Analysis of FOXD3 sequence variation in human ocular disease.

Purpose: The migratory neural crest cell population makes a significant contribution to the anterior segment structures of the eye. Consequently, several anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. The forkhead box D3 (FOXD3) gene encodes a forkhead transcription factor that plays an important role in neural crest specification in vertebrates and therefore may be involved in human eye disease.

Methods: We screened 310 probands with developmental ocular conditions for variations in FOXD3.

Results: Six nonsynonymous FOXD3 variants were identified. Four of these changes, c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), and c.818_829dup (p.Arg273_Gly276dup), affected conserved regions and were observed primarily in probands with aniridia or Peters anomaly; out of these four variants, one, p.Arg273_Gly276dup, was not detected in control populations and two, p.Pro120Leu and p.Asn173His, were statistically enriched in cases with aniridia or Peters anomaly. The p.Arg273_Gly276dup variant was seen in a proband with aniridia as well as two additional unrelated probands affected with anophthalmia or congenital cataracts. The p.Asn173His variant affects Helix 2 of the DNA-binding domain and was observed in two unrelated patients with Peters anomaly or aniridia; in both cases, one parent carried the same allele.

Conclusions: FOXD3 variants increase the risk of anterior segment dysgenesis phenotypes in humans. The p.Asn173His mutation affects a residue in the forkhead domain that is 100% conserved among vertebrate orthologs and is predicted to participate in protein-protein interactions. Its phenotypic effects may be modulated by transcriptional cofactors which have yet to be identified.