Deciphering novel TCF4-driven mechanisms underlying a common triplet repeat expansion-mediated disease

• DOI: 10.1371/journal.pgen.1011230
• Publication Date: 2024-05-07T17:38:25Z
• Authors: Nihar Bhattacharyya; Niuzheng Chai; Nathaniel J. Haff...; Amanda N. Sadan; Anita Szabo; Christina Zarouch...; Jana Jedlickova; Szi Kay Leung; Tianyi Liao; Lubica Dudakova; Pavlina Skalicka; Mohit Parekh; Ismail Moghul; Aaron R. Jeffries; Michael E. Cheetham; Kirithika Muthusamy; Alison J. Hardcastle; Nikolas Pontikos; Petra Liskova; Stephen J. Tuft; Alice E. Davidson
• Keywords: Male; Alternative Splicing; Transcription Factor 4; Fuchs' Endothelial Dystrophy; Endothelium, Corneal; Genetics; Humans; Endothelial Cells; QH426-470; Trinucleotide Repeat Expansion; Transcriptome; Research Article; 3. Good health

Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up 80% European FECD cases have been attributed expansion a non-coding CTG element (termed CTG18.1) located within ubiquitously expressed transcription factor encoding gene, TCF4. The nature transcriptomic complexity TCF4 made it extremely challenging experimentally decipher molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven components primary patient-derived cells (CECs), generated from large cohort individuals with CTG18.1-expanded (Exp+) 18.1-independent (Exp-) FECD. We employ long-read, short-read, spatial techniques interrogate expansion-specific biomarkers. Interrogation long-read sequencing alternative splicing analysis short-read data together reveals global extent altered occurring Exp+ FECD, unique transcripts associated CTG18.1-expansions. Similarly, differential gene expression highlights total consequences CECs. Furthermore, exon usage, pathway enrichment transcriptomics reveal isoform ratio skewing solely potential downstream functional consequences. Lastly, exome 134 Exp- identified rare (minor allele frequency <0.005) potentially deleterious (CADD>15) variants 7/134 cases, suggesting that independent may increase risk. In summary, our study supports hypothesis at least two distinct pathogenic mechanisms, RNA toxicity isoform-specific dysregulation, both underpin pathophysiology anticipate these will inform guide development translational interventions for triplet-repeat mediated