Calcium Channels/genetics; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Migraine with Aura/genetics; Polymorphism, Single Nucleotide
Abstract :
[en] Migraine is a common disorder with a significant genetic component. Mutations in the CACNA1A gene are found in hemiplegic migraine (HM). Basilar-type (BM), another subtype of migraine with aura, differs from HM only by the absence of motor deficits. BM and HM may thus share common genetic features. In the present study, two single nucleotide polymorphisms (SNPs) of the CACNA1A gene were characterized in a population of migraine patients and healthy controls. The polymorphisms, E918D, predicting a glutamic acid-to-aspartic acid substitution at codon 918 and E993V, predicting a glutamic acid-to-valine substitution at codon 993, were frequently detected among patients and controls. Seven BM, 10 SHM, 5 FHM, 57 migraine with typical aura, 32 migraine without aura patients and 107 healthy controls were screened. The E918D and E993V SNPs were found in 30/117 (25.6%) and 32/117 (27.3%) migraine patients, respectively. The prevalence of these SNPs taken separately was not significantly different from that of control subjects (n=28/107, 26.2% for E918D; n=29/107 for E993V, 27.1%) neither for the total migraine population nor for the various migraine subtypes. By contrast, coexistence of both SNPs was more frequent in migraineurs (25/117, 21%) than in healthy controls (12/107, 11%; p=0.048), a difference that was significant for every migraine subtype. This result suggests that the interplay of minor genetic variants such as single nucleotide polymorphisms may influence the P/Q-type calcium channel function in several subtypes of migraine.
Disciplines :
Neurology
Author, co-author :
D'Onofrio, Mara
Ambrosini, Anna
Di Mambro, Alessandra
Arisi, Ivan
Santorelli, Filippo M
Grieco, Gaetano S
Nicoletti, Ferdinando
Nappi, Giuseppe
Pierelli, Francesco
Schoenen, Jean ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Neuro-anatomie
Buzzi, Maria Gabriella
Language :
English
Title :
The interplay of two single nucleotide polymorphisms in the CACNA1A gene may contribute to migraine susceptibility.
Ambrosini A., D'Onofrio M., Grieco G.S., Di Mambro A., Montagna G., Fortini D., Nicoletti F., Nappi G., Sances G., Schoenen J., Buzzi M.G., Santorelli F.M., and Pierelli F. Familial basilar-type migraine associated with a new mutation in the ATP1A2 gene. Neurology 65 (2005) 1826-1828
Ayata C., Jin H., Kudo C., Dalkara T., and Moskowitz M.A. Suppression of cortical spreading depression in migraine prophylaxis. Ann. Neurol. 59 (2006) 652-661
Bolay H., Reuter U., Dunn A.K., Huang Z., Boas D.A., and Moskowitz M.A. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8 (2002) 136-142
Buzzi M.G., and Moskowitz M.A. The pathophysiology of migraine: year 2005. J. Headache Pain 6 (2005) 105-111
Cao Y.Q., and Tsien R.W. Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc. Natl. Acad. Sci. 102 (2005) 2590-2595
Catterall W.A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16 (2000) 521-555
Fumal A., and Schoenen J. Genetics of migraines: from ionic channels to single nucleotide polymorphisms?. Rev. Med. Liege 59 (2004) 367-377
Hadjikhani N., Sanchez Del Rio M., Wu O., Schwartz D., Bakker D., Fischl B., Kwong K.K., Cutrer F.M., Rosen B.R., Tootell R.B., Sorensen A.G., and Moskowitz M.A. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl. Acad. Sci. 98 (2001) 4687-4692
Headache Classification Committee of the International Headache Society, The International Classification of Headache Disorders, 2nd edition, Cephalalgia 24 (2004) 1-152.
Jen J.C., Kim G.W., Dudding K.A., and Baloh R.W. No mutations in CACNA1A and ATP1A2 in probands with common types of migraine. Arch. Neurol. 61 (2004) 926-928
Kim E.Y., Rumpf C.H., Fujiwara Y., Cooley E.S., Van Petegem F., and Minor Jr. D.L. Structures of CaV2 Ca2+/CaM-IQ domain complexes reveal binding modes that underlie calcium-dependent inactivation and facilitation. Structure 16 (2008) 1455-1467
Moskowitz M.A., Bolay H., and Dalkara T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann. Neurol. 55 (2004) 276-280
Ophoff R.A., Terwindt G.M., Vergouwe M.N., van Eijk R., Oefner P.J., Hoffman S.M., Lamerdin J.E., Mohrenweiser H.W., Bulman D.E., Ferrari M., Haan J., Lindhout D., van Ommen G.J., Hofker M.H., Ferrari M.D., and Frants R.R. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87 (1996) 543-552
Pietrobon D. Familial hemiplegic migraine. Neurotherapeutics 4 (2007) 274-284
van den Maagdenber A.M., Pietrobon D., Pizzorusso T., Kaja S., Broos L.A., Cesetti T., van de Ven R.C., Tottene A., van der Kaa J., Plomp J.J., Frants R.R., and Ferrari M.D. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41 (2004) 701-710
Vitko I., Chen Y., Arias J.M., Shen Y., Wu X.R., and Perez-Reyes E. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J. Neurosci. 25 (2005) 4844-4855
Weiss N., Tournier-Lasserve E., and De Waard M. Role of P/Q calcium channel in familial hemiplegic migraine. Med. Sci. 23 (2007) 53-63
