Communicated by Arnold Munnich
Rare missense variants in ATP1A2 in families with clustering of common forms of migraine†
Article first published online: 18 AUG 2005
© 2005 Wiley-Liss, Inc.
Volume 26, Issue 4, pages 315–321, October 2005
How to Cite
Todt, U., Dichgans, M., Jurkat-Rott, K., Heinze, A., Zifarelli, G., Koenderink, J. B., Goebel, I., Zumbroich, V., Stiller, A., Ramirez, A., Friedrich, T., Göbel, H. and Kubisch, C. (2005), Rare missense variants in ATP1A2 in families with clustering of common forms of migraine. Hum. Mutat., 26: 315–321. doi: 10.1002/humu.20229
- Issue published online: 30 AUG 2005
- Article first published online: 18 AUG 2005
- Manuscript Accepted: 12 APR 2005
- Manuscript Received: 17 DEC 2004
- Deutsche Forschungsgemeinschaft. Grant Numbers: FOR 423, TPA2, KFG K1 027, KFG K1 028
- National Genome Network, Bundesministerium für Bildung und Forschung. Grant Number: FKZ-01GS0115
- Max Planck Society for the Advancement of Science
- complex diseases
Migraine is a recurrent neurovascular disease. Its two most common forms—migraine without aura (MO) and migraine with aura (MA)—both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na+/K+-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [c.520G>A (p.E174 K) and c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM-mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na+/K+-ATPases, 4) the functional effect of C515Y, and 5) the involvement of ATP1A2 in a monogenic form of migraine. Hum Mutat 26(4), 315–321, 2005. © 2005 Wiley-Liss, Inc.