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The Genetic Basis of Migraine: How Much Do We Know?

Published online by Cambridge University Press:  02 December 2014

Kathy Gardner*
Affiliation:
Department of Neurology, University of Pittsburgh, PA, USA
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Abstract

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Migraine with and without aura is thought to be genetically complex with aggregation in families due to a combination of environmental and genetic tendencies. Twin studies are most important in establishing the multifactorial nature of migraine with heritability approaching 50%. Familial hemiplegic migraine (FHM) on the other hand is an autosomal dominant, highly penetrant, though rare form of migraine with strong genetic tendency. Fifty percent of families with FHM are linked to chromosome 19p13 and mutations demonstrated for some in a brain expressed calcium channel alpha 1A subunit, CACNL1A4. Other FHM loci have been identified on chromosome 1q and further genetic heterogeneity is likely. The exact role of the mutated calcium channel in the pathway leading to hemiplegic migraine is yet to be established. Changes in the electrophysiologic properties of the mutated forms of the CACNL1A4 calcium channel expressed in heterologous systems help establish the functional significance of the mutations and suggest that chromosome 19p-linked FHM, an episodic disorder, represents a CNS channelopathy. Additional candidate genes causative for migraine might include other calcium channel subunits and related proteins important for neuronal membrane stability. Delineating the cascade of biochemical events leading to hemiplegic migraine will serve as a model for understanding the pathophysiology of more common forms of migraine. The evidence suggesting that some families of migraine with and without aura might also be related to the chromosome 19p locus, chromosome Xq28 locus, or DRD2 receptor polymorphisms is reviewed.

Résumé

RÉSUMÉ

On pense généralement que la migraine avec et sans aura est complexe au point de vue génétique et que l’agrégation de cas dans les familles est due à une combinaison de tendances environnementales et génétiques. Les études sur les jumeaux sont très importantes pour établir la nature multifactorielle de la migraine dont l’héritabilité est de près de 50%. D’autre part, la migraine hémiplégique familiale (MHF), une maladie autosomale dominante dont la pénétrance est élevée, est une forme de migraine rare à forte tendance génétique. Chez cinquante pourcent des familles atteintes de MHF la maladie est liée au chromosome 19, en 19p13, et chez certaines familles, des mutations ont été démontrées dans la sous-unité 1A d’un canal calcique exprimé dans le cerveau, CACNL1A4. D’autres loci ont été identifiés sur le chromosome 1, en1q, et il existe sans doute une grande hétérogénéité génétique. Le rôle exact du canal calcique muté dans la voie qui est atteinte dans la MHF n’a pas encore été établi. Les changements dans les propriétés électrophysiologiques des formes mutées du canal calcique CACNL1A4 exprimé dans les systèmes hétérologues aident à établir la signification fonctionnelle des mutations et suggèrent que la MHF liée au chromosome 19, en 19p, un trouble épisodique, représente une canalopathie du SNC. Les gènes d’autres sous-unités de canaux calciques et de protéines associées, qui sont importants pour la stabilité de la membrane des neurones, pourraient être des gènes candidats dans l’étiologie de la migraine. La définition de la cascade d’événements biochimiques conduisant à la MHF servira de modèle pour comprendre la physiopathologie de formes plus communes de migraine. Les observations suggérant que dans certaines familles atteintes de migraine avec et sans aura la maladie pourrait également être liée aux loci sur le chromosome 19, en 19p, sur le chromosome X, en Xq28, ou aux polymorphismes du récepteur DRD2 sont revues.

Type
Research Article
Copyright
Copyright © The Canadian Journal of Neurological 1999

