Abstract
Fuchs endothelial corneal dystrophy (FECD) is a common cause for heritable visual loss in the elderly. Since the first description of an association between FECD and common polymorphisms situated within the transcription factor 4 (TCF4) gene, genetic and molecular studies have implicated an intronic CTG trinucleotide repeat (CTG18.1) expansion as a causal variant in the majority of FECD patients. To date, several non-mutually exclusive mechanisms have been proposed that drive and/or exacerbate the onset of disease. These mechanisms include (i) TCF4 dysregulation; (ii) toxic gain-of-function from TCF4 repeat-containing RNA; (iii) toxic gain-of-function from repeat-associated non-AUG dependent (RAN) translation; and (iv) somatic instability of CTG18.1. However, the relative contribution of these proposed mechanisms in disease pathogenesis is currently unknown. In this review, we summarise research implicating the repeat expansion in disease pathogenesis, define the phenotype-genotype correlations between FECD and CTG18.1 expansion, and provide an update on research tools that are available to study FECD as a trinucleotide repeat expansion disease. Furthermore, ongoing international research efforts to develop novel CTG18.1 expansion-mediated FECD therapeutics are highlighted and we provide a forward-thinking perspective on key unanswered questions that remain in the field.
Highlights
Evaluation of pre-mRNA splicing patterns using MISO (Mixture of Isoforms) followed by PCR validation in corneal endothelial tissues obtained from two limited datasets of Fuchs endothelial corneal dystrophy (FECD) patients and controls enabled us to identify 24 events that were strongly concordant with CTG18.1 expansion status and FECD (Table 4) (Wieben et al, 2017)
We found that dysregulated pre-mRNA splicing of NUMA1, PPFIBP1, and MBNL1 represented the most robust and consistent signatures of dysregulation associated with CTG18.1 expansions
To further investigate the biological relevance of aberrant pre-mRNA splicing events associated with FECD pathogenesis, we investigated a small cohort of elderly patients with CTG18.1 expansions but without an FECD phenotype (Wieben et al, 2018)
Summary
MPF, EDW, KHB, NB, ANS, NJHT, SJT – no conflicts of interest AED is a member of Triplet Therapeutics Scientific Advisory board.
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