Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

Am J Hum Genet. 2021 Nov 4;108(11):2145-2158. doi: 10.1016/j.ajhg.2021.09.017. Epub 2021 Oct 20.


Dystonia is a neurologic disorder associated with an increasingly large number of genetic variants in many genes, resulting in characteristic disturbances in volitional movement. Dissecting the relationships between these mutations and their functional outcomes is critical in understanding the pathways that drive dystonia pathogenesis. Here we established a pipeline for characterizing an allelic series of dystonia-specific mutations. We used this strategy to investigate the molecular consequences of genetic variation in THAP1, which encodes a transcription factor linked to neural differentiation. Multiple pathogenic mutations associated with dystonia cluster within distinct THAP1 functional domains and are predicted to alter DNA-binding properties and/or protein interactions differently, yet the relative impact of these varied changes on molecular signatures and neural deficits is unclear. To determine the effects of these mutations on THAP1 transcriptional activity, we engineered an allelic series of eight alterations in a common induced pluripotent stem cell background and differentiated these lines into a panel of near-isogenic neural stem cells (n = 94 lines). Transcriptome profiling followed by joint analysis of the most robust signatures across mutations identified a convergent pattern of dysregulated genes functionally related to neurodevelopment, lysosomal lipid metabolism, and myelin. On the basis of these observations, we examined mice bearing Thap1-disruptive alleles and detected significant changes in myelin gene expression and reduction of myelin structural integrity relative to control mice. These results suggest that deficits in neurodevelopment and myelination are common consequences of dystonia-associated THAP1 mutations and highlight the potential role of neuron-glial interactions in the pathogenesis of dystonia.

Keywords: CRISPR; RNA-seq; THAP1; dystonia; genome editing; induced pluripotent stem cells; myelination; neurodevelopment; transcriptomics; variant-to-function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Apoptosis Regulatory Proteins / genetics*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • DNA-Binding Proteins / genetics*
  • Dystonia / genetics*
  • Dystonic Disorders / genetics*
  • Humans
  • Mice
  • Mutation*
  • Myelin Sheath / genetics*


  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • THAP1 protein, human