ERMP1 and Keratoconus

Recent genetic investigations have implicated ERMP1 in keratoconus, a corneal ectasia disorder with complex inheritance. Two independent exome‐based studies have identified candidate variants in ERMP1 that may contribute to disease, with one study reporting the missense variant c.341A>T (p.Asp114Val) in a Chinese keratoconus cohort (PMID:32744102) and a second study demonstrating autosomal dominant segregation of ERMP1 variants in keratoconus trios (PMID:40098727).

The genetic evidence is primarily based on the detection of a recurrent candidate variant in a limited number of probands. In the first study, exome sequencing of 28 patients revealed c.341A>T (p.Asp114Val) in ERMP1 in one affected individual, while the trio‐based study corroborated the autosomal dominant mode with heterozygous changes co‑segregating in families. Such findings, though promising, are tempered by the low number of unrelated cases and minimal replication across larger cohorts.

Functional assessments of ERMP1 have been reported in studies examining its role in coagulation factor XIII deficiency. These studies, which include expression assays in yeast and mammalian systems (PMID:7727776; PMID:9531593), demonstrate impaired protein stability and aberrant enzymatic function. However, these experimental models were conducted in the context of coagulation abnormalities and do not directly validate a mechanistic link to the corneal changes observed in keratoconus.

Overall, while the identification of the ERMP1 c.341A>T (p.Asp114Val) variant and its autosomal dominant segregation in keratoconus families provides initial support for a gene‐disease association, the evidence remains limited by small sample sizes and a lack of direct functional studies in corneal tissue. Additional replication in larger cohorts and targeted functional studies are necessary to conclusively establish ERMP1 as a keratoconus susceptibility gene.

The key take‑home message is that although current genetic data suggest a potential role for ERMP1 in keratoconus pathogenesis, cautious interpretation is warranted until further validation is achieved.

References

• Ophthalmic Genetics • 2020 • Exome sequencing identification of susceptibility genes in Chinese patients with keratoconus PMID:32744102
• Molecular Vision • 2025 • Subclinical parents assist in the detection of genetic variants in keratoconus by trio‑based whole‑exome sequencing PMID:40098727
• Blood • 1995 • Mutations causing coagulation factor XIII subunit A deficiency: characterization of the mutant proteins after expression in yeast PMID:7727776
• Blood • 1998 • Molecular mechanisms of type II factor XIII deficiency: novel Gly562‑Arg mutation and C‑terminal truncation of the A subunit cause factor XIII deficiency as characterized in a mammalian expression system PMID:9531593

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