TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease

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.

Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion

“…In the unrelated cohort, we also identified CTG18.1 expansion, defined as ≥40 repeats, in 7.7% (95% CI, 4%–11%) of 235 control subjects (≥50 years old), consistent with previous reports in US and European cohorts, 33 but higher than that in studies of Asian cohorts. 12 As a group, our CTG18.1exp+ control subjects did not have repeat lengths significantly different than CTG18.1exp+ FECD patients, so we cannot conclude that CTG18.1exp+ controls have relatively shorter expansions. In fact, one control participant harbored a very large repeat length of approximately 2000 repeats.…”

“…The high prevalence of CTG18.1 expansion in this study is comparable to that reported by other studies that have investigated US and European cohorts but is higher than that found by studies of Asian, Indian, and African American US cohorts. 12 The higher frequency of CTG18.1 expansion in certain populations may be the driving mechanism explaining the higher reported prevalence of guttae and the perceived higher incidence of FECD among individuals of northern European and Scandinavian descent, but we are not aware of studies that answer this question using direct epidemiologic comparisons. 29 , 30 …”

“… 11 Short TNR expansions are typically stable and non-pathologic, whereas TNR expansions surpassing a certain threshold tend to be unstable, both somatically and intergenerationally, and contribute to disease through gain-of-function mechanisms such as RNA toxicity, in which transcribed repeat RNA accumulates intranuclearly and sequesters RNA splicing factors such as muscleblind-like 1. 12 Depending on whether transmission is maternal or paternal, TNR expansion disorders may also demonstrate clinical anticipation, which refers to phenotypic presentation at younger ages or increased disease severity in subsequent generations, and intergenerational repeat length instability, in which TNR expansions significantly lengthen or shorten between generations. 13 Myotonic dystrophy type 1, for example, is caused by a non-coding CTG repeat expansion and may present with profound anticipation and intergenerational repeat length instability skewed toward expansions, particularly when transmitted maternally.…”

Comparison of TCF4 repeat expansion length in corneal endothelium and leukocytes of patients with Fuchs endothelial corneal dystrophy

“…Approximately 78% of FECD patients in the United States have an expansion of a CTG repeat sequence in an intron of the TCF4 gene. Traditionally, researchers in the field have generated estimations of repeat length from leukocyte DNA rather than the targeted diseased tissue and have correlated these data with mechanistic changes in affected corneal tissue which includes the role of RNA toxicity, repeat-associated non-AUG translation, and changes in TCF4 expression (see review [ 15 ]). In FECD, technical limitations have previously made it impossible to quantify the TCF4 TNR expansion length in corneal endothelial DNA.…”

Should Patients with Kearns-Sayre Syndrome and Corneal Endothelial Failure Be Genotyped for a TCF4 Trinucleotide Repeat, Commonly Associated with Fuchs Endothelial Corneal Dystrophy?

“…Both the FECD and PPCD are genetically heterogenous. However, the most common cause of FECD is the expansion of a non-coding repeat element (termed CTG18.1), which is present in up to 80% of patients with FECD [ 8 ].…”