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John Gottsch, Shivakumar Vasanth, Nicholas Katsanis, S. Amer Riazuddin; AGBL1 implicated in the pathogenesis of late-onset FCD and interacts with TCF4. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4561.
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© ARVO (1962-2015); The Authors (2016-present)
Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and a leading cause of corneal transplantation in the United States. The following study was undertaken to investigate the causality of FCD in a large family.
A large familial case of FCD was ascertained with nine affected and six unaffected individuals in three generations. A genome-wide linkage scan was completed with an Affymetrix SNP genotyping array. Two-point Lod scores were calculated and all regions with Lod scores >1 were confirmed by closely-spaced fluorescently-labeled short tandem repeat (STR) markers. Next-generation sequencing of captured exons in the critical region was employed to identify the causal allele(s) responsible for the phenotype. Immunohistochemical (IHC) analyses were performed on corneal sections to investigate the expression in the corneal endothelium and a co-immunoprecipitation (Co-IP) approach was used to investigate protein-protein interactions.
The genome-wide linkage analyses identified two causal loci, present on chromosomes 3p and 15q that were confirmed by genotyping closely-spaced fluorescently-labeled STR markers. Alleles at these loci were not sufficient to independently localize the causal phenotype; however, taken together alleles at these two loci could explain the causality and the severity associated with the phenotype. Subsequently, we identified a premature termination in a cytosolic carboxypeptidase termed CCP4 also known as AGBL1 present within the critical interval of 15q. This gene was identified previously in a serial analysis of gene expression (SAGE) of the corneal endothelium. The premature termination variant was not present in 384 ethnically matched control chromosomes. Subsequently, we identified two independent sporadic cases that harbored the same premature termination mutation and a second missense variation in three unrelated sporadic cases. IHC analyses identified AGBL1 expression in the corneal endothelium and co-IP experiments confirmed that AGBL1 and TCF4 proteins can bind.
We identify two novel FCD loci and implicate AGBL1 in the pathogenesis of late-onset FCD. Our data provides first evidence of physical interactions between two late-onset FCD genes. We are investigating the functional significance of AGBL1-TCF4 protein-protein interactions in late-onset FCD.
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