Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4

Abstract

Fuchs corneal dystrophy (FCD) is a hereditary dystrophy of the corneal endothelium and is responsible for majority of the corneal transplantation performed in the United States. Here, we describe three generations of a family with 12 individuals affected by late-onset FCD and in which three individuals are unaffected. Genome-wide mapping provided suggestive linkage at two loci on chromosomal arms 3p and 15q. Alleles at either locus alone were not sufficient to explain FCD; however, considered together, both loci could explain the disorder in this pedigree. Subsequent next-generation sequencing identified a nonsense mutation in AGBL1 in the 15q locus; this mutation would result in a premature termination of AGBL1. Consistent with a causal role for this transcript, further sequencing of our cohort of late-onset-FCD-affected individuals identified two cases harboring the same nonsense mutation and a further three unrelated individuals bearing a second missense allele. AGBL1 encodes a glutamate decarboxylase previously identified in serial analysis of gene expression of corneal endothelium, a finding confirmed by immunohistochemical staining. Wild-type AGBL1 localizes predominantly to the cytoplasm; in sharp contrast, the truncated protein showed distinct nuclear localization. Finally, we show that AGBL1 interacts biochemically with the FCD-associated protein TCF4 and that the mutations found in our cohort of FCD individuals diminish this interaction. Taken together, our data identify a locus for FCD, extend the complex genetic architecture of the disorder, provide direct evidence for the involvement of TCF4 in FCD pathogenesis, and begin to explain how causal FCD mutations affect discrete biochemical complexes.

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

“…and extend these results by demonstrating sex-specific effects. In contrast, we observed only modest association at loci previously identified through family-based and candidate-gene studies101112383940.…”

CTG18.1 Expansion in TCF4 Increases Likelihood of Transplantation in Fuchs Corneal Dystrophy

“…We have previously demonstrated a family in which individuals with both the FCD4 disease allele and a p.Q840P mutation in TCF8 underwent corneal transplantation, while those with only a single disease allele demonstrated mild disease. 9 Families associated with the FCD1 10 and FCD2 11 loci, and causative mutations in SLC4A11 , 12 LOXHD1 13 and ABGL1 14 have also had members who underwent corneal transplantation, suggesting a role for additional genetic factors associated with progression to transplantation.…”

Transcript profile of cellular senescence-related genes in Fuchs endothelial corneal dystrophy

“…They include COL8A2( Biswas et al, 2001; Gottsch et al, 2005), SLC4A11( Vithana et al, 2008), TCF4( Baratz et al, 2010), TCF8( Riazuddin et al, 2010), LOXHD1( Riazuddin et al, 2012), AGBL1( Riazuddin et al, 2013). However, the molecular pathomechanisms unifying these genetic modifications and leading to the common FECD phenotype are still poorly understood.…”