References

1. Honkasalo, ML, Kapri, J, Heikkila, K, Sillanpaa, M, Koskenvuo, M. Apopulation-based survey of headache and migraine in 22,809 adults. Headache 1993; 33:403–12.CrossRefGoogle Scholar
2. Larsson, B, Bille, B, Pedersen, NL. Genetic influence in headaches:a Swedish twin study. Headache 1995; 3:513519.CrossRefGoogle Scholar
3. Merikangas, K, Tierney, C, Martin, N, Heath, A and NR. Genetics of Migraine in the Australian Twin Registry. In: New Advances in Headache Research 4 Ed. Rose, C. London: Smith-Gordon and Company Ltd, 1994: 2728.Google Scholar
4. Joutel, A, Bousser, MG, Biousse, V, Labauge, P, Chabriat, H et al. A gene for familial hemiplegic migraine maps to chromosome 19. Nature Genetics 1993; 5:4045.Google Scholar
5. Ducros, A, Joutel, A, Vahedi, K, Cecillon, M, Ferreira, A, Bernard, E et al. Mapping of a second locus for familial hemiplegic migraine to 1q21-23 and evidence of further genetic heterogeneity. Ann Neurol 1997; 42:885890..CrossRefGoogle Scholar
6. Gardner, K, Barmada, MM, Ptacek, LJ, Hoffman, EP. A new locus forhemiplegic migraine maps to chromosome 1q31. Neurology 1997; 49:12311238.CrossRefGoogle ScholarPubMed
7. Ophoff, RA, Terwindt, GM, Vergouwe, MN et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87:543552.Google ScholarPubMed
8. Zamponi, GW, Bourinet, E, Nelson, D, Nargeot, J, Snutch, TP. Crosstalk between G proteins and protein kinase C mediated by the calcium channel alpha1 subunit. Nature 1997; 385:442426.CrossRefGoogle ScholarPubMed
9. Rettig, J, Sheng, ZH, Kim, DK et al. Isoform-specific interaction ofthe alpha1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc Natl Acad Sci USA 1996; 93:73637368.CrossRefGoogle Scholar
10. Gardner, K, Badger, J, Barmada, MOCJ, Hoffman, E. Expansion ofthe Chromosome 1q31 locus for hemiplegic migraine. In: Genetics of Headache Disorders. Frontiers in Headache Research. Vol. 8. Eds Olesen, J, Bousser, M. New York: Lippincott-Raven Publishers, NY, 1998.Google Scholar
11. Gardner, KBJ, Barmada, MM, O’Connell, J, Hoffman, EP. A two locusmodel for hemiplegic migraine on Chr1q and candidate gene screening (abstract). Am J Human Genetics 1998; 63:A30, 154.Google Scholar
12. May, A, Ophoff, RA, Terwindt, GM et al. Familial hemiplegicmigraine locus on 19p13 is involved in the common forms of migraine with and without aura. Human Genetics 1995; 96:604608.CrossRefGoogle ScholarPubMed
13. Nyholt, DR, Lea, RA, Goadsby, PJ, Brimage, PJ, Griffiths, LR. Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 1998; 50:1428–32.CrossRefGoogle ScholarPubMed
14. Nyholt, DR, Dawkins, JL, Brimage, PJ, Goadsby, PJ, Nicholson, GA, Griffiths, LR. Evidence for an X-linked genetic component in familial typical migraine. Human Molecular Genetics 1998;7:459463.CrossRefGoogle ScholarPubMed
15. Peroutka, SJ, Wilhoit, T, Jones, K. Clinical susceptibility to migrainewith aura is modified by dopamine D2 receptor (DRD2) Ncol alleles. Neurology 1997; 49:201–6.CrossRefGoogle Scholar
16. Del Zompo, M, Cherchi, A, Palmas, MA et al. Association betweendopamine receptor genes and migraine without aura in a Sardinian sample. Neurology 1998; 51:781786.CrossRefGoogle Scholar
17. Stewart, WF, Staffa, J, Lipton, RB, Ottman, R. Familial risk of migraine: a population-based study. Ann Neurol 1997; 41:166172.Google Scholar
18. Russell, MB, Iselius, L, Olesen, J. Migraine without aura andmigraine with aura are inherited disorders. Cephalalgia 1996;16:305309.CrossRefGoogle ScholarPubMed
19. Merikangas, KR. Genetics of migraine and other headache. Current Opinion in Neurology 1996; 9:202205.Google Scholar
20. Honkasalo, ML, Kaprio, J, Winter, T et al. Migraine and concomitantsymptoms among 8167 adult twin pairs. Headache 1995; 35:7078.Google Scholar
21. Risch, N. Linkage strategies for genetically complex traits. II. Thepower of affected relative pairs. Am J Hum Genet 1990; 46:229241.Google Scholar
22. Risch, N, Merikangas, K. The future of genetic studies of complexhuman diseases. Science 1996; 273:15161517.CrossRefGoogle Scholar
23. Clark, J. On recurrent motor paralysis in migraine. Br Med J 1910;1:15341538..Google Scholar
24. Whitty, C. Familial hemiplegic migraine. J Neurol Neurosurg Psychiatry 1953; 16:172177.Google Scholar
