Modifiers of penetrance and expressivity in monogenic dystonia: Insights from systems biology

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Mutations in several genes, including THAP1 (THAP domain-containing apoptosis-associated protein 1), SGCE (sarcoglycan, epsilon), and GCH1 (GTP cyclohydrolase 1) have been confirmed as inherited cause of dystonia. Penetrance of mutations in these genes is about 50%, and there is enormous variable expressivity among the affected carriers. In the first funding period, we focused on genetic modifiers of THAP1 penetrance. For this, we generated 20 iPSC clones from fibroblast lines of 5 affected and 5 unaffected THAP1 mutation carriers. These clones and 14 matched control lines have been differentiated into cortical neuronal lines and used for transcriptome analysis. Further, 13 affected and unaffected THAP1 mutation carriers were whole genome- sequenced and Chromosome Conformation Capture-on-Chip (4C) data of a cortical neuronal line without THAP1 mutation were generated. Using these comprehensive data resources, we demonstrated differential expression of several genes linked to diverse pathways including response to type I interferon, membrane fusion, and mitochondrial fission. For several of those genes, binding of the THAP1 transcription factor has been shown within the respective promoter regions (ENCODE data). Further, the genome data ruled out simple, coding sequence variants in other dystonia genes in the affected carriers. Finally, a common variant within the promoter of KAT6A (lysine acetyltransferase 6A) has been nominated as a potential modifier of THAP1 penetrance based on 3D interaction with the THAP1 gene and segregation in a family.Within this proposal, the overall hypothesis is that penetrance and expressivity of mutations in THAP1, SGCE, or GCH1 are modified by further genetic variants and/or epigenetic marks affecting gene expression and/or metabolites. To substantiate this hypothesis, we will re-analyze existing data for THAP1 with a focus on molecular function combining transcriptome, genome, and regulome data in a trans-Omics multi-variate modeling approach to elucidate synergistic actions relevant to the penetrance of THAP1 mutations (Objective 1). We will broaden our focus to SGCE and GCH1. While the reduced penetrance in SGCE is mainly explained by maternal imprinting, as we demonstrated earlier, the impact of differential methylation and gene expression on the variable expressivity is largely elusive and will be targeted by transcriptome, genome, and methylome studies (Objective 2). Finally, the highly reduced penetrance in, especially, male GCH1 mutation carriers will be investigated by transcriptomics, genome sequencing, and metabolomics (Objective 3). This approach will contribute to a better understanding of molecular variations in THAP1, SGCE, and GCH1 mutation carriers and potentially elucidate factors influencing reduced penetrance and variable expressivity of mutations in these genes.P4 will closly collaborate with P5, P8, and P9 in terms of dystonia, and methodologically with P10 and the Cores in Z2, P1 and P3.