Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia

Background The ΔGAG deletion of the TOR1A gene (DYT1) is responsible for DYT1 dystonia. However, no other TOR1A mutation has been reported in the Chinese population. Methods Two hundred one dystonia patients without the ΔGAG deletion were screened for other mutations in TOR1A. Gene function changes were analyzed by subcellular distribution and luciferase reporter assay. Results A novel TOR1A mutation (c.581A>T, p.Asp194Val) was found in a patient with early-onset segmental dystonia harboring a THAP1 mutation (c.539T>C, p.Leu180Ser). Overexpression of mutant TOR1A Asp194Val protein induces inclusion formation in SK-N-AS cell lines, and the repressive activity of the mutant THAP1 Leu180Ser protein on TOR1A gene expression is decreased compared with wild-type THAP1. Conclusions This is the first report about a dystonia patient harboring two distinct dystonia gene mutations. Functional analysis indicated a potential additive effect of these two mutations, which might provoke the occurrence of dystonic symptoms in this patient. © 2014 International Parkinson and Movement Disorder Society