| Summary: | Background: Variations in TOR1A were thought to be associated with early-onset isolated dystonia. The variant S287Y (NM_000113.2: c.860C > A, p. Ser287Tyr, rs766483672) was found in our late-onset isolated dystonia patient. This missense variant is adjacent to R288Q (c.863G > A, p. Arg288Gln), which was reported to be associated with isolated dystonia. The potentially pathogenic role of S287Y is not conclusively known. Methods: Cytological and molecular biological analyses were performed in vitro to determine whether this variant damages the structure and function of the cell. Results: Compared with the SH-SY5Y cells overexpressing wild-type TOR1A, the cells overexpressing the protein with S287Y have an enlarged peri-nuclear space. The same changes in nuclear morphology were also found in the cells overexpressing the pathogenic variants ΔE (NM_000113.2:c.904_906delGAG, p. Glu302del), F205I (NM_000113.2:c.613 T > A, p. Phe205Ile), and R288Q (NM_000113.2:c.863G > A, p. Arg288Gln). Mutated proteins with S287Y presented a higher tendency to form dimers under reducing conditions. The same tendencies were observed in other mutated proteins but not in wild-type torsinA. Conclusions: TorsinA with S287Y damages the structure of the cell nucleus and may be a novel pathogenic mutation that causes isolated dystonia.
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