Analysis of FOXD3 sequence variation in human ocular disease

Bethany A Volkmann Kloss, Linda M. Reis, Dominique Brémond-Gignac, Thomas M Glaser, Elena V. Semina

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1740-1749
Number of pages10
JournalMolecular Vision
Volume18
StatePublished - Jun 27 2012
Externally publishedYes

Fingerprint

Aniridia
Eye Diseases
Neural Crest
Vertebrates
Anophthalmos
Anterior Eye Segment
Forkhead Transcription Factors
Phenotype
Mutation
Cataract
Population
Genes
Proteins
Alleles
DNA
Peters anomaly

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Kloss, B. A. V., Reis, L. M., Brémond-Gignac, D., Glaser, T. M., & Semina, E. V. (2012). Analysis of FOXD3 sequence variation in human ocular disease. Molecular Vision, 18, 1740-1749.

Analysis of FOXD3 sequence variation in human ocular disease. / Kloss, Bethany A Volkmann; Reis, Linda M.; Brémond-Gignac, Dominique; Glaser, Thomas M; Semina, Elena V.

In: Molecular Vision, Vol. 18, 27.06.2012, p. 1740-1749.

Research output: Contribution to journalArticle

Kloss, BAV, Reis, LM, Brémond-Gignac, D, Glaser, TM & Semina, EV 2012, 'Analysis of FOXD3 sequence variation in human ocular disease', Molecular Vision, vol. 18, pp. 1740-1749.
Kloss BAV, Reis LM, Brémond-Gignac D, Glaser TM, Semina EV. Analysis of FOXD3 sequence variation in human ocular disease. Molecular Vision. 2012 Jun 27;18:1740-1749.
Kloss, Bethany A Volkmann ; Reis, Linda M. ; Brémond-Gignac, Dominique ; Glaser, Thomas M ; Semina, Elena V. / Analysis of FOXD3 sequence variation in human ocular disease. In: Molecular Vision. 2012 ; Vol. 18. pp. 1740-1749.
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abstract = "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.",
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AU - Semina, Elena V.

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