Trinucleotide repeat in TCF4 responsible for Fuchs' endothelial corneal dystrophy

Variation in the transcription factor 4 (TCF4) gene is known to be a major contributor to Fuchs' endothelial corneal dystrophy (FECD). Researchers at Mayo Clinic's campus in Rochester, Minnesota, however, have identified the specific genetic defect in the TCF4 gene that appears to be responsible for FECD.

"The defect is a trinucleotide repeat — an uncommon type of genetic defect that, up until now, was only seen in neurological and neuromuscular degenerations such as Huntington's disease and myotonic dystrophy," says Keith H. Baratz, M.D., with the Department of Ophthalmology at Mayo Clinic. "Our data demonstrate a strong association between expansion of a noncoding trinucleotide repeat in the TCF4 gene and FECD."

Dr. Baratz's team tested for an association between an intronic thymine-guanine-cytosine (TGC) trinucleotide repeat in TCF4 and FECD by determining repeat length in 66 affected participants with severe FECD and 63 control subjects with normal corneas in a three-stage discovery, replication and validation study.

For the study, polymerase chain reaction primers flanking the repeat were used to amplify leukocyte-derived genomic DNA. Repeat length was determined by direct sequencing, short tandem repeat (STR) assay. Genomic Southern blots were used to evaluate samples for which only a single allele was identified by STR analysis.

Outcomes for data compiled from the three arms of the study include:

  • A TGC repeat length > 50 was present in 52 of 66 (79 percent) of FECD cases and in only 2 of 63 (3 percent) of normal control cases (p < 0.001).
  • Among FECD cases, 13 subjects (20 percent) had < 40 repeats and one (2 percent) had an intermediate repeat length.
  • The repeat length was greater than 1,000 in four FECD cases and no control cases.
  • The sensitivity and specificity of > 50 TGC repeats identifying FECD in this patient cohort was 79 percent and 96 percent, respectively.

"Our data indicate that the expansion of the TGC repeat within the TCF4 gene is found in a very high proportion of patients with FECD, which suggests the likelihood that FECD is a trinucleotide repeat expansion disorder in the majority of cases," says Dr. Baratz. "The TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD. A repeat length > 50 is highly specific for the disease. This association suggests that trinucleotide expansion may be a predictor of disease risk."

Incidence of expanded repeat

In the study, 6 of the 52 patients with FECD and none of the control cases had two expanded alleles > 50 TGC repeats. There were no distinguishing clinical features, such as disease severity or age of onset, among the FECD cases homozygous for repeat expansion.

"It is not clear from the data whether the occurrence of expanded alleles in unaffected individuals reflects reduced penetrance, delayed disease onset or the possibility of linkage disequilibrium between another causative allele and the expanded repeat," says Dr. Baratz. "If the repeat expansion is causative for FECD, we hypothesize that the effect is to alter the expression of the gene in some way rather than to simply inactivate it."

The frequency of FECD, ease of assessing the phenotype and availability of diseased tissue from corneal transplant patients indicate that further investigation may yield information generalizable to other rare but devastating trinucleotide repeat disorders. "The interesting aspect, from a genetic standpoint, is that trinucleotide repeat diseases have various mechanisms through which they cause disease," says Dr. Baratz.

This research was presented in part at the May 2012 Association for Research in Vision and Ophthalmology annual meeting and published in PLOS ONE in November 2012.

For more information

Wieben ED, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLOS ONE. 2012;7:e49083.

Expanded trinucleotide repeat in TCF4, E2-2 may be a functional cause of Fuchs corneal dystrophy. Ophthalmology Update. Mayo Clinic. 2012;2(1):1.

Research confirms association between TCF4 gene and Fuchs corneal dystrophy. Ophthalmology Update. Mayo Clinic. 2011;1(1):4.