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

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Fuchs endothelial corneal dystrophy (FECD) is a common, age-related vision loss disorder.
• It is frequently caused by CTG18.1 repeat expansions within the TCF4 gene, a major challenge for mechanistic studies.
• Understanding the molecular basis of FECD is crucial for developing effective therapies.

Purpose of the Study:

• To comprehensively investigate the molecular mechanisms of FECD driven by CTG18.1 repeat expansions.
• To identify expansion-specific transcriptomic biomarkers in patient-derived corneal endothelial cells (CECs).
• To explore alternative pathogenic mechanisms in FECD cases independent of CTG18.1 expansions.

Main Methods:

• Utilized long-read, short-read, and spatial transcriptomic techniques on primary CECs from FECD patients.
• Performed alternative splicing analysis, differential gene expression analysis, and differential exon usage analysis.
• Analyzed exome data to identify rare TCF4 variants in FECD cases without CTG18.1 expansions.

Main Results:

• Identified global alterations in splicing and unique transcripts associated with CTG18.1 expansions in FECD.
• Revealed significant differential gene expression and TCF4 isoform ratio skewing in expanded cases.
• Discovered rare, potentially deleterious TCF4 variants in FECD cases lacking CTG18.1 expansions.

Conclusions:

• FECD pathogenesis involves at least two distinct mechanisms: RNA toxicity and TCF4 isoform dysregulation.
• These findings provide critical insights into FECD pathophysiology.
• The data will guide the development of translational interventions for this common triplet-repeat disease.