PAX6 – Peters Anomaly

Heterozygous variants in the paired box gene PAX6 are implicated in Peters anomaly, a dominantly inherited anterior segment dysgenesis. Three unrelated patients have been reported with de novo or familial PAX6 missense mutations in Peters anomaly: c.51C>A (p.Asn17Lys) (PMID:20405024), c.155G>A (p.Cys52Tyr) (PMID:25182519), and c.194G>T (p.Gly65Val) (PMID:24281366). Each variant affects a highly conserved residue within the paired or homeodomain and was absent in unaffected controls, supporting pathogenicity.

Functional assays demonstrate that PAX6 missense alleles, such as p.Arg26Gly, impair DNA binding at paired-domain consensus sites and reduce transactivation, consistent with a hypomorphic mechanism leading to anterior segment maldevelopment (PMID:9147640). While segregation data are limited, the concordance of variant absence in controls and functional impairment provides moderate experimental support. Additional reports and larger pedigrees will be needed to elevate the evidence beyond the current limited genetic series. Key Take-home: PAX6 heterozygous missense variants should be considered in the genetic evaluation of Peters anomaly.

References

• Molecular Vision | 2010 | A novel mutation of PAX6 in Chinese patients with new clinical features of Peters' anomaly. PMID:20405024
• Human Genetics | 2014 | Whole exome sequence analysis of Peters anomaly. PMID:25182519
• European Journal of Human Genetics | 2014 | Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1. PMID:24281366
• Human Molecular Genetics | 1997 | Functional analysis of paired box missense mutations in the PAX6 gene. PMID:9147640

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