From Genes to Disease: Reassessing LOXHD1 and AGBL1’s Contribution to Fuchs’ Dystrophy

TL;DR

This study challenges the role of LOXHD1 and AGBL1 genes in causing Fuchs’ dystrophy by finding no gene expression or disease signs in carriers.

Contribution

The study provides new evidence refuting the causal link between LOXHD1 and AGBL1 gene variants and Fuchs’ dystrophy.

Findings

LOXHD1 and AGBL1 genes are not expressed in normal or FECD-affected corneal endothelia or progenitor cells.

Carriers of LOXHD1 and AGBL1 variants and their relatives over 50 showed no FECD symptoms.

The causal role of LOXHD1 and AGBL1 variants in FECD is not supported by the findings.

Abstract

Fuchs’ endothelial corneal dystrophy (FECD) is a genetically complex eye disease associated with multiple genes. A recent systematic review has raised concerns about the causal role of variants in the LOXHD1 and AGBL1 genes in the development of FECD. Conflicting data have been reported on the expression of the LOXHD1 and AGBL1 genes in the corneal endothelium. Furthermore, only partial segregation of the variants was observed in familial cases. An analysis of published datasets was conducted to examine the expression of LOXHD1 and AGBL1 genes in normal and FECD-affected corneal endothelia and progenitor cells. Neither LOXHD1 nor AGBL1 genes were expressed in normal or FECD corneal endothelia or progenitor cells. In-house cohorts were screened for carriers of previously reported LOXHD1 and AGBL1 variants. Carriers and their first-degree relatives were invited for an ophthalmological examination to reassess the causal relationship of these variants with FECD phenotype. Three carriers of LOXHD1 variants (one carrier of rs200242497 and two carriers of rs192376005) and two carriers of AGBL1 variants (rs181958589 and rs185919705) were recruited. None of the carriers or first-degree relatives over 50 years exhibited phenotypic signs of FECD via ophthalmic examination. The causal role of the AGBL1 and LOXHD1 variants found in the carriers was not confirmed. Taken together, our findings do not support a causal role for AGBL1 and LOXHD1 in the development of FECD.

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