Document Detail

Rare missense variants in ATP1A2 in families with clustering of common forms of migraine.
MedLine Citation:
PMID:  16110494     Owner:  NLM     Status:  MEDLINE    
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.
Unda Todt; Martin Dichgans; Karin Jurkat-Rott; Axel Heinze; Giovanni Zifarelli; Jan B Koenderink; Ingrid Goebel; Vera Zumbroich; Anne Stiller; Alfredo Ramirez; Thomas Friedrich; Hartmut Göbel; Christian Kubisch
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human mutation     Volume:  26     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-05     Completed Date:  2006-06-19     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  315-21     Citation Subset:  IM    
Copyright Information:
(c) 2005 Wiley-Liss, Inc.
Institut für Humangenetik, Universitätsklinikum Bonn, Bonn, Germany.
Data Bank Information
Bank Name/Acc. No.:
OMIM/141500;  157300;  182340;  601011;  602481;  607498;  607501
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MeSH Terms
Aged, 80 and over
Amino Acid Sequence
Genetic Testing
Genetic Variation*
Middle Aged
Migraine Disorders / genetics*
Migraine with Aura / genetics,  metabolism
Models, Biological
Molecular Sequence Data
Mutation, Missense*
Sequence Alignment
Sodium-Potassium-Exchanging ATPase / genetics*,  physiology
Time Factors
Xenopus / metabolism
Reg. No./Substance:
EC 3.6.1.-/ATP1A2 protein, human; EC ATPase

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