LOXHD1 – Fuchs’ Endothelial Dystrophy

LOXHD1 was first implicated in late-onset Fuchs’ corneal dystrophy (FECD) through an autosomal-dominant pedigree in which the c.159T>G (p.Asp53Glu) variant segregated with disease and 15 additional rare heterozygous missense changes were found in >200 sporadic FECD cases but absent from >800 controls (PMID:22341973). However, recent systematic analyses failed to confirm LOXHD1 expression in corneal endothelium and classified no LOXHD1 variants as pathogenic in FECD (PMID:37441688).

Functional studies showed LOXHD1 mRNA in cultured human corneal endothelial cells, increased antibody punctate staining in affected endothelia, and cytoplasmic aggregates upon mutant allele expression, suggesting a possible dominant-negative mechanism (PMID:22341973). In contrast, transcriptomic profiling detected no LOXHD1 in normal or FECD endothelia and carriers of reported LOXHD1 variants did not exhibit FECD signs on ophthalmological exam (PMID:40244234).

Given the conflicting segregation, expression, and functional data, the causal role of LOXHD1 in Fuchs’ endothelial dystrophy remains disputed.

References

• American Journal of Human Genetics • 2012 • Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy. PMID:22341973
• Frontiers in Medicine • 2023 • Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs’ endothelial corneal dystrophy. PMID:37441688
• International Journal of Molecular Sciences • 2025 • From Genes to Disease: Reassessing LOXHD1 and AGBL1's Contribution to Fuchs' Dystrophy. PMID:40244234

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