A G301R Na+/K+-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs

Spadaro, M; Ursu, Simona; Lehmann‐Horn, Frank; Veneziano, Liana; Antonini, Giovanni; Giunti, Paola; Frontali, Marina; Jurkat‐Rott, Karin

doi:10.1007/s10048-005-0004-2

Cited by 41 publications

(69 citation statements)

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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%

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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“…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%

Familial Hemiplegic Migraine

2007

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“…The range of disease phenotypes produced by alleles at both of these FHM loci is quite broad, but clearly includes seizures and ataxia as well as migraine [1][2][3][4][5][10][11][12], with the FHM1 CACNA1A locus having alleles that cause a spectrum of diseases that include Episodic Ataxia type 2 (EA2), Spinocerebellar Ataxia type 6, as well as many individuals comorbid with FHM, ataxia or seizures. Likewise alleles at the FHM2 ATP1A2 locus cause a spectrum of diseases that includes comorbidity with Benign Familial Infantile Convulsions, and ataxia.…”

Section: Introductionmentioning

confidence: 99%

Novel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3

Gargus

Tournay

2007

Pediatric Neurology

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While the gene encoding the neuronal voltage-gated sodium channel, type 1A is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12 megabase disease-associated haplotype at the Familial Hemiplegic Migraine, type 3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. This report presents a family segregating the novel T1174S missense mutation of this gene detected in a heterozygous female child who presented with myoclonus and an abnormal EEG, and in her mother who has an ataxic migraine syndrome similar to that of her own mother. This threegeneration family exhibits the broad phenotypic spectrum of the dominant neuronal hyperexcitability syndromes produced by even a given allele of this sodium channel gene. It also exhibits the second allele of this sodium channel gene associated with a migraine syndrome similar to those caused at the two other Familial Hemiplegic Migraine loci, confirming that this gene itself, not some linked gene, is the Familial Hemiplegic Migraine, type 3 locus.

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“…The Na + /K + -ATPase carboxy-terminus has been highlighted as a critical structural element for voltage-dependence and interaction with cations. 10 In the present study, we analyze the molecular consequences of three additional ATP1A2 missense mutations, G301R 11 (FHM), R908Q 12 (SHM) and P979L 13 (FHM), by measuring stationary pump currents and transient currents in Xenopus laevis oocytes, and monitoring protein expression in these and in mammalian HEK293FT cells at different temperatures.…”

Section: Introductionmentioning

confidence: 99%

Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine

Tavraz

Dürr

Koenderink³

et al. 2009

Channels

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Mutations in three different genes have been implicated in familial hemiplegic migraine (FHM), two of them code for neuronal voltage-gated cation channels, CACNA1A and SCN1A, while the third encodes ATP1A2, the α 2 -isoform of the Na + / K + -ATPase's catalytic subunit, thus classifying FHM as an ion channel/ion transporter disorder. The Na + /K + -ATPase maintains the physiological gradients for Na + and K + ions and is therefore critical for the activity of ion channels and transporters involved in neurotransmitter uptake or Ca 2+ signaling. Diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations, which reach far beyond simple loss-of-function. We have shown recently that ATP1A2 mutations frequently lead to changes in the enzyme's voltage-dependent properties, kinetics or apparent cation affinities. Here, we present functional data on a so far uncharacterized set of ATP1A2 mutations (G301R, R908Q and P979L) upon expression in Xenopus oocytes and HEK293FT cells, and provide evidence for a novel pathophysiological mechanism. Whereas the G301R mutant was inactive, no functional changes were observed for mutants R908Q and P979L in the oocyte expression system. However, the R908Q mutant was less effectively expressed in the plasma membrane of oocytes, making it the first missense mutation to result in defective plasma membrane targeting. Notably, the P979L mutant exhibited the same cellular expression profile as the wild-type protein, both in Xenopus oocytes and in transfected HEK293FT cells grown at 28°C, but much less P979L protein was found upon cell growth at 37°C, showing for the first time that temperature-sensitive effects on protein stability can underlie ATP1A2 loss-of-function.

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A G301R Na+/K+-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs

Abstract: The authors would like to point out that a mistake occurred in the order of the names of the authors for the article "A G301R Na(+)/K(+)-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs, Neuroge

Cited by 41 publications

References 0 publications

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine

Novel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3

Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine

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