In affected members of a family with familial hemiplegic migraine-2 (602481), Vanmolkot et al. (2003) identified a heterozygous 2296T-C transition in exon 16 of the ATP1A2 gene, resulting in a met731-to-thr (M731T) substitution.
Segall et al. (2005) found that the mutant M731T and R689Q (182340.0004) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. In addition, M731T showed an increased apparent affinity for ATP. Segall et al. (2005) suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling.
Castro et al. (2007) identified the M731T mutation in 3 affected members of a Portuguese family with FHM2. A fourth mutation carrier had only migraine with aura.
Schack et al. (2012) noted that the M731T mutation occurs in the P domain. Expression of the mutation in COS-1 cells showed a severe reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+.
