Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition

Arystarkhova, Elena; Haq, Ihtsham; Luebbert, Timothy; Mochel, Fanny; Saunders‐Pullman, Rachel; Bressman, Susan; Feschenko, Polina; Salazar, Cynthia; Cook, Jared; Demarest, Scott; Brashear, Allison; Ozelius, Laurie J.; Sweadner, Kathleen J.

doi:10.1016/j.nbd.2019.104577

Cited by 36 publications

(66 citation statements)

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“…In silico pathogenicity predictions for p.Gln851Arg, p.Arg901Met, p.Leu924Pro, and c.2921+1G>A suggest these variants are likely deleterious and disease causing ( Table S1 ). Two amino acid substitutions reported here, Leu924Pro and Gln851Arg, were previously associated with EIEE and AHC without MCD(Arystarkhova et al, 2019; Masoud et al, 2017), further supporting the wide spectrum of ATP1A3 phenotypes resulting from single amino acid variants ( Table S3 ). Leu924Pro pathogenicity was also demonstrated to affect ATPase trafficking to the plasma membrane, categorized functionally as loss-of-function (LOF), or viewed as a toxic gain-of-function effect.…”

Section: Resultssupporting

confidence: 80%

“…Leu924Pro pathogenicity was also demonstrated to affect ATPase trafficking to the plasma membrane, categorized functionally as loss-of-function (LOF), or viewed as a toxic gain-of-function effect. (Arystarkhova et al, 2019) Together, the conservation of nucleotides and absence of variants in population databases suggests these PMG ATP1A3 alleles are likely pathogenic.…”

Section: Resultsmentioning

confidence: 99%

“…( C) Overview of genotype-phenotype correlation of ATP1A3 associated disease single nucleotide variants, phenotypes were grouped by primary symptomatic presentation: including early infantile epileptic encephalopathy (EIEE); alternating hemiplegia of childhood (ACH); cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS); rapid-onset dystonia-parkinsonism (RDP); and childhood onset schizophrenia (COS), and/or a cortical malformation syndrome (MCD+), cerebellar ataxia (CA). Alleles from several sources including(Arystarkhova et al, 2019; Brashear et al, 1993; Holm et al, 2016; Sweadner et al, 2019). See supplemental Figure S7 and Table S3 for complete allele to protein topology breakdown.…”

Section: Resultsmentioning

confidence: 99%

“…These diseases include (in approximate order of onset in childhood development): early infantile epileptic encephalopathy (EIEE); alternating hemiplegia of childhood (ACH); cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS); childhood onset schizophrenia (COS); and rapid-onset dystonia-parkinsonism (RDP)(Brashear et al, 1993; Smedemark-Margulies et al, 2016). Variants in ATP1A3 associated with these postnatal diseases are generally categorized as heterozygous loss-of-function single nucleotide variants(Arystarkhova et al, 2019; Holm et al, 2016) which, among other deficits, have been shown to lead to depolarized Vm, such as in neurons from AHC patients(Simmons et al, 2018). During development, bioelectric changes can dramatically alter both intrinsic trajectories of individual cells(Levin et al, 2017) and cortical lamination more broadly(Hurni et al, 2017; Vitali et al, 2018), suggesting that bioelectric alterations in early brain development could in part contribute to subsequent ATP1A3- related neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

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Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Smith

Florio

Akula

et al. 2020

Preprint

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Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function that is catalyzed by the Na,K-ATPase alpha subunit. In vertebrates, four paralogous genes, ATP1A1-4, encode distinct alpha subunit isoforms (a1-a4), three of which (a1, a2, a3) are expressed in the brain, and two (a1, a3) predominantly in neurons. The a3 isoform, encoded by ATP1A3, is critical to neuronal physiology, and a growing spectrum of neurological diseases are associated with ATP1A3 pathogenic variants, with ages of onset ranging from early childhood to adulthood. Here, we describe ATP1A3 variants encoding dysfunctional a3 subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we established a transcriptional atlas of ATP1A3 expression during cortical development using mRNA in situ hybridization and transcriptomic profiling of ~125,000 individual cells with single-cell RNA sequencing (Drop-Seq) from various areas of the midgestational human neocortex. We find that fetal expression of ATP1A3 is restricted to a subset of excitatory neurons carrying transcriptional signatures of neuronal activity and maturation characteristic of the developing subplate. Furthermore, by performing Drop-Seq on ~52,000 nuclei from four different areas of an infant human neocortex, we show that ATP1A3 expression persists throughout early postnatal development, not only within excitatory neurons across all cortical layers, but also and more predominantly in inhibitory neurons, with specific enrichment in fast-spiking basket cells. In addition, we show that ATP1A3 expression, both in fetal and postnatal neurons, tends to be higher in frontal cortical areas than in occipital areas, in a pattern consistent with the rostro-caudal maturation gradient of the human neocortex. Finally, we discover distinct co-expression patterns linking catalytic α subunit isoforms (ATP1A1,2,3) and auxiliary isoforms (ATP1B1,2,3), suggesting the ATPase pump may form non-redundant, cell-type specific α-β combinations. Together, the importance of the developmental phenotypes and dynamic expression patterns of ATP1A3 point to a key role for a3 in the development and function of human cortex.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Smith

Florio

Akula

et al. 2020

Preprint

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“…77 Moreover, in a very recent study (2019), Arystarkhova et al point out that severity of phenotype cannot be explained solely by reduction of pump activity and other cellular mechanisms are hypothesized from experimental data, including misfolding protein at Golgi apparatus level and consequent ratio between good and bad alleles, by competition. 78…”

Section: Cellular Studiesmentioning

confidence: 99%

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Capuano¹,

Garone²,

Tiralongo³

et al. 2020

TACG

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Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na + / K + ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p. Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na + /K + ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.

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Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump

Fedosova

Habeck

Nissen

2021

Comprehensive Physiology

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Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition

Cited by 36 publications

References 66 publications

Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump

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Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition

Cited by 36 publications

References 66 publications

Role for the Na+/K+ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Role for the Na+/K+ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump

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Product

Resources

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Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Role for the Na⁺/K⁺ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex