Genetic studies of Polish migraine patients: screening for causative mutations in four migraine-associated genes
Tóm tắt
Migraine is the most common neurological disorder, affecting approximately 12 % of the adult population worldwide, caused by both environmental and genetic factors. Three causative genes have been identified in familial hemiplegic migraine (FHM) families: CACNA1A, ATP1A2, and SCNA1A. Recently, several mutations in KCNK18 have also been found as causative factors in migraine development. The aim of our study was to identify the genetic background of migraine in the Polish population. Sixty patients with migraine without aura (MO) or with different types of migraine with aura (MA), including sporadic hemiplegic, familial hemiplegic, and probable familial hemiplegic, were screened for mutations in the four genes previously linked with different types of migraine (ATP1A2, CACNA1A, SCN1A, and KCNK18). Two missense mutations were found. One novel mutation in SCN1A, encoding α subunit of sodium channel, causing amino acid change M1500V localized to a region encoding inactivation loop between transmembrane domains III and IV of the channel, was detected in a female FHM patient. The M1500V mutation was absent in a group of 62 controls, as well as in the ExAC database. The second, already known missense mutation S231P in KCNK18 was found in a female MA patient. Additionally, a novel intronic polymorphism possibly affecting alternative splicing of SCN1A, at chr2:16685249, g.77659T>C, and c.4581+32A>G, located between exons 24 and 25, in a region encoding the inactivation loop of the sodium channel was found in a female MO patient. No mutations in ATP1A2 or CACNA1A were found in the study group. The presence of SCN1A mutations and absence of mutations in ATP1A2 or CACNA1A suggest that the Polish patients represent FHM type 3. On the other hand, the presence of KCNK18 mutation indicated another FHM subtype. It could be speculated that contrary to other European populations, the genetic basis of migraine in the Polish population involves mutations in genes not included in the study. Next-generation sequencing methods should be implemented to identify other migraine-associated variants.
Tài liệu tham khảo
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87:543–52.
Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E, et al. Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001;58:292–5.
Pietrobon D. CaV2.1 channelopathies. Pflugers Arch. 2010;460:375–93.
Gallanti A, Cardin V, Tonelli A, Bussone G, Bresolin N, Mariani C et al. The genetic features of 24 patients affected by familial and sporadic hemiplegic migraine. Neurol Sci. 2011;32 Suppl 1:S141–2.
Dichgans M, Freilinger T, Eckstein BE, Babini E, Lorenz-Depiereux B, Biskup S et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet. 2005;366:371–7.
Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Investig. 2005;115:2010–7.
Lafrenière RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N et al. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med. 2010;16:1157–60.
Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27:1293–300.
Schürks M. Genetics of migraine in the age of genome-wide association studies. J Headache Pain. 2012;13:1–9.
Todt U, Netzer C, Toliat M. New genetic evidence for involvement of the dopamine system in migraine with aura. Hum Genet. 2009;125:265–79.
Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, North American Brain Expression Consortium, UK Brain Expression Consortium, International Headache Genetics Consortium, et al. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet. 2013;45:912–7.
Style Matters: Statements from the Vancouver Group. http://dx.doi.org/10.1136/bmj.302.6786.1194. BMJ 1991; 302:1194.
The International Classification of Headache Disorders, 3rd edition (beta version) Part one: the primary headaches. Cephalalgia 2013;33(9):644–658.
Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. In: Curr Protoc Hum Genet, Chapter 7:Unit7.20. 2013.
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015;31(16):2745–7.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.
Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS + 2. Nat Genet. 2000;24(4):343–5.
Witkowska-Olearska K. Epidemiology of vascular headache and migraine in the population of Warsaw. Neurol Neurochir Pol. 1975;9:495–502.
Szczudlik A. Migraine awareness, treatment, and education in Poland. Cephalalgia. 1998;18:65–6.
Vahedi K, Depienne C, Le Fort D, Riant F, Chaine P, Trouillard O et al. Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology. 2009;72:1178–83.
Weller CM, Pelzer N, de Vries B, López MA, De Fàbregues O, Pascual J, et al. Two novel SCN1A mutations identified in families with familial hemiplegic migraine. Cephalalgia. 2014;34:1062–9.
Kahlig KM, Misra SN, George Jr AL. Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. J Neurosci. 2006;26:10958–66.
Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafrenière RG et al. Functional analysis of missense variants in the TRESK (KCNK18) K channel. Sci Rep. 2012;2:237.
Rainero I, Rubino E, Gallone S, Zavarise P, Carli D, Boschi S et al. KCNK18 (TRESK) genetic variants in Italian patients with migraine. Headache. 2014;54:1515–22.
Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol. 2003;4:207.
Intiso D, Crociani P, Fogli D, Grandone E, Cappucci G, Di Rienzo F et al. Occurrence of factor V Leiden mutation (Arg506Gln) and anticardiolipin antibodies in migraine patients. Neurol Sci. 2002;22:455–8.
Soriani S, Borgna-Pignatti C, Trabetti E, Casartelli A, Montagna P, Pignatti PF et al. Frequency of factor V Leiden in juvenile migraine with aura. Headache. 1998;38:779–81.
Brackenbury WJ, Isom LL. Na channel β subunits: overachievers of the ion channel family. Front Pharmacol. 2011;28(2):53.