Biomedical papers, 2017 (vol. 161), issue 1

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017, 161(1):107-110 | 10.5507/bp.2016.066

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

Andrea Petrovicovaa, Miroslav Brozmana, Egon Kurcab, Tibor Goboa, Jana Dluhab, Klaudia Kalmarovab, Vladimir Nosalb, Martina Hikkelovac, Adriana Krajciovac, Tatiana Burjanivovad, Stefan Sivakb
a Department of Neurology, Faculty Hospital, Constantine Philosopher University, Spitalska 6, 94901 Nitra, Slovak Republic
b Clinic of Neurology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Kollarova 2, 03659 Martin, Slovak Republic
c Alphamedical, s.r.o, Laboratory of Medical Genetics, Radlinskeho 9, 81000 Bratislava,
d Department of Molecular Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4b, 03659 Martin, Slovak Republic

Introduction: Episodic ataxias (EAs) are rare dominantly inherited neurological disorders characterized by recurrent episodes of ataxia lasting minutes to hours. The most common subtype is EA type 2 (EA2) caused by pathogenic variants of calcium voltage-gated channel subunit alpha1 A gene (CACNA1A) on chromosome 19p13.

Subjects and Methods: We examined a Slovak three-generation family. Genomic DNA of the family members was extracted from peripheral blood and amplified by polymerase chain reaction. CACNA1A variants were screened by Sanger sequencing.

Results: We identified four family members with recurrent episodes of ataxia. Complex differential diagnosis was performed. Genetic analysis with direct sequencing revealed a novel heterozygous variant of CACNA1A - c.5264A>G (p.Glu1755Gly) located in the pore loop of domain IV of calcium channel alpha-1A subunit.

Conclusion: We identified a novel missense variant of a voltage-dependent P/Q-type calcium channel alpha-1A subunit in a Slovak three-generation family with recurrent episodes of ataxia. The heterozygous missense variant resulted in changing a highly conserved glutamic acid within the pore loop of domain IV.

Keywords: episodic ataxia type 2, novel variant, CACNA1A, pore loop

Received: July 1, 2016; Accepted: December 20, 2016; Prepublished online: January 13, 2017; Published: March 27, 2017


References

  1. Conroy J, McGettigan P, Murphy R, Webb D, Murphy SM, McCoy B, Albertyn C, McCreary D, McDonagh C, Walsh O, Lynch S, Ennis S. A novel locus for episodic ataxia:UBR4 the likely candidate. Eur J Hum Genet 2014;22(4):505-10. Go to original source... Go to PubMed...
  2. 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;87(3):543-52. Go to original source... Go to PubMed...
  3. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods 2010;7(4):248-9. Go to original source... Go to PubMed...
  4. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014;11(4):361-2. Go to original source... Go to PubMed...
  5. Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch TP, Catterall WA. Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci 1995;15(10):6403-18. Go to PubMed...
  6. Nachbauer W, Nocker M, Karner E, Stankovic I, Unterberger I, Eigentler A, Schneider R, Poewe W, Delazer M, Boesch S. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J Neurol 2014;261(5):983-91. Go to original source... Go to PubMed...
  7. 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;87(3):543-52. Go to original source... Go to PubMed...
  8. 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;15(1):62-9. Go to original source... Go to PubMed...
  9. Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 2001;358(9284):801-7. Go to original source... Go to PubMed...
  10. 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;57(10):1843-8. Go to original source... Go to PubMed...
  11. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 2011;3(8):a003947. Go to original source... Go to PubMed...
  12. 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;41(6):e82. Go to original source... Go to PubMed...
  13. 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;249(11):1515-9. Go to original source... Go to PubMed...
  14. Wan J, Khanna R, Sandusky M, Papazian DM, Jen JC, Baloh RW. CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology 2005;64(12):2090-7. Go to original source... Go to PubMed...
  15. Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology 2004;62(1):17-22. Go to original source... Go to PubMed...
  16. 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;61(5):1078-87. Go to original source... Go to PubMed...
  17. Bürk K, Kaiser FJ, Tennstedt S, Schöls L, Kreuz FR, Wieland T, Strom TM, Büttner T, Hollstein R, Braunholz D, Plaschke J, Gillessen-Kaesbach G, Zühlke C. A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression. Eur J Med Genet 2014;57(5):207-11. Go to original source... Go to PubMed...
  18. Cuenca-León E, Banchs I, Serra SA, Latorre P, Fernàndez-Castillo N, Corominas R, Valverde MA, Volpini V, Fernández-Fernández 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;280(1-2):10-4. Go to original source... Go to PubMed...
  19. 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;345(1):17-24. Go to original source... Go to PubMed...
  20. Geerlings RP, Koehler PJ, Haane DY, Stam AH, de Vries B, Boon EM, Haan J. Head tremor related to CACNA1A mutations. Cephalalgia 2011;31(12):1315-9. Go to original source... Go to PubMed...
  21. Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E. Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol 2001;58(2):292-5. Go to original source... Go to PubMed...
  22. 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;53(1):26-33. Go to original source... Go to PubMed...
  23. 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;56(2):213-20. Go to original source... Go to PubMed...
  24. Bertholon P, Chabrier S, Riant F, Tournier-Lasserve E, Peyron R. Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood. J Neurol Neurosurg Psychiatry 2009;80(11):1289-92. Go to original source... Go to PubMed...
  25. Bain PG, O'Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol 1992;31(2):147-54. Go to original source... Go to PubMed...