25. Whitty, C.W.M. Familial hemiplegic migraine. Handbook of Clinical Neurology. Elsevier Science Publishers, 1986. 141153.Google Scholar
26. Ducros, A, Joutel, A, Vahedi, K, Bousser, M, Tournier-Lasserve, E. Genotype-phenotype correlations in familial hemiplegicmigraine (FHM). Neurology 1998; 50:A352.Google Scholar
27. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalagia Suppl 1988; 8:1928.Google Scholar
28. Hayashi, R, Tachikawa, H, Watanabe, R et al. Familial hemiplegicmigraine with irreversible brain damage. Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) Ncol alleles. Intern Med 1998; 37:166168.CrossRefGoogle Scholar
29. Montagna, P, Gallassi, R, Medori, R et al. MELAS syndrome:characteristic migrainous and epileptic features and maternal transmission. Neurology 1988; 38:751754.CrossRefGoogle ScholarPubMed
30. Tournier-Lasserve, E, Iba-Zizen, MT, Romero, N, Bousser, MG. Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke 1991; 22:12971302.Google Scholar
31. Auburger, G. New genetic concepts and stroke prevention. Cerebrovasc Dis 1998; 8 Suppl 5:2832.CrossRefGoogle Scholar
32. Aalto-Setala, K, Palomaki, H, Miettinen, H et al. Genetic risk factorsand ischaemic cerebrovascular disease: role of common variation of the genes encoding apolipoproteins and angiotensin-converting enzyme. Ann Med 1998; 30:224233.Google Scholar
33. Kontula, K, Ylikorkala, A, Miettinen, H et al. Arg506Gln factor Vmutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995; 73:558560.Google Scholar
34. Tournier-Lasserve, E, Joutel, A, Melki, J et al. Cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nature Genetics 1993; 3:256259.CrossRefGoogle Scholar
35. Vahedi, K, Joutel, A, Van Bogaert, P et al. A gene for hereditaryparoxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 1995; 37:289293.CrossRefGoogle ScholarPubMed
36. Joutel, A, Corpechot, C, Ducros, A et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383:707710.CrossRefGoogle ScholarPubMed
37. Zhuchenko, O, Bailey, J, Bonnen, P et al. Autosomal dominantcerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nature Genetics 1997; 15:6269.CrossRefGoogle ScholarPubMed
38. Stea, A, Soong, TW, Snutch, TP. Voltage-gated calcium channels. Handbook of Receptors and Channels. CRC Press, Inc, 1995; 113151.Google Scholar
39. Westenbroek, RE, Sakurai, T, Elliott, EM et al. Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci 1995; 15:64036418.Google Scholar
40. Takahashi, T, Momiyama, A. Different types of calcium channelsmediate central synaptic transmission. Nature 1993; 366:156158.Google Scholar
41. Elliott, EM, Malouf, AT, Catterall, WA. Role of calcium channel subtypes in calcium transients in hippocampal CA3 neurons. J Neurosci 1995; 15:64336444.CrossRefGoogle ScholarPubMed
42. Zhang, JF, Ellinor, PT, Aldrich, RW, Tsien, RW. Multiple structuralelements in voltage-dependent Ca2+ channels support their inhibition by G proteins. Neuron 1996; 17:9911003.CrossRefGoogle ScholarPubMed
43. Kraus, RL, Sinnegger, MJ, Glossmann, H, Hering, S, Striessnig, J. Familial hemiplegic migraine mutations change alpha1A Ca2+channel kinetics. J Biol Chem 1998; 273:55865590.Google Scholar
44. Terwindt, GM, Ophoff, RA, Haan, J et al. Variable clinical expressionof mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Dutch Migraine Genetics Research Group. Neurology 1998; 50:11051110.Google Scholar
45. Ducros, A, Joutel, A, Vahedi, K, Bousser, M, Tournier-Lasserve, E. Genotype-phenotype correlations in familial hemiplegic migraine (FHM). 8th International Headache Research Seminar; Genetics of Headache Disorders 1997; (abstract) 31.Google Scholar
46. Hovatta, I, Kallela, M, Farkkila, M, Peltonen, L. Familial migraine:exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p. Genomics 1994; 23:707709.Google Scholar
47. Stewart, WF, Shechter, A, Rasmussen, BK. Migraine prevalence. Areview of population-based studies. Neurology 1994; 44:S17–23.Google Scholar
48. Yue, Q, Jen, JC, Thwe, MM, Nelson, SF, Baloh, RW. De novo mutationin CACNA1A caused acetazolamide-responsive episodic ataxia. Am J Med Genet 1998; 77:298301.Google Scholar
49. Yue, Q, Jen, JC, Nelson, SF, Baloh, RW. Progressive ataxia due to amissense mutation in a calcium-channel gene. Am J Hum Genet 1997; 61:10781087.CrossRefGoogle Scholar