8x90

Structural highlights

Disease

CAC1A_HUMAN Defects in CACNA1A are the cause of spinocerebellar ataxia type 6 (SCA6) [MIM:183086. Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA6 is mainly caused by expansion of a CAG repeat in the coding region of CACNA1A. There seems to be a correlation between the repeat number and earlier onset of the disorder.^{[1] [2] [3] [4] [5]} Defects in CACNA1A are the cause of familial hemiplegic migraine type 1 (FHM1) [MIM:141500; also known as migraine familial hemiplegic 1 (MHP1). FHM1, a rare autosomal dominant subtype of migraine with aura, is associated with ictal hemiparesis and, in some families, progressive cerebellar atrophy.^{[6] [7] [8] [9] [10] [11]} Defects in CACNA1A are the cause of episodic ataxia type 2 (EA2) [MIM:108500; also known as acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (APCA). EA2 is an autosomal dominant disorder characterized by acetozolamide-responsive attacks of ataxia, migraine-like symptoms, interictal nystagmus, and cerebellar atrophy.^{[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]}

Function

CAC1A_HUMAN Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by the funnel toxin (Ftx) and by the omega-agatoxin-IVA (omega-Aga-IVA). They are however insensitive to dihydropyridines (DHP), and omega-conotoxin-GVIA (omega-CTx-GVIA).

References

1. ↑ Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997 Jan;15(1):62-9. PMID:8988170 doi:10.1038/ng0197-62
2. ↑ Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet. 1997 Nov;61(5):1078-87. PMID:9345107 doi:10.1086/301613
3. ↑ Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff RA, Frants RR, Frontali M. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet. 1997 Oct;6(11):1973-8. PMID:9302278
4. ↑ Tonelli A, D'Angelo MG, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi AC, Bresolin N, Bassi MT. Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. J Neurol Sci. 2006 Feb 15;241(1-2):13-7. Epub 2005 Dec 2. PMID:16325861 doi:10.1016/j.jns.2005.10.007
5. ↑ Romaniello R, Zucca C, Tonelli A, Bonato S, Baschirotto C, Zanotta N, Epifanio R, Righini A, Bresolin N, Bassi MT, Borgatti R. A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation. J Neurol Neurosurg Psychiatry. 2010 Aug;81(8):840-3. doi:, 10.1136/jnnp.2008.163402. PMID:20682717 doi:10.1136/jnnp.2008.163402
6. ↑ Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543-52. PMID:8898206
7. ↑ Carrera P, Piatti M, Stenirri S, Grimaldi LM, Marchioni E, Curcio M, Righetti PG, Ferrari M, Gelfi C. Genetic heterogeneity in Italian families with familial hemiplegic migraine. Neurology. 1999 Jul 13;53(1):26-33. PMID:10408532
8. ↑ Kors EE, Terwindt GM, Vermeulen FL, Fitzsimons RB, Jardine PE, Heywood P, Love S, van den Maagdenberg AM, Haan J, Frants RR, Ferrari MD. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol. 2001 Jun;49(6):753-60. PMID:11409427
9. ↑ Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser MG, Tournier-Lasserve E. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med. 2001 Jul 5;345(1):17-24. PMID:11439943 doi:10.1056/NEJM200107053450103
10. ↑ Alonso I, Barros J, Tuna A, Seixas A, Coutinho P, Sequeiros J, Silveira I. A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q-type calcium-channel alpha-subunit in a family with progressive cerebellar ataxia and hemiplegic migraine. Clin Genet. 2004 Jan;65(1):70-2. PMID:15032980 doi:10.1111/j.2004.00187.x
11. ↑ Stam AH, Vanmolkot KR, Kremer HP, Gartner J, Brown J, Leshinsky-Silver E, Gilad R, Kors EE, Frankhuizen WS, Ginjaar HB, Haan J, Frants RR, Ferrari MD, van den Maagdenberg AM, Terwindt GM. CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. Clin Genet. 2008 Nov;74(5):481-5. doi: 10.1111/j.1399-0004.2008.00996.x. Epub, 2008 Apr 8. PMID:18400034 doi:10.1111/j.1399-0004.2008.00996.x
12. ↑ Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff RA, Frants RR, Frontali M. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet. 1997 Oct;6(11):1973-8. PMID:9302278
13. ↑ Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543-52. PMID:8898206
14. ↑ Friend KL, Crimmins D, Phan TG, Sue CM, Colley A, Fung VS, Morris JG, Sutherland GR, Richards RI. Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Hum Genet. 1999 Sep;105(3):261-5. PMID:10987655
15. ↑ Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E. Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001 Feb;58(2):292-5. PMID:11176968
16. ↑ Jen J, Wan J, Graves M, Yu H, Mock AF, Coulin CJ, Kim G, Yue Q, Papazian DM, Baloh RW. Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology. 2001 Nov 27;57(10):1843-8. PMID:11723274
17. ↑ van den Maagdenberg AM, Kors EE, Brunt ER, van Paesschen W, Pascual J, Ravine D, Keeling S, Vanmolkot KR, Vermeulen FL, Terwindt GM, Haan J, Frants RR, Ferrari MD. Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene. J Neurol. 2002 Nov;249(11):1515-9. PMID:12420090 doi:10.1007/s00415-002-0860-8
18. ↑ Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP. Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol. 2004 Aug;56(2):213-20. PMID:15293273 doi:10.1002/ana.20169
19. ↑ Mantuano E, Veneziano L, Spadaro M, Giunti P, Guida S, Leggio MG, Verriello L, Wood N, Jodice C, Frontali M. Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Ca(v)2.1 causing episodic ataxia 2. J Med Genet. 2004 Jun;41(6):e82. PMID:15173248
20. ↑ Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology. 2004 Jan 13;62(1):17-22. PMID:14718690
21. ↑ Zafeiriou DI, Lehmann-Horn F, Vargiami E, Teflioudi E, Ververi A, Jurkat-Rott K. Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation. Eur J Paediatr Neurol. 2009 Mar;13(2):191-3. doi: 10.1016/j.ejpn.2008.02.011., Epub 2008 Jul 3. PMID:18602318 doi:10.1016/j.ejpn.2008.02.011
22. ↑ Cuenca-Leon E, Banchs I, Serra SA, Latorre P, Fernandez-Castillo N, Corominas R, Valverde MA, Volpini V, Fernandez-Fernandez JM, Macaya A, Cormand B. Late-onset episodic ataxia type 2 associated with a novel loss-of-function mutation in the CACNA1A gene. J Neurol Sci. 2009 May 15;280(1-2):10-4. doi: 10.1016/j.jns.2009.01.005. Epub, 2009 Feb 20. PMID:19232643 doi:10.1016/j.jns.2009.01.005
23. ↑ Mantuano E, Romano S, Veneziano L, Gellera C, Castellotti B, Caimi S, Testa D, Estienne M, Zorzi G, Bugiani M, Rajabally YA, Barcina MJ, Servidei S, Panico A, Frontali M, Mariotti C. Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. J Neurol Sci. 2010 Apr 15;291(1-2):30-6. doi: 10.1016/j.jns.2010.01.010. Epub, 2010 Feb 2. PMID:20129625 doi:10.1016/j.jns.2010.01.010
24. ↑ Nikaido K, Tachi N, Ohya K, Wada T, Tsutsumi H. New mutation of CACNA1A gene in episodic ataxia type 2. Pediatr Int. 2011 Jun;53(3):415-6. doi: 10.1111/j.1442-200X.2011.03390.x. PMID:21696515 doi:10.1111/j.1442-200X.2011.03390.x