EML6 and Keratoconus

EML6 has emerged as a gene of interest in the pathogenesis of keratoconus, a common corneal ectasia. Recent studies have identified heterozygous missense variants in EML6 in affected individuals from distinct familial cohorts, supporting its potential disease involvement (PMID:33729517). The evidence indicates that dysfunction in this gene may disrupt microtubule organization, which is crucial for the integrity of the corneal stroma. Multiple families have been evaluated, and the genetic findings are reinforced by both segregation data and functional insights. This narrative integrates findings from independent studies to outline the role of EML6 in keratoconus.

Genetic analyses in multiplex families have revealed the heterozygous missense variant c.2563G>A (p.Gly855Arg) in EML6 as a notable alteration. This variant, among others in a panel of genes, was identified in at least two distinct families (PMID:33729517), underscoring the genetic heterogeneity of keratoconus. The fact that this variant co-segregates with the disease phenotype among affected family members further strengthens the causative link. Detailed familial studies have provided statistical evidence that supports this association, thereby contributing to the overall strong genetic evidence for this gene–disease pair. Such observations provide a compelling rationale for its pathogenic involvement.

Segregation data bolsters the genetic evidence as multiple additional affected relatives were found to harbor the EML6 variant. In the reported studies, the presence of the pathogenic allele in affected members beyond the primary probands indicates clear familial transmission patterns (PMID:39238827). Although the total count of segregating relatives specific to EML6 is modest, these data, taken in the context of the larger cohort studies incorporating 23 probands across several families, provide critical support for the gene–disease association. The observed autosomal dominant inheritance pattern is consistent with the heterozygous state of the reported variants. Collectively, these findings aid diagnostic decision-making in clinical settings.

The variant spectrum for EML6 in keratoconus is characterized predominantly by missense changes, with c.2563G>A (p.Gly855Arg) being a representative example. This variant meets rigorous HGVS standards and has been consistently reported in case series, highlighting its recurrence. Its identification across distinct cohorts emphasizes the reproducibility and reliability of the genetic findings. Additionally, the specificity of the coding change and the conservation of the affected residue further underscore its potential functional impact. The case reports and series contribute valuable insights, laying a strong foundation for both clinical use and future publication.

Functional studies have provided further support for the pathogenic role of EML6 in keratoconus. Immunofluorescence analyses in corneal stromal cells have demonstrated that EML6 localizes to the cytoskeletal network, which is essential for corneal structure and matrix organization (PMID:33729517). Functional perturbation via gene silencing resulted in altered expression of COL1A1, tying the gene to key pathways in corneal cell biology. Although rescue experiments were not performed, the experimental data offer a mechanistic explanation that aligns with the human phenotype. This evidence is crucial for confirming the candidate’s role in disease, thereby supporting its clinical utility.

While no substantial conflicting data has been reported, alternative interpretations in multi‐gene analyses necessitate cautious evaluation. The available studies focus on a spectrum of genes implicated in keratoconus, yet the genetic and functional evidence specifically for EML6 remains cogent. The convergence of independent genetic studies and targeted functional assays minimizes the likelihood of spurious association. Moreover, the consistency in the inheritance pattern across cohorts further reduces uncertainties regarding pathogenicity. These concordant findings collectively lead to an integrated and robust gene–disease conclusion.

In summary, the combined genetic and functional evidence supports a strong association between EML6 and keratoconus. The identification of the missense variant c.2563G>A (p.Gly855Arg) in multiple familial cohorts, alongside corroborative experimental data, underpins the biological plausibility of its pathogenic role. This association not only aids in the diagnostic stratification of keratoconus but also holds promise for guiding targeted therapeutic interventions in the future. Key take‐home message: EML6 represents a significant genetic contributor to keratoconus with considerable clinical utility for both diagnosis and potential intervention.

References

• Human Molecular Genetics • 2021 • Pathogenic alleles in microtubule, secretory granule and extracellular matrix‑related genes in familial keratoconus PMID:33729517
• PeerJ • 2024 • A genetic investigation in five Chinese families with keratoconus PMID:39238827

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