Functional characterization of a novel C-terminal ATP1A2 mutation causing hemiplegic migraine and epilepsy

BackgroundWe describe a four-generation Italian family with familial hemiplegic migraine (FHM) and epilepsy due to a novel ATP1A2 missense mutation (R1007W).Case resultsMutational 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 impai...