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Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in  THAP1  encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1 F81L ) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1 F81L  exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1 F81L  normally binds DNA but is unable to efficiently organize an active transcription complex.

A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding