To describe a new FHM kindred, and to analyse the functional consequences of the disease-associated ATP1A2 p.G301R mutation in human cellular models grown at 37°C. Seven patients were clinically evaluated and gave informed consent for molecular analysis. Extra-pyramidal rigidity of the limbs was present in four subjects and in three of them tongue apraxia was also observed. ATP1A2 and CACNA1A were analysed by direct sequencing. Functional consequences of the mutation were investigated by cell viability assays, Western blots, and immunocytochemistry. Three-dimensional models of the human Na(+)/K(+)-ATPase α2 subunit were generated by homology modelling using SWISS-MODEL. Analysis of ATP1A2 showed a heterozygous mutation, c.901G>A predicting the replacement of arginine for glycine at residue 301 (p.G301R). Functional analysis suggested that the mutation completely abolished Na(+)/K(+)-ATPase function. The phenotypic spectrum of our FHM2 family includes some peculiar features. Functional data confirm that Na(+)/K(+)-ATPase haploinsufficiency caused by the ATP1A2 p.G301R mutation is responsible for FHM in the described family.
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