title: Rare missense variants in ATP1A2 in families with clustering of common forms of migraine.
abstract: 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.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Unda
authors.initials: U
authors.lastname: Todt
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.forename: Axel
authors.initials: A
authors.lastname: Heinze
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zifarelli
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.forename: Vera
authors.initials: V
authors.lastname: Zumbroich
authors.forename: Anne
authors.initials: A
authors.lastname: Stiller
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.forename: Thomas
authors.initials: T
authors.lastname: Friedrich
authors.forename: Hartmut
authors.initials: H
authors.lastname: Göbel
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics*; D020325:Migraine with Aura / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016415:Sequence Alignment; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D014981:Xenopus / Q000378:metabolism
chemical_list: C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase