence: 99%

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ATP1A3 Disease Spectrum Includes Paroxysmal Weakness and Encephalopathy Not Triggered by Fever

Immanneni,

Calame,

Jiao

et al. 2024

Neurol Genet

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Background and Objectives Heterozygous pathogenic variants in ATP1A3 , which encodes the catalytic alpha subunit of neuronal Na + /K + -ATPase, cause primarily neurologic disorders with widely variable features that can include episodic movement deficits. One distinctive presentation of ATP1A3 -related disease is recurrent fever-triggered encephalopathy. This can occur with generalized weakness and/or ataxia and is described in the literature as relapsing encephalopathy with cerebellar ataxia. This syndrome displays genotype-phenotype correlation with variants at p.R756 causing temperature sensitivity of ATP1A3. We report clinical and in vitro functional evidence for a similar phenotype not triggered by fever but associated with protein loss-of-function. Methods We describe the phenotype of an individual with de novo occurrence of a novel heterozygous ATP1A3 variant, NM_152296.5:c.388_390delGTG; p.(V130del). We confirmed the pathogenicity of p.V130del by cell survival complementation assay in HEK293 cells and then characterized its functional impact on enzymatic ion transport and extracellular sodium binding by two-electrode voltage clamp electrophysiology in Xenopus oocytes. To determine whether variant enzymes reach the cell surface, we surface-biotinylated oocytes expressing N-tagged ATP1A3. Results The proband is a 7-year-old boy who has had 2 lifetime episodes of paroxysmal weakness, encephalopathy, and ataxia not triggered by fever. He had speech regression and intermittent hand tremors after the second episode but otherwise spontaneously recovered after episodes and is at present developmentally appropriate. The p.V130del variant was identified on clinical trio exome sequencing, which did not reveal any other variants possibly associated with the phenotype. p.V130del eliminated ATP1A3 function in cell survival complementation assay. In Xenopus oocytes, p.V130del variant Na + /K + -ATPases showed complete loss of ion transport activity and marked abnormalities of extracellular Na + binding at room temperature. Despite this clear loss-of-function effect, surface biotinylation under the same conditions revealed that p.V130del variant enzymes were still present at the oocyte's cell membrane. Discussion This individual's phenotype expands the clinical spectrum of ATP1A3 -related recurrent encephalopathy to include presentations without fever-triggered events. The total loss of ion transport function with p.V130del, despite enzyme presence at the cell membrane, indicates that haploinsufficiency can cause relatively mild phenotypes in ATP1A3 -related disease.

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Temperature instability of a mutation at a multidomain junction in Na,K-ATPase isoform ATP1A3 (p.Arg756His) produces a fever-induced neurological syndrome

Cited by 7 publications

References 53 publications

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress

Novel compound heterozygous ATP1A2 variants in a patient with fetal akinesia/hypokinesia sequence

ATP1A3 Disease Spectrum Includes Paroxysmal Weakness and Encephalopathy Not Triggered by Fever

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