FOXD3 – Aniridia

Neural crest cells contribute critically to anterior segment structures, and disruption of FOXD3, a forkhead transcription factor essential for neural crest specification, may underlie aniridia. In a screen of 310 probands with developmental ocular conditions, four conserved FOXD3 variants (c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), c.818_829dup (p.Arg273_Gly276dup)) were observed primarily in aniridia or Peters anomaly cases, with two variants statistically enriched in aniridia (PMID:22815627). One in-frame duplication (c.818_829dup (p.Arg273_Gly276dup)) was absent from controls and found in an aniridia proband, while p.Asn173His segregated in two unrelated patients with aniridia or Peters anomaly but with reduced penetrance.

Functional evidence from zebrafish demonstrates that the mosm188 mutation disrupts a neural crest-specific regulatory element of foxd3, leading to loss of foxd3 expression in neural crest progenitors, depletion of neural crest derivatives, and rescue upon injection of foxd3–containing clones (PMID:17013879). This supports a haploinsufficiency mechanism contributing to anterior segment dysgenesis.

These data support a limited clinical validity of FOXD3 in aniridia predisposition, warranting further validation in larger cohorts. Key take-home: FOXD3 variants may act as risk factors for aniridia with reduced penetrance.

References

• Molecular Vision • 2012 • Analysis of FOXD3 sequence variation in human ocular disease. PMID:22815627
• Developmental Dynamics • 2006 • The mother superior mutation ablates foxd3 activity in neural crest progenitor cells and depletes neural crest derivatives in zebrafish. PMID:17013879

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