PAX6 – Autosomal Dominant Keratitis

Autosomal dominant keratitis (ADK) is characterized by progressive corneal opacification, vascularization, and foveal hypoplasia. The paired box transcription factor PAX6 is critical for anterior segment development and visual axis formation. Given its established role in aniridia, PAX6 was investigated as a candidate gene for ADK.

Linkage analysis in a four-generation kindred demonstrated significant linkage between ADK and two polymorphic markers in the PAX6 region (peak LOD 4.45; θ = 0.00 with D11S914), supporting autosomal dominant inheritance and a single-gene etiology (PMID:7668281). Mutation screening via SSCP and direct sequencing identified a splice-acceptor variant, c.959-2A>T, in exon 11 of PAX6 segregating with disease in 15 affected individuals across four generations (14 additional relatives) (PMID:7668281).

The c.959-2A>T alteration disrupts the exon 11 splice-acceptor site, predicted to result in exon skipping and premature truncation of the proline-serine-threonine–rich (PST) transactivation domain. This loss-of-function mechanism is consistent with PAX6 haploinsufficiency in anterior segment malformations.

Functional concordance was demonstrated by the SeyNeu mouse, which harbors an analogous splice-donor mutation in Pax6 exon 10. SeyNeu homozygotes exhibit corneal opacity, vascularization, and foveal hypoplasia mirroring human ADK, confirming the pathogenic mechanism (PMID:7668281).

Collectively, this evidence establishes a Strong clinical validity for PAX6 in ADK, supported by robust genetic segregation and an in vivo model that recapitulates the human phenotype.

Key Take-home: PAX6 splice-site mutations cause autosomal dominant keratitis via haploinsufficiency, enabling molecular diagnosis and informing family counseling.

References

• American Journal of Human Genetics • 1995 • Mutation of the PAX6 gene in patients with autosomal dominant keratitis. PMID:7668281

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