ATP1A2 mutations in 11 families with familial hemiplegic migraine

Riant, Florence; Fusco, Maurizio De; Aridon, Paolo; Ducros, Anne; Ploton, Claire; Marchelli, Florence; Maciazek, Jacqueline; Bousser, Marie Germaine; Casari, Giorgio; Tournier‐Lasserve, Elisabeth

doi:10.1002/humu.9361

Cited by 88 publications

(78 citation statements)

References 15 publications

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“…Clinical variation and reduced penetrance in FHM2 families has been reported before. 10,11 In this respect, it is interesting to note that Todt et al 12 identified two ATP1A2 variations that are possibly involved in the susceptibility to common forms of migraine. Importantly, the patient described here shows that compound heterozygosity for ATP1A2 is compatible with life.…”

Section: Discussionmentioning

confidence: 99%

First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine

et al. 2007

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Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. This is the first case of compound heterozygosity for any of the known FHM genes.

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Section: Discussionmentioning

confidence: 99%

First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine

et al. 2007

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“…Intriguingly, inherited mutations of the ATPA2 gene associated with hemiplegic migraine have been mapped to the TM8-TM9 loop region (32,33). Indeed, a single-residue polymorphism R933P identified in these studies has been shown to dramatically disable the activity of the Na + /K + -ATPase (5,34,35).…”

Section: Molecular Mechanism Of Selectivity In Namentioning

confidence: 99%

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

Razavi

Delemotte

Berlin

et al. 2017

Journal of Biological Chemistry

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Na+ /K + -ATPase transports Na + and K + ions across the cell membrane via an ion-binding site becoming alternatively accessible to the intra-and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free energy perturbation approaches to identify probable protonation states of Na + and K + coordinating residues in E1P and E2P conformations of Na + /K + -ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na + -coordinating residue D926. This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion binding stoichiometry and selectivity. Na + /K + -ATPase is a membrane protein that actively transports sodium ions out of the cell while importing potassium ions, both against their electrochemical gradients, thus providing potential energy necessary for many essential cellular functions (1-3). Malfunction of Na + /K + -ATPase has been linked to numerous diseases including impaired memory and learning, familial hemiplegic migraine 2, rapid-onset dystonia Parkinsonism, and heart failure (4-6), thus, Na + /K + -ATPase is an important target for treatment of brain and heart conditions (7,8).By harnessing chemical energy stored in ATP, the Na + /K + -ATPase cycles between two major conformational states during active ion pumping: one state with high affinity for sodium ions (E1), and a second with high affinity for potassium ion (E2).While the complete mechanism of function of the Na Na+ /K + -ATPase and ion selectivity 2 more complicated, involving several conformational transitions described more fully in the Post-Albers scheme (9-11), here we focus on the sodium-bond E1P and potassium-bound E2P states (i.e. phosphorylated E1 and E2), for which crystal structures are available (12)(13)(14)(15)(16)(17). One of the central features of ion transport by the Na + /K + -ATPase is a change in ion selectivity between E1 and E2 conformations (3). The origin of this selectivity change has been a focus of Na + /K + -ATPase research since its discovery by Jens Christian Skou in 1957 (1). Extensive mutational studies have identified key residues involved in ion binding, which include five acidic residues: Asp804, Asp808, and Asp926, Glu327 and Glu779 (13) whose orientation, distance, and ion coordination have been proposed to be involved in determining selectivity (3). The first crystal structure of the Na + /K + -ATPase, solved for the potassium-bound E2P state in 2007 (15) and later followed by several higher resolution structures (14,16,17), revealed a ...

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“…2). 10,52,[63][64][65][66][67][68][69][70] All produce substitutions of conserved amino acids in important functional regions including the intracellular 4-5 loop, where…”

Section: Familial Hemiplegic Migraine Type 2 (Fhm2)mentioning

confidence: 99%

“…most of the mutations are located and the extracellular 7-8 loop, a domain responsible for ␤ subunit binding. 62 Two additional mutations associated with FHM2 are deletions, one in frame and one leading to a frameshift and a premature stop codon 67 (FIG. 2).…”

Section: Figmentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

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Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

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ATP1A2 mutations in 11 families with familial hemiplegic migraine

Cited by 88 publications

References 15 publications

First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine

First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

Familial Hemiplegic Migraine

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