Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A

Imbrici, Paola; Eunson, Louise H; Graves, Tracey D.; Bhatia, KP; Wadia, N. H.; Kullmann, Dimitri M.; Hanna, Michael G.

doi:10.1212/01.wnl.0000176069.64200.28

Cited by 54 publications

(43 citation statements)

References 10 publications

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“…In fact, a dominant negative effect of several missense and truncation mutants was found when the EA2 mutations were inserted in certain Ca V 2.1 isoforms, including a human Ca V 2.1 with a long C terminus [52,54,93], but not when they were inserted in a human Ca V 2.1 with a short C terminus [35,42,43,52,140]. Moreover, oocytes expressing short human Ca V 2.1 channels carrying four different EA2 mutations, including two mutations that in mammalian cells led to complete loss of function of the channel [139,140], displayed a measurable (although strongly reduced) Ca 2+ current [42,43,140]. Differences in the ER retention and cellular degradative capacities between oocytes and mammalian cells likely explain the different loss-of-function and dominant negative effects of EA2 mutants in the two expression systems.…”

Section: Functional Consequences Of Ea2 Mutations On Recombinant Humamentioning

confidence: 99%

CaV2.1 channelopathies

Pietrobon

2010

Pflugers Arch - Eur J Physiol

196

194

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Mutations in the CACNA1A gene that encodes the pore-forming alpha1 subunit of human voltage-gated CaV2.1 (P/Q-type) Ca2+ channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). For each channelopathy, the review describes the disease phenotype as well as the functional consequences of the disease-causing mutations on recombinant human CaV2.1 channels and, in the case of FHM1 and SCA6, on neuronal CaV2.1 channels expressed at the endogenous physiological level in knockin mouse models. The effects of FHM1 mutations on cortical spreading depression, the phenomenon underlying migraine aura, and on cortical excitatory and inhibitory synaptic transmission in FHM1 knockin mice are also described, and their implications for the disease mechanism discussed. Moreover, the review describes different ataxic spontaneous cacna1a mouse mutants and the important insights into the cerebellar mechanisms underlying motor dysfunction caused by mutant CaV2.1 channels that were obtained from their functional characterization.

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Section: Functional Consequences Of Ea2 Mutations On Recombinant Humamentioning

confidence: 99%

CaV2.1 channelopathies

Pietrobon

2010

Pflugers Arch - Eur J Physiol

196

194

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“…7,9 -11 Such late onset may be related to certain mutations, such as, for example, multiple-base pair insertions in CACNA1A. 12 Clinically, EA 2 is characterized by recurrent attacks of ataxia lasting for several hours to days, which are provoked by physical exertion, emotional stress, or alcohol. 9,13 Several patients also have mild myasthenic symptoms (due to impaired neuromuscular transmission; see below).…”

Section: Clinical Features Of Episodic Ataxia Typementioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

160

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Summary: Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca V 2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

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“…The Ca v 2.1 calcium channel subtype regulates neurotransmission throughout the nervous system, but is predominantly expressed within cerebellar Purkinje cells (Usowicz et al, 1992;Stea et al, 1994;Westenbroek et al, 1995). Not surprisingly, cerebellar dysfunction is the primary feature of EA2 attacks, as patients experience bouts of symptoms such as ataxia, migraine and vertigo, in response to Functional expression studies involving EA2 mutations have firmly established that non-or hypo-conductive α 1 2.1 subunits cause the disorder (Guida et al, 2001;Jen et al, 2001;Jouvenceau et al, 2001;Wappl et al, 2002;Imbrici et al, 2004;Spacey et al, 2004;Imbrici et al, 2005;Wan et al, 2005b;Jeng et al, 2006), which is largely but not exclusively associated with expression of α 1 2.1 truncation mutants (Ophoff et al, 1996;Yue et al, 1998;Battistini et al, 1999;Denier et al, 1999;Jen et al, 1999;Denier et al, 2001;van den Maagdenberg et al, 2002;Wappl et al, 2002;Subramony et al, 2003;Jen et al, 2004;Mantuano et al, 2004;Eunson et al, 2005;Spacey et al, 2005;Wan et al, 2005a;Wan et al, 2005b;Scoggan et al, 2006). However, the molecular mechanisms by which nonfunctional α 1 2.1 pores generate disease in EA2 are still debated.…”

Section: Introductionmentioning

confidence: 99%

“…However, the molecular mechanisms by which nonfunctional α 1 2.1 pores generate disease in EA2 are still debated. Although some studies have suggested that the loss of channel function in EA2 simply induces a haplo-insufficiency of Ca v 2.1 currents (Wappl et al, 2002;Imbrici et al, 2004;Imbrici et al, 2005), substantial evidence argues that non-conductive α 1 2.1 mutants in EA2 actually suppress the functional contributions of Ca v 2.1 channels composed of wild-type subunits through a dominantnegative mechanism (Jouvenceau et al, 2001;Raghib et al, 2001;Arikkath et al, 2002;Page et al, 2004;Jeng et al, 2006). Studies have suggested that impaired translation or stability of wild-type α 1 2.1 subunits contributes to EA2 pathogenesis (Raghib et al, 2001;Page et al, 2004), while other evidence implicates the interactions between non-conductive α 1 2.1 mutants and auxiliary β subunits in the dominant-negative suppression of wild-type α 1 2.1 subunit function (Arikkath et al, 2002;Jeng et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Dominant-negative suppression of Cav2.1 currents by α12.1 truncations requires the conserved interaction domain for β subunits

Raike

Kordasiewicz

Thompson

et al. 2007

Molecular and Cellular Neuroscience

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Episodic ataxia type 2 (EA2) is an autosomal dominant disorder arising from CACNA1A mutations, which commonly predict heterozygous expression of Ca v 2.1 calcium channels with truncated α 1 2.1 pore subunits. We hypothesized that α 1 2.1 truncations in EA2 exert dominantnegative effects on the function of wild-type subunits. Wild-type and truncated α 1 2.1 subunits with fluorescent-protein tags were transiently co-expressed in cells stably expressing Ca v auxiliary β subunits, which facilitate α 1 -subunit functional expression through high-affinity interactions with the alpha interaction domain (AID). Co-expression of wild-type subunits with truncations often resulted in severely reduced whole-cell currents compared to expression of wild-type subunits alone. Cellular image analyses revealed that current suppression was not due to reduced wild-type expression levels. Instead, the current suppression depended on truncations terminating distal to the AID. Moreover, only AID-bearing α 1 2.1 proteins co-immunoprecipitated with Ca v β subunits. These results indicate that Ca v β subunits may play a prominent role in EA2 disease pathogenesis.

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Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A

Cited by 54 publications

References 10 publications

CaV2.1 channelopathies

CaV2.1 channelopathies

Episodic Ataxia Type 2

Dominant-negative suppression of Cav2.1 currents by α12.1 truncations requires the conserved interaction domain for β subunits

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