Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission

Jen, Joanna C.; Wan, Jijun; Graves, Michael C.; Yu, Huimin; Mock, Allan F.; Coulin, Carola; Kim, G.; Yue, Qing; Papazian, Diane M.; Baloh, Robert W.

doi:10.1212/wnl.57.10.1843

Cited by 128 publications

(100 citation statements)

References 22 publications

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“…The CACNA1A gene mutations responsible for the EA2 and tottering phenotypes reduce current density from Ca v 2.1 channels (Wakamori et al, 1998;Guida et al, 2001;Jen et al, 2001;Jouvenceau et al, 2001;Wappl et al, 2002;Spacey et al, 2004), which are expressed abundantly in cerebellar Purkinje and granule cells (Stea et al, 1994;Tanaka et al, 1995;Volsen et al, 1995). This may result in a general reduction in Purkinje cell firing rates and loss of inhibition at the deep cerebellar nuclei.…”

Section: Discussionmentioning

confidence: 99%

“…EA2 and FHM are both caused by mutations in the CACNA1A gene, which encodes the pore-forming ␣ 1 2.1 subunit of Ca v 2.1 (P/Qtype) voltage-gated calcium channels (Ophoff et al, 1996). Functional expression studies of some FHM mutations and all EA2 mutations demonstrate reduced Ca v 2.1 currents (Guida et al, 2001;Jen et al, 2001;Jouvenceau et al, 2001;Wappl et al, 2002;Cao et al, 2004;Spacey et al, 2004), implicating decreased neuronal excitability in disease pathogenesis. Indeed, 4-aminopyridine (4-AP), a nonselective blocker of the K v family of voltage-gated potassium channels, increases Purkinje cell excitability (Etzion and Grossman, 2001) and prevents attacks in patients with EA2 (Strupp et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Weisz¹,

Raike²,

Soria-Jasso³

et al. 2005

J. Neurosci.

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Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the ␣ 1 2.1 subunit of Ca v 2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K v voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K v channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K v channels, reduced the frequency of restraint-and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K v channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K v channels. That both stress-and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Weisz¹,

Raike²,

Soria-Jasso³

et al. 2005

J. Neurosci.

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“…Most of the mutations are predicted to produce truncated ␣ 1 subunits with no significant channel activity by introducing a premature stop codon or leading to aberrant splicing. Single missense mutations can also result in the production of complete or partial loss-of-function subunits and these mutation sites are likely to be restricted to amino acid residues at transmembrane segments or loops known to be important for channel activity (7)(8)(9).…”

mentioning

confidence: 99%

Essential, Completely Conserved Glycine Residue in the Domain III S2–S3 Linker of Voltage-gated Calcium Channel α1 Subunits in Yeast and Mammals

Iida

Teng

Tada

et al. 2007

Journal of Biological Chemistry

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Voltage-gated Ca 2ϩ channels (VGCCs) 5 in the plasma membrane mediate the influx of Ca 2ϩ that serves as the second messenger of electrical signals to initiate many cellular events, including muscle contraction, neurotransmitter release, and gene expression (1). The pore-forming component of VGCCs is provided by the ␣ 1 subunit, a protein of about 2000 amino acid residues (2). This subunit contains four structurally conserved domains (I-IV), each of which contains six transmembrane segments (S1-S6) and a membrane-associated loop between S5 and S6 (called the pore loop or P-loop). The voltage sensitivity of VGCCs and structurally related cation channels is conveyed by the S4 segments, which contain several positively charged residues. S2 and S3 contain conserved negative charges that are likely to interact electrostatically with the positively charged residues of S4. The S5-P-loop-S6 region forms the pore domain (see Fig. 1).Mutations in the ␣ 1 subunits resulting in structural aberrations cause hereditary diseases (called Ca 2ϩ channelopathies) in mammals, such as incomplete congenital stationary night blindness, hypokalemic periodic paralysis, episodic ataxia type 2 and familial hemiplegic migraine in humans, and ataxia and seizures in mice (3-6). Most of the mutations are predicted to produce truncated ␣ 1 subunits with no significant channel activity by introducing a premature stop codon or leading to aberrant splicing. Single missense mutations can also result in the production of complete or partial loss-of-function subunits and these mutation sites are likely to be restricted to amino acid residues at transmembrane segments or loops known to be important for channel activity (7-9).A eukaryotic model organism, the yeast Saccharomyces cerevisiae, carries only one gene (designated CCH1) coding for a protein structurally homologous to the animal ␣ 1 subunits of VGCCs. Physiologically, the Cch1 protein is necessary for mating pheromone-induced Ca 2ϩ uptake (10 -13), store-operated Ca 2ϩ entry (14), endoplasmic reticulum stress-induced Ca 2ϩ uptake (15), and a hyperosmotic stressinduced increase in cytosolic Ca 2ϩ concentration (16).

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“…7 ), spinocerebellar ataxia type 6 (SCA6, MIM#183086) (ref. 8 ), epilepsy 9 , and myasthenic syndrome 10 . Alpha-1A subunit is a protein which consists of about 2500 amino acids.…”

Section: Discussionmentioning

confidence: 99%

Novel missense variant of CACNA1A gene in a Slovak family with episodic ataxia type 2

Petrovičová¹,

Brozman²,

Kurča³

et al. 2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission

Cited by 128 publications

References 22 publications

Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Essential, Completely Conserved Glycine Residue in the Domain III S2–S3 Linker of Voltage-gated Calcium Channel α1 Subunits in Yeast and Mammals

Novel missense variant of CACNA1A gene in a Slovak family with episodic ataxia type 2

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