Objective: To evaluate the role of expressional changes in carriers of a THAP1 mutation in relation to penetrance of dystonia.

Background: THAP1 encodes a transcription factor that regulates its own expression and may also impact on the expression of TOR1A. Mutations in the THAP1 and TOR1A gene, respectively, can lead to early-onset, isolated, generalized dystonia (DYT-THAP1 and DYT-TOR1A, respectively). Notably, while ~50% of THAP1 and ~30% of TOR1A mutation carriers develop dystonia, a considerably number of carriers remains unaffected by dystonia throughout their lives, a phenomenon known as reduced penetrance. The underlying mechanisms of the reduced penetrance in DYT-THAP1 remain elusive. Maturing neurons generated from induced pluripotent stem cells (iPSCs) could serve as an in-vitro model to unravel penetrance-relevant mechanisms.

Method: iPSCs were generated by reprogramming human dermal fibroblasts from 11 controls and 10 mutation carriers (5 affected, 5 unaffected) from three families with different THAP1 mutations using non-integrating Sendai virus. Thirty-two iPSCs clones (1-2 clones per individual) were differentiated into cortical neurons according to the protocol described by Shi et al. 2012 (PMID 22976355). Cortical neurons were harvested on day 44 of differentiation for gene expression analysis by quantitative PCR.

Results: Gene expression analysis in the 44-day old neuronal lines revealed higher expression of THAP1 in carriers of the p.Lys158Asnfs*23 and p.Ser21Cys mutations, but not in p.Arg13His carriers. A trend of increased THAP1 expression in affected compared to unaffected carriers was observed. TOR1A expression seemed unaltered. Furthermore, THAP1 expression was independent of a putatively penetrance-linked polymorphism in the KAT6A promotor, a region that loops to the THAP1 promotor as shown by 4C analysis.

Conclusion: We observed higher expression of THAP1 in some mutation carriers compared to controls depending on the mutation, which may be explained by the autoregulation of THAP1. Further, the THAP1 expression level might correlate with the disease status. Future transcriptomic profiling will shed light on dysregulated signaling pathways resulting in DYT-THAP1 dystonia.A similar abstract on the same topic has been submitted to the Annual Meeting of the European Society of Human Genetics to be presented in June 2019 in Gothenburg, Sweden.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expression-analysis-of-candidate-genes-in-a-cell-model-of-affected-and-unaffected-thap1-mutation-carriers-and-controls/