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Episodic ataxia, type 2; EA2

Disease ID:329
Name:Episodic ataxia, type 2; EA2
Associated with:1 target
Episodic ataxia | Familial paroxysmal ataxia
Database Links
Disease Ontology: DOID:963
OMIM: 108500
Orphanet: ORPHA97


Comments:  EA-2 genetic alterations are distributed throughout the channel, with a large number of missense and premature truncations identified within the pore-forming p-loops. EA-2 truncations and missense mutations consistently show a loss-of-function phenotype with a net reduction of available channels and calcium entry; depolarizing shift in V0.5,act, increased rate of inactivation, reduced rate of recovery from inactivation, and reduced current density proposed to be a result of fewer channels being properly folded and reaching the membrane. Some EA-2 mutations occur in mutually exclusive alternative exons thus CACNA1A differential splicing is likely to affect phenotypic expression. Other mutations appear to result in aberrant splicing.
References:  1,4,13
Mutations:  Cav2.1 is associated with 36 mutation. Click here for details


No ligand related data available for Episodic ataxia, type 2; EA2


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1. Adams PJ, Snutch TP. (2007) Calcium channelopathies: voltage-gated calcium channels. Subcell Biochem, 45: 215-51. [PMID:18193639]

2. Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, Castelnovo G, Deonna T, Gérard P, Devoize JL et al.. (1999) High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology, 52 (9): 1816-21. [PMID:10371528]

3. Friend KL, Crimmins D, Phan TG, Sue CM, Colley A, Fung VS, Morris JG, Sutherland GR, Richards RI. (1999) Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Hum Genet, 105 (3): 261-5. [PMID:10987655]

4. Graves TD, Imbrici P, Kors EE, Terwindt GM, Eunson LH, Frants RR, Haan J, Ferrari MD, Goadsby PJ, Hanna MG et al.. (2008) Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2. Neurobiol Dis, 32 (1): 10-5. [PMID:18606230]

5. Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, Fellin T, Spadaro M, Stauderman K, Williams M et al.. (2001) Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet, 68 (3): 759-64. [PMID:11179022]

6. Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C, Robertson R, Kullmann DM, Hanna MG. (2004) Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain, 127 (Pt 12): 2682-92. [PMID:15483044]

7. Jen J, Kim GW, Baloh RW. (2004) Clinical spectrum of episodic ataxia type 2. Neurology, 62 (1): 17-22. [PMID:14718690]

8. Jen J, Wan J, Graves M, Yu H, Mock AF, Coulin CJ, Kim G, Yue Q, Papazian DM, Baloh RW. (2001) Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology, 57 (10): 1843-8. [PMID:11723274]

9. Jen J, Yue Q, Nelson SF, Yu H, Litt M, Nutt J, Baloh RW. (1999) A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. Neurology, 53 (1): 34-7. [PMID:10408533]

10. Jeng CJ, Chen YT, Chen YW, Tang CY. (2006) Dominant-negative effects of human P/Q-type Ca2+ channel mutations associated with episodic ataxia type 2. Am J Physiol, Cell Physiol, 290 (4): C1209-20. [PMID:16306128]

11. Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG. (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet, 358 (9284): 801-7. [PMID:11564488]

12. Kipfer S, Jung S, Lemke JR, Kipfer-Kauer A, Howell JP, Kaelin-Lang A, Nyffeler T, Gutbrod K, Abicht A, Müri RM. (2013) Novel CACNA1A mutation(s) associated with slow saccade velocities. J Neurol, 260 (12): 3010-4. [PMID:24046065]

13. Mantuano E, Romano S, Veneziano L, Gellera C, Castellotti B, Caimi S, Testa D, Estienne M, Zorzi G, Bugiani M et al.. (2010) Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. J Neurol Sci, 291 (1-2): 30-6. [PMID:20129625]

14. Mantuano E, Veneziano L, Spadaro M, Giunti P, Guida S, Leggio MG, Verriello L, Wood N, Jodice C, Frontali M. (2004) Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Ca(v)2.1 causing episodic ataxia 2. J Med Genet, 41 (6): e82. [PMID:15173248]

15. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M et al.. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell, 87 (3): 543-52. [PMID:8898206]

16. Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP. (2004) Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol, 56 (2): 213-20. [PMID:15293273]

17. Spacey SD, Materek LA, Szczygielski BI, Bird TD. (2005) Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. Arch Neurol, 62 (2): 314-6. [PMID:15710862]

18. Tonelli A, D'Angelo MG, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi AC, Bresolin N, Bassi MT. (2006) Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. J Neurol Sci, 241 (1-2): 13-7. [PMID:16325861]

19. van den Maagdenberg AM, Kors EE, Brunt ER, van Paesschen W, Pascual J, Ravine D, Keeling S, Vanmolkot KR, Vermeulen FL, Terwindt GM et al.. (2002) Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene. J Neurol, 249 (11): 1515-9. [PMID:12420090]

20. Wan J, Khanna R, Sandusky M, Papazian DM, Jen JC, Baloh RW. (2005) CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology, 64 (12): 2090-7. [PMID:15985579]

21. Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, Groschner K, Glossmann H, Kraus RL, Grabner M et al.. (2002) Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem, 277 (9): 6960-6. [PMID:11742003]

22. Yue Q, Jen JC, Nelson SF, Baloh RW. (1997) Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet, 61 (5): 1078-87. [PMID:9345107]