Found a variant S287Y late-onset isolated dystonia patient.
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In vitro, the trosinA with S287Y presented a higher tendency to form dimer.
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The cells overexpressing trosinA S287Y have an enlarged peri-nuclear space.
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The may be a likely pathogenic mutation that causes isolated dystonia.
Abstract
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.