title: Functional characterization of a novel C-terminal ATP1A2 mutation causing hemiplegic migraine and epilepsy.
abstract: BACKGROUND
  We describe a four-generation Italian family with familial hemiplegic migraine (FHM) and epilepsy due to a novel ATP1A2 missense mutation (R1007W).
  
  
  METHODS
  Mutational analysis revealed a heterozygous nucleotide substitution c.3019C>T resulting in the missense substitution p.Arg1007Trp (p.R1007W) in seven subjects: Three individuals had hemiplegic migraine, two exhibited a clinical overlap between migraine and epilepsy, one had migraine and one was unaffected. The identified ATP1A2 mutation was not found in an ethnically matched control population of 190 individuals and was not reported in a polymorphisms database. In two-electrode voltage-clamp experiments on XENOPUS oocytes, the ATP1A2 R1007W mutant showed (i) reduced ion pumping activity due to a more profound voltage dependence and (ii) decreased apparent affinity for extracellular K⁺ at voltages around the cellular resting potential. This distinct type of loss of function has not been reported for other FHM2 mutations and can lead to impaired K⁺ clearance and elevated K⁺ levels in the CNS.
  
  
  CONCLUSIONS
  The functional data and clinical evidence suggest that in FHM2 migraine and epilepsy may originate from the same pathogenic mechanisms associated with genetically determined alterations of ion channels and pumps. Our data also support the hypothesis that the new mutation R1007W in our family may be a susceptibility factor for epilepsy.
authors.affiliation: Pediatric Neurology and Neurogenetics Unit, Children's Hospital A. Meyer, University of Florence, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pisano
authors.forename: Susan
authors.initials: S
authors.lastname: Spiller
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Carlo
authors.initials: C
authors.lastname: Cianchetti
authors.forename: Thomas
authors.initials: T
authors.lastname: Friedrich
authors.forename: Dario
authors.initials: D
authors.lastname: Pruna
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020325:Migraine with Aura / Q000150:complications / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D055815:Young Adult
chemical_list: C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A2 mutation; FHM; electrophysiology; epilepsy