In a man with late-onset focal torsion dystonia (DYT1; 128100) of the oromandibular region, Calakos et al. (2010) identified a heterozygous 613T-A transversion in exon 3 of the TOR1A gene, resulting in a phe205-to-ile (F205I) substitution in a highly conserved residue in the beta-strand motif in the AAA domain. The mutation was not found in 1,600 control chromosomes. The patient had onset of involuntary jaw movements and grimacing in his fifth decade. Neurologic examination showed cogwheel tone without rigidity and mild action tremor in the upper limbs, as well as absent ankle reflexes. He had a history of bipolar disorder, treatment with lithium, and remote history of treatment with a dopamine receptor blocking agent. There was a family history of tremor and depression, but no family history of dystonia. In vitro functional expression studies in cultured cells showed that the F205I-mutant protein produced TOR1A inclusion bodies that colocalized with the endoplasmic reticulum in about 44% of cells. Transfection of the common GAGdel mutation (605204.0001) produced inclusions in 79% of cells, and wildtype TOR1A produced inclusions in about 10% of cells. The findings suggested that the F205I mutation had impaired function that differed from the GAGdel mutation, and that F205I may contribute to the milder phenotype in this patient.
In vitro cellular expression studies by Hettich et al. (2014) indicated that the F205I mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype.
